Idiopathic Pulmonary Fibrosis Disease Coverage...Datamonitor e althcare Pharma intelliene 1 Idiopathic Pulmonary Fibrosis Disease Coverage Ref Code: DMKC12770 Authors: Hardik Patel,

Datamonitor HealthcarePharma intelligence |

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Idiopathic Pulmonary Fibrosis Disease Coverage

Ref Code: DMKC12770Authors: Hardik Patel, Casey Godbout



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Idiopathic pulmonary fibrosis Disease Coverage DMKC12770

© Informa UK Ltd. This document is a licensed product and is not to be reproduced or redistributed

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CONTENTS 6 FORECAST: IDIOPATHIC PULMONARY FIBROSIS6 Executive Summary7 Market Overview and Trends12 Market Definition and Methodology23 Esbriet (pirfenidone)28 Ofev (nintedanib)32 Primary Research Methodology

34 TREATMENT: IDIOPATHIC PULMONARY FIBROSIS34 Executive Summary35 Primary Research Methodology37 Disease Definition and Diagnosis45 Patient Segmentation52 Country Treatment Trees53 Current Treatment Options59 Prescribing Trends

79 EPIDEMIOLOGY: IDIOPATHIC PULMONARY FIBROSIS79 Executive Summary80 Sources and Methodology86 Forecast95 Epidemiologist Insight97 Strengths and Limitations

99 MARKETED DRUGS: IDIOPATHIC PULMONARY FIBROSIS99 Executive Summary100 Product Overview101 Product profile: Esbriet124 Product profile: Ofev

144 PIPELINE: IDIOPATHIC PULMONARY FIBROSIS144 Executive Summary145 Clinical Pipeline Overview146 Target Product Profile165 Clinical Trial Design174 Product profile (late stage): FG-3019182 Product profile (late stage): PRM-151


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List of figures 7 Figure 1: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by

country ($m), 2015–24

9 Figure 2: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by

product ($m), 2015–24

11 Figure 3: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by

severity ($m), 2015

12 Figure 4: Patient-based forecast methodology for idiopathic pulmonary fibrosis

14 Figure 5: Annual dose per patient, by region

15 Figure 6: Price sources and calculations, by country

17 Figure 7: Discounted annual cost of treatment, by country, 2015

24 Figure 8: Esbriet sales for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets,

by country ($m), 2015–24

29 Figure 9: Ofev sales for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets,


45 Figure 10: Distribution of diagnosed idiopathic pulmonary fibrosis patients across the US, Japan, and five

major EU markets, by severity and country (%)

46 Figure 11: Estimated percentage of idiopathic pulmonary fibrosis patients in each severity who remain

undiagnosed across the US, Japan, and five major EU markets

48 Figure 12: Estimated percentage of IPF patients who experience acute exacerbation in the US, Japan,

and five major EU markets, by severity and country

56 Figure 13: Overview of the ATS/ERS/JRS/ALAT evidence-based guidelines for the treatment of idiopathic

pulmonary fibrosis

59 Figure 14: Percentage of IPF patients who fall into each treatment category in the US, Japan, and five

major EU markets, by severity and country

61 Figure 15: Top five pharmacological treatment regimens used in mild IPF patients across the US, Japan,

and five major EU markets, by country

62 Figure 16: Top five pharmacological treatment regimens used in moderate IPF patients across the US,

Japan, and five major EU markets, by country

65 Figure 17: Top five pharmacological treatment regimens used in severe IPF patients across the US,

Japan, and five major EU markets, by country

67 Figure 18: Use of Esbriet and Ofev, whether alone or in a combination, across the US, Japan, and five

major EU markets, by severity and country

68 Figure 19: Percentage use of Esbriet and Ofev as monotherapy and in each combination across the US,

Japan, and five major EU markets, by severity

70 Figure 20: Patients who receive supplemental anti-gastroesophageal reflux medications across the US,

Japan, and five major EU markets, by severity and country (%)

71 Figure 21: Non-pharmacological treatments used in mild idiopathic pulmonary fibrosis patients across the

US, Japan, and five major EU markets, by country

72 Figure 22: Non-pharmacological treatments used in moderate idiopathic pulmonary fibrosis patients

across the US, Japan, and five major EU markets, by country

73 Figure 23: Non-pharmacological treatments used in severe idiopathic pulmonary fibrosis patients across

the US, Japan, and five major EU markets, by country

88 Figure 24: Growth in incident cases of diagnosed idiopathic pulmonary fibrosis in the US, Japan, and five

major EU markets, by country, 2015–35


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List of tables

89 Figure 25: Gender-specific diagnosed incident cases of idiopathic pulmonary fibrosis in the US, Japan,

and five major EU markets, by country, 2015

92 Figure 26: Growth in diagnosed prevalent cases of idiopathic pulmonary fibrosis in the US, Japan, and

five major EU markets, by country, 2015–35

112 Figure 27: Esbriet for idiopathic pulmonary fibrosis – SWOT analysis

113 Figure 28: Datamonitor Healthcare’s drug assessment of Esbriet for idiopathic pulmonary fibrosis

113 Figure 29: Datamonitor Healthcare’s drug assessment of Esbriet for idiopathic pulmonary fibrosis

118 Figure 30: Comparison of Esbriet’s and Ofev’s Phase III registrational trials

134 Figure 31: Ofev for idiopathic pulmonary fibrosis – SWOT analysis

135 Figure 32: Datamonitor Healthcare’s drug assessment of Ofev for idiopathic pulmonary fibrosis

135 Figure 33: Datamonitor Healthcare’s drug assessment of Ofev for idiopathic pulmonary fibrosis

139 Figure 34: Comparison of Esbriet’s and Ofev’s Phase III registrational trials

165 Figure 35: Primary and secondary endpoints used in Ofev and Esbriet's key late-phase trials

178 Figure 36: FG-3019 for idiopathic pulmonary fibrosis – SWOT analysis

179 Figure 37: Datamonitor Healthcare’s drug assessment of FG-3019 for idiopathic pulmonary fibrosis

179 Figure 38: Datamonitor Healthcare’s drug assessment of FG-3019 for idiopathic pulmonary fibrosis

187 Figure 39: PRM-151 for idiopathic pulmonary fibrosis – SWOT analysis

188 Figure 40: Datamonitor Healthcare’s drug assessment of PRM-151 for idiopathic pulmonary fibrosis

188 Figure 41: Datamonitor Healthcare’s drug assessment of PRM-151 for idiopathic pulmonary fibrosis

7 Table 1: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by

country ($m), 2015–24

8 Table 2: Idiopathic pulmonary fibrosis market patient numbers in the US, Japan, and five major EU

markets, by country, 2015–24

10 Table 3: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by

product ($m), 2015–24

12 Table 4: Summary of brands in Datamonitor Healthcare’s idiopathic pulmonary fibrosis patient-based

forecast, 2015

17 Table 5: Exchange rates used for calculating prices

24 Table 6: Esbriet sales for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets,


25 Table 7: Esbriet patient numbers for idiopathic pulmonary fibrosis across the US, Japan, and five major

EU markets, by country, 2015–24

29 Table 8: Ofev sales for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets, by

country, 2015–24

30 Table 9: Ofev patient numbers for idiopathic pulmonary fibrosis across the US, Japan, and five major EU

markets, by country ($m), 2015–24

32 Table 10: Pulmonologists surveyed for the idiopathic pulmonary fibrosis primary research study, 2015

35 Table 11: Pulmonologists surveyed for the idiopathic pulmonary fibrosis primary research study, 2015

37 Table 12: Subtypes of idiopathic interstitial pneumonias

45 Table 13: Datamonitor Healthcare’s definition of idiopathic pulmonary fibrosis severity

47 Table 14: Estimated percentage of idiopathic pulmonary fibrosis patients in each severity who remain

undiagnosed across the US, Japan, and five major EU markets


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53 Table 15: Approved treatments available for idiopathic pulmonary fibrosis across the US, Japan, and five

major EU markets

53 Table 16: Off-label therapies used in the treatment of idiopathic pulmonary fibrosis across the US, Japan,

and five major EU markets

55 Table 17: Non-pharmacological therapies used in the treatment of idiopathic pulmonary fibrosis across

the US, Japan, and five major EU markets

61 Table 18: Pharmacological treatment regimens used in mild idiopathic pulmonary fibrosis patients across

the US, Japan, and five major EU markets, by country

63 Table 19: Pharmacological treatment regimens used in moderate idiopathic pulmonary fibrosis patients


65 Table 20: Pharmacological treatment regimens used in severe idiopathic pulmonary fibrosis patients


80 Table 21: Sources used for idiopathic pulmonary fibrosis data in the US, Japan, and five major EU

markets

86 Table 22: Diagnosed incident cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EU


89 Table 23: Age-specific diagnosed incident cases of idiopathic pulmonary fibrosis in the US, Japan, and

five major EU markets, by country, 2015

90 Table 24: Diagnosed prevalent cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EU


93 Table 25: Age-specific diagnosed prevalent cases of idiopathic pulmonary fibrosis in the US, Japan, and

five major EU markets, by country, 2015

100 Table 26: Key marketed drugs for idiopathic pulmonary fibrosis

101 Table 27: Esbriet drug profile

104 Table 28: Esbriet’s pivotal trial data in idiopathic pulmonary fibrosis

111 Table 29: Esbriet ongoing late-phase clinical trials in idiopathic pulmonary fibrosis

124 Table 30: Ofev drug profile

127 Table 31: Ofev pivotal trial data in idiopathic pulmonary fibrosis

133 Table 32: Ofev ongoing late-phase clinical trials in idiopathic pulmonary fibrosis

145 Table 33: Phase II pipeline products in development for idiopathic pulmonary fibrosis

146 Table 34: Esbriet drug profile

148 Table 35: Esbriet’s pivotal trial data in idiopathic pulmonary fibrosis

155 Table 36: Ofev drug profile

157 Table 37: Ofev pivotal trial data in idiopathic pulmonary fibrosis

174 Table 38: FG-3019 drug profile

176 Table 39: FG-3019 Phase II data in idiopathic pulmonary fibrosis

178 Table 40: FG-3019 Phase II trial in idiopathic pulmonary fibrosis

182 Table 41: PRM-151 drug profile

184 Table 42: PRM-151 Phase I data in idiopathic pulmonary fibrosis

187 Table 43: PRM-151 Phase II trial in idiopathic pulmonary fibrosis


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Idiopathic pulmonary fibrosis Disease Coverage | Forecast: IdiopathicPulmonary Fibrosis DMKC12770


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Forecast: Idiopathic Pulmonary Fibrosis Executive Summary The US will account for the majority of branded IPF

drug sales

The idiopathic pulmonary fibrosis (IPF) market is forecast to grow at a compound annual growth rate

of 12.3% over 2015–24, reaching a peak of almost $3.0bn in 2021. The vast majority of this growth

can be attributed to the US market, which has grown rapidly since the simultaneous approvals of the

first two drugs indicated for IPF in 2014. Increasing drug prices and market penetration will allow

sales in the US to more than triple over 2015–21, while other markets will remain relatively stable.

Both Esbriet and Ofev will continue to draw

patient share from other treatments

As the first two therapies clinically proven to significantly slow disease progression in IPF patients,

both Esbriet (pirfenidone; Roche/Shionogi) and Ofev (nintedanib; Boehringer Ingelheim) will enjoy

notable uptake in all markets. In addition to patients receiving off-label pharmacological therapies,

patients previously treated with non-pharmacological treatments will also continue to switch to

treatment with Esbriet or Ofev.

Esbriet will lead the market until it loses exclusivity Although both Esbriet and Ofev are forecast to become blockbusters by 2019, Esbriet is estimated to

retain its position as market leader until the end of its market exclusivity in 2021. Roche has made

an effort to delay this event, although Esbriet’s orphan drug exclusivity continues to be the

company’s only certain form of protection from generic competitors.


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Market Overview and Trends Current and future market dynamics overview

Datamonitor Healthcare estimates the branded idiopathic pulmonary fibrosis (IPF) market will total$970m in 2015 across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, andthe UK). IPF market sales will grow at a compound annual growth rate of 12.3% over 2015–24,reaching a peak of almost $3.0bn in 2021 before contracting due to the entry of generic competitors.The primary driver of market growth will be the expanded use of high-priced approved brands Esbriet(pirfenidone; Roche/Shionogi) and Ofev (nintedanib; Boehringer Ingelheim) in place of off-labelpharmacological therapies and non-pharmacological treatments. The rising number of diagnosedprevalent IPF cases across each of the analyzed markets will also contribute to sales growth,increasing from 199,320 to 234,110 cases over 2015–24 (see Datamonitor Healthcare’s Epidemiology:Idiopathic Pulmonary Fibrosis).

The majority of IPF drug sales can be attributed to the US market, which is estimated to make up 89%of sales in the forecast peak year, 2021. The high prevalence of IPF combined with inflating drugprices will drive sales in the US. Conversely, lower prevalence and lower costs of treatment willrestrict sales in Japan and the five major EU markets.

Figure 1: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by country ($m),2015–24

Source: Datamonitor Healthcare


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Table 1: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by country ($m),2015–24

Country 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

US 703 994 1,391 1,724 2,004 2,296 2,620 2,611 2,427 2,459

Japan 51 52 55 55 49 46 45 45 45 45

France 43 46 51 54 53 51 43 38 36 35

Germany 63 70 82 93 98 100 98 91 85 86

Italy 56 61 70 77 79 79 64 61 60 60

Spain 32 36 43 49 52 53 47 46 45 45

UK 21 24 29 34 37 37 34 32 29 29

Grand total 970 1,284 1,721 2,087 2,372 2,662 2,951 2,925 2,727 2,760

Note: totals may not sum due to rounding.



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Esbriet is forecast to remain the market leader

Datamonitor Healthcare estimates that Esbriet will remain the highest-selling brand in IPF untilgeneric competitors enter the market in 2021, eroding the drug’s sales and allowing Ofev to becomethe market leader. Esbriet holds a significant advantage in Europe and Japan due to its first-to-marketstatus. This advantage is heightened by the drug’s statistically significant impact on mortalitydemonstrated in clinical trials, and likely has a knock-on effect in the US where Esbriet and Ofev wereapproved simultaneously (FDA, 2014a; FDA, 2014b). Esbriet’s sales are forecast to grow quickly,reaching blockbuster status by 2018; however, the product’s lifecycle will be shortened in the US asits primary patents have already expired. The only guaranteed protection Roche and Shionogi possessagainst generic competitors is Esbriet’s orphan drug exclusivity, which expires in October 2021 (US),October 2018 (Japan), and February 2021 (EU). Roche has been granted several additional method ofuse patents covering Esbriet, but it is uncertain if this strategy will successfully prevent generics fromentering the market (Medtrack, November 2015, Copyright Informa UK). The launch of lower-pricedgeneric pirfenidone is also estimated to affect sales of Ofev, but not enough to keep it fromsurpassing Esbriet in revenue. Sales of Ofev are forecast to reach $1,610m by 2024, and may exceedDatamonitor Healthcare’s initial projections if trials testing it as an add-on to Esbriet are successful(ClinicalTrials.gov identifiers: NCT02579603, NCT02598193).

Table 2: Idiopathic pulmonary fibrosis market patient numbers in the US, Japan, and five major EU markets, by country,2015–24

Country 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

US 38,818 51,058 60,332 64,008 65,638 67,128 68,638 70,219 71,841 73,484

Japan 3,416 3,789 4,238 4,520 4,566 4,580 4,590 4,604 4,618 4,632

France 3,580 4,122 4,721 5,084 5,193 5,268 5,339 5,406 5,478 5,549

Germany 4,783 5,448 6,282 6,874 7,024 7,109 7,188 7,269 7,348 7,426

Italy 4,697 5,318 6,039 6,503 6,621 6,689 6,757 6,825 6,898 6,975

Spain 2,638 3,049 3,551 3,903 4,012 4,083 4,154 4,229 4,308 4,391

UK 1,723 2,040 2,427 2,697 2,761 2,797 2,832 2,868 2,905 2,945

Grand total 59,656 74,824 87,592 93,589 95,815 97,654 99,498 101,421 103,396 105,401




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The majority of IPF drug sales can be attributed to patients with moderate diseaseseverity

Figure 2: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by product ($m),2015–24


Table 3: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by product ($m),2015–24

Drug 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

Esbriet 637 770 969 1,166 1,321 1,475 1,568 1,075 691 625

Ofev 333 515 752 920 1,043 1,172 1,317 1,446 1,502 1,610

generic pirfenidone 0 0 0 0 9 14 66 404 534 524

Grand total 970 1,284 1,721 2,087 2,372 2,662 2,951 2,925 2,727 2,760




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Due to the design of clinical trials, guidelines from reimbursement bodies, the nature of diseaseprogression, and the distribution of patients by severity, the majority of IPF drug sales stem frompatients with moderate IPF. Datamonitor Healthcare estimates that in 2015, moderate patients willaccount for approximately 50% of total IPF market sales, whereas mild and severe patients will makeup 21% and 29% of sales, respectively. This is predominantly because moderate patients compriseabout 43% of the total IPF population in the US, Japan, and five major EU markets. Additionally,registrational trials of both Esbriet and Ofev excluded patients with severe IPF, and as a result manypayers have not recommended either drug to be used in this subgroup. Furthermore, approximately31% of mild patients across the analyzed markets are not recommended for any form of treatment asthey typically do not experience debilitating symptoms (Datamonitor Healthcare’s proprietary IPFsurvey, July 2015). Although this currently limits the use of Esbriet or Ofev in mild patients, results oftrials demonstrating the potential benefit of initiating treatment earlier in the course of disease mayincrease the usage of pharmacological treatments in this group (ClinicalTrials.gov identifier:NCT01979952).

Bibliography

FDA (2014a) FDA approves Esbriet to treat idiopathic pulmonary fibrosis. Available from:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418991.htm [Accessed 17November 2015].

FDA (2014b) FDA approves Ofev to treat idiopathic pulmonary fibrosis. Available from:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418994.htm [Accessed 17November 2015].

Figure 3: Idiopathic pulmonary fibrosis drug sales across the US, Japan, and five major EU markets, by severity ($m),2015



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Market Definition and Methodology Market definition for idiopathic pulmonary fibrosis

For the purposes of this patient-based forecast, Datamonitor Healthcare defines the idiopathicpulmonary fibrosis (IPF) market in the US, Japan, and five major EU markets (France, Germany, Italy,Spain, and the UK) as comprising the brands shown below.

Patient-based forecast methodology

Datamonitor Healthcare has used a patient-based methodology in constructing its forecast of the IPFdrug market. The forecast is based on both primary research and secondary sources. DatamonitorHealthcare’s primary research includes a survey of 220 pulmonologists in the US, Japan, and fivemajor EU markets, which was conducted in July 2015. METHODOLOGY FLOW

Datamonitor Healthcare’s methodology for this forecast is summarized in the figure below, whichshows how forecasts of each included product were calculated.

Table 4: Summary of brands in Datamonitor Healthcare’s idiopathic pulmonary fibrosis patient-based forecast, 2015

ATC code Molecules included Brands included

L04AX05 Immunosuppressants, other immunosuppressants pirfenidone Esbriet

L01XE31 Antineoplastic agents, protein kinase inhibitors nintedanib Ofev

ATC = Anatomical Therapeutic Chemical

Source: Datamonitor Healthcare; Esbriet product information, 2015; Ofev product information,2015


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EPIDEMIOLOGY

The starting point for Datamonitor Healthcare’s patient-based IPF forecast is estimated diagnosedprevalence by country, as calculated by Datamonitor Healthcare’s epidemiology team. An in-depthdiscussion of the methodology used in calculating the estimated diagnosed patient population, as wellas the age and gender splits, is available in Datamonitor Healthcare’s Epidemiology: IdiopathicPulmonary Fibrosis. PRICE AND DOSE ASSUMPTIONS

For this forecast, Datamonitor Healthcare calculates each product’s average annual cost of treatmentper patient in each country. This involves taking into account several dosing and pricing assumptions,which are outlined below. DOSE ASSUMPTIONS

The annual dose per patient, assuming full compliance and persistence, is calculated based on eachproduct’s prescribing information. However, evidence from registrational trials, post-approval real-world studies, and company-reported information suggests the compliance and persistence rates with

Figure 4: Patient-based forecast methodology for idiopathic pulmonary fibrosis



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both Esbriet and Ofev are significantly less than 100%. Therefore, compliance and persistence ratesare applied to each drug’s annual dose to yield the following adjusted doses.

The compliance (all compliance rates used in this forecast also factor in dose intensity) andpersistence rates used for Esbriet in the US and five major EU markets are based on data collected byRoche in Europe (Fasci et al., 2015). The compliance rate cited by the company, 72.0%, is expectedlylower than the compliance rate calculated based on the Phase III CAPACITY trials, which was 79.7%(CDER, 2014; Fasci et al., 2015). Similarly, the 50% persistence rate cited by the company issignificantly lower than the persistence observed in clinical trials, which was 89.6% (CDER, 2014;Fasci et al., 2015). This persistence rate is confirmed by the findings of an analysis on the EuropeanPirfenidone Post-Authorisation Safety Registry, which showed the median duration of treatment inthe real-world setting was approximately half that of Esbriet’s registrational trials (Cottin and Maher,2015). Because a different dose of Esbriet is used in Japan versus the US and the EU, a separate real-world study conducted in Japan is used to approximate compliance and persistence in this region. Apost-marketing surveillance study in Japan found that the average dose per day was 1,283mg and theaverage duration of treatment was 366 days (Ogura et al., 2015), translating into yearly complianceand persistence rates of 71.3% and 100.0%, respectively.

The results of real-world studies monitoring the usage of Ofev are not yet available, therefore the

Figure 5: Annual dose per patient, by region

Source: Datamonitor Healthcare; Esbriet prescribing information, 2015; Fasci et al., 2015;Ofev prescribing information, 2014; Ogura et al., 2015; Shionogi press release, 2012


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ratio of Esbriet’s compliance and persistence rates in the real-world setting versus the clinical trialsetting was taken and applied to Ofev’s clinical trial compliance and persistence rates to arrive atanalogous estimates. PRICING ASSUMPTIONS

Datamonitor Healthcare uses national formularies to gather pricing information per product. As theprices presented in formularies can differ, showing prices at different stages in the supply chain,Datamonitor Healthcare uses backing-out formulas to adjust formulary prices in order to obtainestimates of ex-factory wholesale prices for each country.

The following table outlines the sources and calculations used in the US and EU. For Japan, prices aretaken from the National Health Insurance (NHI) drug database. These prices are the retail priceexclusive of consumption tax, and therefore it is important to note that the sales given for Japan maybe inflated compared to other countries, depending on the extent of price markups at different stagesin the supply chain. However, Datamonitor Healthcare has validated its patient-based sales estimateswith company-reported sales in Japan where available, and believes the impact to be minimal.


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Figure 6: Price sources and calculations, by country

Source: Datamonitor Healthcare; various (see above)


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Using the calculated ex-factory wholesale price, the price per mg is calculated. This is multiplied byDatamonitor Healthcare’s annual dosing assumptions in order to obtain an annual price per patient.All prices are shown in US dollars, using the average 2014 exchange rate from Open Exchange Rates.

PATIENT ACCESS SCHEMES AND PRICE DISCOUNTS

Patient access schemes and price discounts are typically offered for expensive drugs in variousmarkets but are difficult to explicitly quantify as most of these agreements are confidential due totheir commercially sensitive nature. However, in the case of rare diseases such as IPF, the majority ofrevenue generated by a drug is attributed to its cost rather than patient volume; therefore thesediscounts must be taken into account in order to accurately forecast brand sales.

The tables below outline Datamonitor Healthcare’s estimates of Esbriet and Ofev’s discounted annualcost per patient.

Table 5: Exchange rates used for calculating prices

Currency Local currency to USD

EUR 1.3266

GBP 1.6463

JPY 0.0094

Source: Open Exchange Rates, 2015


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US

In the US, Esbriet’s average annual cost of treatment is significantly reduced due to multiple patientaccess programs offered by Genentech. The primary programs offered are the Esbriet Co-pay CardProgram and the Genentech Access to Care Foundation (Esbriet, 2015; Genentech, 2015).

Through the Esbriet Co-pay Card Program, patients who have commercial (private or non-governmental) insurance are eligible to receive a card covering up to $24,000 of out-of-pocketexpenses over the course of one year. Based on the age distribution of diagnosed IPF in the US (seeDatamonitor Healthcare’s Epidemiology: Idiopathic Pulmonary Fibrosis) and the percentage ofAmericans who are covered by governmental insurance or are uninsured in each corresponding agegroup (US Census Bureau, 2014a), Datamonitor Healthcare estimates that approximately 31% of USIPF patients are eligible for this program. Although the maximum coverage through the card is

Figure 7: Discounted annual cost of treatment, by country, 2015



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$24,000, typical commercial insurance plans employ an annual out-of-pocket maximum, preventingpatient out-of-pocket costs from reaching this limit in most cases. Therefore, it was estimated thatpatients eligible for the co-pay card would each receive an average of $6,600 in assistance over oneyear (Kaiser Family Foundation, 2015).

The Genentech Access to Care Foundation provides Esbriet free of charge to patients below certainhousehold income thresholds. Uninsured patients are eligible if their annual household income is<$100,000. Based on the age distribution of diagnosed IPF in the US (see Datamonitor Healthcare’sEpidemiology: Idiopathic Pulmonary Fibrosis), the percentage of Americans who are uninsured in eachcorresponding age group (US Census Bureau, 2014a), and the percentage of Americans with an annualhousehold income of <$100,000 in each corresponding age group (US Census Bureau, 2014b),Datamonitor Healthcare estimates that approximately 4% of US IPF patients are eligible for thisportion of the free access program.

Also through the Genentech Access to Care Foundation, insured patients who have an annualhousehold income of <$150,000 and whose out-of-pocket costs of treatment with Esbriet are ≥10%of their annual household income are eligible to receive free treatment. Because all other forms offinancial assistance must be exhausted before insured patients are eligible, it was assumed patientswith commercial insurance only would receive assistance solely from the Esbriet Co-pay Cardprogram. Average out-of-pocket costs for the remaining patients with governmental insurance wereestimated to be approximately $5,000 annually, therefore these patients would need to have anannual household income of <$50,000 in order to be eligible. Based on the age distribution ofdiagnosed IPF in the US (see Datamonitor Healthcare’s Epidemiology: Idiopathic Pulmonary Fibrosis),the percentage of Americans who have governmental insurance in each corresponding age group (USCensus Bureau, 2014a), and the percentage of Americans with an annual household income of<$50,000 in each corresponding age group (US Census Bureau, 2014b), Datamonitor Healthcareestimates that approximately 37% of US IPF patients are eligible for this portion of the free accessprogram.

Like Genentech, Boehringer Ingelheim offers similar co-pay assistance and free access programs in theUS, therefore it was assumed that the impact on the average annual cost of Ofev due to theseprograms would be similar to that on Esbriet (Ofev, 2015). FIVE MAJOR EU MARKETS

In Europe, each country has negotiated its own price and discounts for Esbriet. In Germany, thediscount agreed upon for Esbriet was 11%, which is applied in addition to the national discount of 7%(InterMune 10-Q, 2013; Scrip Intelligence, 2014). In France, no discounts were required beyond thenegotiated ex-factory price (InterMune earnings call transcript, 2012). Initial agreements in Italyinvolved a pay-for-performance style risk-sharing agreement on top of the mandatory 9.75% nationaldiscount (InterMune 8-K, 2013). Although, this risk-sharing scheme was withdrawn, DatamonitorHealthcare assumes that it was replaced with a traditional flat discount rate, estimated to beapproximately 20% (Fasci et al., 2015). The patient access scheme established for Esbriet in the UKconsists of a simple discount off the product’s list price; however, this rate is undisclosed (NICE,


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2012). Based on the National Institute for Health and Care Excellence’s (NICE’s) assessment, historicalsales of Esbriet in Europe, and previous access schemes negotiated in the UK, Datamonitor Healthcareestimates that the discount offered on Esbriet is approximately 20% in the UK. No discounts onEsbriet in Spain have been disclosed; therefore it was assumed that the final ex-factory price in Spainwould be equivalent to the lowest price available in the other five major EU markets.

Discounts arranged for Ofev in the five major EU markets are far less transparent. However,Datamonitor Healthcare estimates that discounts negotiated for Ofev in each market would be similarto those applied to Esbriet in order for Boehringer Ingelheim to maintain its pricing strategy. Bibliography

CDER (2014) Application Number: 022535Orig1s000 (Esbriet). Available from:http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022535Orig1s000MedR.pdf [Accessed 9November 2015].

Centers for Medicare and Medicaid Services (2014) Medicare Part B Drug Average Sales Price:Manufacturer reporting of Average Sales Price (ASP) data. Available from:http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/index.html [Accessed 26 November 2014].

Cottin V, Maher T (2015) Long-term clinical and real-world experience with pirfenidone in thetreatment of idiopathic pulmonary fibrosis. European Respiratory Review, 24(135), 58–64<DOI>10.1183/09059180.00011514</DOI>.

Eco-Santé France (2012) Médicaments: prix et marges. Available from:http://www.ecosante.fr/FRANFRA/610.html [Accessed 16 April 2013].

Esbriet (2015) Esbriet Co-pay Card Program. Available from: https://esbrietcopay.com/ [Accessed 16November 2015].

Esbriet prescribing information (2015) Available from:http://www.gene.com/download/pdf/esbriet_prescribing.pdf [Accessed 9 November 2015].

Esbriet product information (2015) Available from:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002154/WC500103049.pdf [Accessed 9 November 2015].

Fasci A, Ferrario M, Ravasio R, Ena R, Angelini S, Giuliani G (2015) PRS66 – Conditional AgreementsFor Innovative Therapies In Italy: The Case Of Pirfenidone. Value in Health, 18(7), A505<DOI>10.1016/j.jval.2015.09.1440</DOI>.

Genentech (2015) Genentech Access to Care Foundation. Available from: http://www.genentech-access.com/esbriet/patients/find-patient-assistance/access-to-care-foundation [Accessed 16


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November 2015].

German Ministry for Health (2013) Um jeden Preis? Wie Arzneimittelpreise entstehen und wie man siesenken kann. Available from:http://www.bmg.bund.de/krankenversicherung/arzneimittelversorgung/wie-arzneimittelpreise-entstehen.html [Accessed 12 September 2013].

InterMune 8-K (2013) Available from:http://www.sec.gov/Archives/edgar/data/1087432/000119312513259303/d554124d8k.htm [Accessed17 November 2015].

InterMune 10-Q (2013) Available from:http://www.sec.gov/Archives/edgar/data/1087432/000119312513423160/d592262d10q.htm[Accessed 17 November 2015].

InterMune earnings call transcript (2012) InterMune's CEO Discusses France's Economic Committee's(CEPS) Authorization of Reimbursement of Esbriet (Transcript). Available from:http://seekingalpha.com/article/861231-intermunes-ceo-discusses-frances-economic-committees-ceps-authorization-of-reimbursement-of-esbriet-transcript?part=single [Accessed 17 November2015].

Kaiser Family Foundation (2015) The Cost of Care with Marketplace Coverage. Available from:http://kff.org/health-costs/issue-brief/the-cost-of-care-with-marketplace-coverage/ [Accessed 16November 2015].

Medicaid State Prescription Drug Resources (2014) State Medicaid Reimbursement Information.Available from: http://www.medicaid.gov/Medicaid-CHIP-Program-Information/By-Topics/Benefits/Prescription-Drugs/State-Prescription-Drug-Resources.html [Accessed 26 November2014].

NICE (2012) Patient access scheme submission: Pirfenidone for Idiopathic Pulmonary Fibrosis.Available from: https://www.nice.org.uk/guidance/ta282/documents/idiopathic-pulmonary-fibrosis-pirfenidone-updated-patient-access-scheme-submitted-by-intermune2 [Accessed 17 November2015].

Ofev (2015) Ofev: RX Savings. Available from: https://www.ofev.com/prescription-savings [Accessed16 November 2015].

Ofev prescribing information (2014) Available from: http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Ofev/ofev.pdf [Accessed 9 November 2015].

Ofev product information (2015) Available from:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003821/WC500182474.pdf [Accessed 9 November 2015].


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Ogura T, Azuma A, Inoue Y, Taniguchi H, Chida K, Bando M, Niimi Y, Kakutani S, Suga M, Sugiyama Y,Kudoh S, Nukiwa T (2015) All-case post-marketing surveillance of 1371 patients treated withpirfenidone for idiopathic pulmonary fibrosis. Respiratory Investigation, 53(5), 232–241<DOI>10.1016/j.resinv.2015.06.001</DOI>.

Open Exchange Rates (2015) Available from: https://openexchangerates.org/ [Accessed 9 November2015].

Patented Medicine Prices Review Board (2012) 2011 Backing-Out Formulas for Foreign PriceVerification. Available from: http://www.pmprb-cepmb.gc.ca/english/View.asp?x=1603&mp=1600[Accessed 16 April 2013].

Scrip Intelligence (2014) A tweak or an outrage? Germany passes new pricing law. Available from:http://www.scripintelligence.com/home/A-tweak-or-an-outrage-Germany-passes-new-pricing-law-350844 [Accessed 2 December 2015].

Shionogi press release (2012) ILDONG PHARMACEUTICAL Receives a Marketing and ManufacturingApproval for Pirespa® 200mg Tablet. Available from:http://www.shionogi.eu/media/37394/8082012.pdf [Accessed 9 November 2015].

US Census Bureau (2014a) Health Insurance: Current Population Survey (CPS). Available from:http://www.census.gov/hhes/www/cpstables/032015/health/h01_000.htm [Accessed 16 November2015].

US Census Bureau (2014b) Income: Current Population Survey (CPS). Available from:https://www.census.gov/hhes/www/cpstables/032015/hhinc/hinc01_000.htm [Accessed 16 November2015].

Vogler S, Espin J, Habl C (2009) Pharmaceutical Pricing and Reimbursement Information (PPRI) – NewPPRI analysis including Spain. Pharmaceuticals Policy and Law, 11, 213–234. Available from:http://ppri.oebig.at/Downloads/Publications/Article_PPRI_Spain_PharmaceuticalPolicyAndLaw_2009.pdf [Accessed 16 April 2013].


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Esbriet (pirfenidone) Forecast assumptions

Datamonitor Healthcare makes the following assumptions in its forecast of Esbriet (pirfenidone;Roche/Shionogi) for idiopathic pulmonary fibrosis (IPF):

Esbriet was approved for the treatment of IPF in October 2014 (US), October 2008 (Japan),and February 2011 (EU) (FDA, 2014; Shionogi press release, 2012; EMA, 2015).

In the US and five major EU markets (France, Germany, Italy, Spain, and the UK), therecommended dose of Esbriet is three 267mg capsules three times daily (Esbriet prescribinginformation, 2015), to which compliance and persistence rates were applied. In Japan, theprescription dose of Esbriet is three 200mg capsules three times daily (Shionogi press release,2012), to which compliance and persistence rates were applied. Please see DatamonitorHealthcare’s Market Definition and Methodology chapter for more information on dosingassumptions.

Esbriet’s growing body of clinical trial data and real-world evidence will allow it to continueto gain market share in all regions due to patients switching from treatment with off-labelpharmacological therapies and non-pharmacological treatments. The degree of Esbriet’scontinued uptake over the forecast period varies by market and is informed by country-specific primary research with pulmonologists.

In Japan and the five major EU markets, Esbriet will lose market share due to the launch ofcompeting therapy Ofev (nintedanib; Boehringer Ingelheim), which was approved for IPF inJuly 2015 (Japan) and January 2015 (EU) (Boehringer Ingelheim press release, 2015a;Boehringer Ingelheim press release, 2015b). The proportion of newly diagnosed patients whowill initiate treatment with Ofev instead of Esbriet over the forecast period varies by marketand is informed by country-specific primary research with pulmonologists.

Esbriet’s primary patents have expired. Although Roche has been granted several additionalpatents that expire beyond the end of the forecast period, it is uncertain if these patents willsuccessfully prevent generics from entering the market (Medtrack, November 2015, CopyrightInforma UK). Therefore, it was assumed that Esbriet will face generic competition followingthe expiration of its orphan drug exclusivity in October 2021 (US), October 2018 (Japan), andFebruary 2021 (EU). The rate of generic erosion in each market is estimated based on country-specific primary research with pulmonologists.

Esbriet’s sales may exceed forecasts if clinical trials testing the use of Ofev in combinationwith Esbriet are positive, as use in this combination could expand Esbriet’s patient populationas well as potentially extending patients’ duration on treatment (ClinicalTrials.gov identifiers:NCT02579603, NCT02598193).

Datamonitor Healthcare uses national formularies to gather pricing information per productand applies backing-out formulas to adjust formulary prices in order to obtain estimates of


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ex-factory wholesale prices for each country. Furthermore, varying discounts and patientaccess schemes offered for Esbriet in each market were taken into account to adjust theaverage cost of treatment and more accurately forecast product sales. Please see DatamonitorHealthcare’s Market Definition and Methodology chapter for more information on pricingassumptions.

Please view the accompanying interactive dashboard and Excel deliverable for further detail onDatamonitor Healthcare’s forecast of Esbriet.

For further details on Datamonitor Healthcare’s assessment of Esbriet and its competitive positioning,please refer to the full drug profile. Esbriet forecast, 2015–24

The figure and tables below show Datamonitor Healthcare’s forecast of Esbriet in IPF, by country, over2015–24.

Figure 8: Esbriet sales for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets, by country($m), 2015–24



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Table 6: Esbriet sales for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets, by country($m), 2015–24

Country 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

US 414 550 752 949 1,113 1,275 1,425 970 614 552

Japan 51 50 47 44 29 21 19 19 19 19

France 35 33 31 31 30 29 19 13 9 8

Germany 43 43 44 47 49 50 38 25 16 15

Italy 49 48 47 48 48 48 31 23 17 16

Spain 25 25 25 26 28 28 21 16 11 11

UK 20 20 21 22 24 24 16 10 4 4

Grand total 637 770 969 1,166 1,321 1,475 1,568 1,075 691 625




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Bibliography

Boehringer Ingelheim press release (2015a) New data demonstrate sustained long-term efficacy ofOFEV®* on slowing disease progression and safety in patients with IPF. Available from:http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/29_september_2015_ipf.html [Accessed 17November 2015].

Boehringer Ingelheim press release (2015b) OFEV® (nintedanib*) approved in the EU for the treatmentof IPF. Available from: http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/19_january_2015_ipf.html [Accessed 17November 2015].

EMA (2015) EPAR summary for the public: Esbriet. Available from:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002154/WC500102979.pdf [Accessed 17 November 2015].

Esbriet prescribing information (2015) Available from:http://www.gene.com/download/pdf/esbriet_prescribing.pdf [Accessed 18 November 2015].

Table 7: Esbriet patient numbers for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets, bycountry, 2015–24

Country 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

US 23,689 29,431 34,958 37,686 38,728 39,607 37,098 20,099 15,282 15,262

Japan 3,304 3,242 3,131 2,923 1,818 1,499 1,480 1,485 1,489 1,494

France 2,815 2,806 2,828 2,973 3,036 3,080 2,307 1,488 1,206 1,220

Germany 3,422 3,449 3,561 3,830 3,917 3,965 2,914 1,812 1,428 1,441

Italy 4,096 4,060 4,067 4,239 4,310 4,354 3,698 2,600 2,149 2,170

Spain 2,087 2,080 2,106 2,238 2,298 2,339 1,972 1,343 1,085 1,104

UK 1,569 1,603 1,678 1,817 1,860 1,884 1,241 564 324 327

Grand total 40,983 46,673 52,330 55,706 55,967 56,728 50,710 29,391 22,965 23,018




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FDA (2014) FDA approves Esbriet to treat idiopathic pulmonary fibrosis. Available from:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418991.htm [Accessed 17November 2015].

Shionogi press release (2012) Shionogi Provides Pirespa 200mg Tablet to ILDONG PHARMACEUTICALfor the Treatment of Idiopathic Pulmonary Fibrosis in South Korea. Available from:http://www.shionogi.co.jp/en/company/news/2012/pmrltj0000000w2d-att/e_121012.pdf [Accessed17 November 2015].


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Ofev (nintedanib) Forecast assumptions

Datamonitor Healthcare makes the following assumptions in its forecast of Ofev (nintedanib;Boehringer Ingelheim) for idiopathic pulmonary fibrosis (IPF):

Ofev was approved for the treatment of IPF in October 2014 (US), July 2015 (Japan), andJanuary 2015 (EU) (FDA, 2014; Boehringer Ingelheim press release, 2015a; BoehringerIngelheim press release, 2015b).

In all markets, the recommended dose of Ofev is one 150mg capsule twice daily (Ofevprescribing information, 2014), to which compliance and persistence rates were applied.Please see Datamonitor Healthcare’s Market Definition and Methodology chapter for moreinformation on dosing assumptions.

Ofev’s growing body of clinical trial data and real-world evidence will allow it to continue togain market share in all regions due to patients switching from treatment with off-labelpharmacological therapies and non-pharmacological treatments. The degree of Ofev’scontinued uptake over the forecast period varies by market and is informed by country-specific primary research with pulmonologists.

In Japan and the five major EU markets (France, Germany, Italy, Spain, and the UK), Ofev willtake market share from first-to-market competitor Esbriet (pirfenidone; Roche/Shionogi). Theproportion of newly diagnosed patients who will initiate treatment with Ofev instead ofEsbriet over the forecast period varies by market and is informed by country-specific primaryresearch with pulmonologists.

Generic pirfenidone is expected to launch in October 2021 (US), October 2018 (Japan), andFebruary 2021 (EU) following the loss of Esbriet’s orphan drug exclusivity. Although the entryof generic pirfenidone will primarily impact the market share of Esbriet, it is assumed thelower cost of generics will also somewhat erode sales of Ofev. The rate of generic erosion ineach market is estimated based on country-specific primary research with pulmonologists.

Ofev’s sales may exceed forecasts if clinical trials testing the use of Ofev in combination withEsbriet are positive, as use in this combination would expand Ofev’s patient population(ClinicalTrials.gov identifiers: NCT02579603, NCT02598193).

Datamonitor Healthcare uses national formularies to gather pricing information per productand applies backing-out formulas to adjust formulary prices in order to obtain estimates ofex-factory wholesale prices for each country. Furthermore, varying discounts and patientaccess schemes offered for Ofev in each market were taken into account to adjust theaverage cost of treatment and more accurately forecast product sales. Please see DatamonitorHealthcare’s Market Definition and Methodology chapter for more information on pricingassumptions.


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Please view the accompanying interactive dashboard and Excel deliverable for further detail onDatamonitor Healthcare’s forecast of Ofev.

For further details on Datamonitor Healthcare’s assessment of Ofev and its competitive positioning,please refer to the full drug profile. Ofev forecast, 2015–24

The figure and tables below show Datamonitor Healthcare’s forecast of Ofev in IPF, by country, over2015–24.

Figure 9: Ofev sales for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets, by country ($m),2015–24



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Table 8: Ofev sales for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets, by country,2015–24

Country 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

US 289 444 639 776 891 1,021 1,169 1,305 1,372 1,481

Japan 0 3 7 11 12 11 10 10 10 10

France 9 13 19 23 23 22 21 19 17 16

Germany 20 27 38 46 49 50 49 47 44 43

Italy 7 13 23 29 31 30 30 28 26 26

Spain 7 11 17 23 24 25 25 24 23 23

UK 1 4 9 12 13 13 13 12 11 11

Grand total 333 515 752 920 1,043 1,172 1,317 1,446 1,502 1,610




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Bibliography

Boehringer Ingelheim press release (2015a) New data demonstrate sustained long-term efficacy ofOFEV®* on slowing disease progression and safety in patients with IPF. Available from:http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/29_september_2015_ipf.html [Accessed 17November 2015].

Boehringer Ingelheim press release (2015b) OFEV® (nintedanib*) approved in the EU for the treatmentof IPF. Available from: http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/19_january_2015_ipf.html [Accessed 17November 2015].

FDA (2014) FDA approves Ofev to treat idiopathic pulmonary fibrosis. Available from:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418994.htm [Accessed 17November 2015].

Ofev prescribing information (2014) Available from: http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Ofev/ofev.pdf [Accessed 18 November 2015].

Table 9: Ofev patient numbers for idiopathic pulmonary fibrosis across the US, Japan, and five major EU markets, bycountry ($m), 2015–24

Country 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

US 15,129 21,627 25,374 26,322 26,910 27,520 28,082 27,143 25,278 25,246

Japan 112 546 1,107 1,378 1,346 1,252 1,231 1,235 1,239 1,243

France 765 1,316 1,892 2,111 2,156 2,187 2,151 1,986 1,920 1,945

Germany 1,361 1,999 2,721 3,044 3,107 3,145 3,080 2,827 2,721 2,749

Italy 601 1,257 1,972 2,264 2,311 2,335 2,299 2,151 2,093 2,116

Spain 551 969 1,446 1,665 1,714 1,744 1,727 1,619 1,583 1,613

UK 154 436 749 880 902 913 888 791 751 760

Grand total 18,673 28,151 35,262 37,664 38,446 39,097 39,458 37,753 35,585 35,672




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Primary Research Methodology Physician research

Datamonitor Healthcare conducted primary research with a sample of 220 pulmonologists in the US,Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). The research wasconducted in June and July 2015. The sample breakdown by country is shown in the table below,together with some key respondent metrics.

The primary research study was conducted online, with all the respondents self-completing a 30-minute questionnaire in their own language. The questionnaire was divided into three sections:

screening questions

main questionnaire

demographic questions.

Datamonitor Healthcare’s questionnaire was carefully designed and included a number of screeningquestions to ensure the most appropriate targeting of respondents for this study. Respondents neededto have clinical responsibility for the treatment and management of a minimum number of idiopathicpulmonary fibrosis (IPF) patients to ensure that responses were broadly representative of currenttreatment practices. The participating physicians also had to be working in clinical practice daily, havea minimum number of years’ experience in their specialty, and to not work directly for apharmaceutical company, other than involvement in clinical trials. All these criteria aimed to ensure,as far as possible, that respondents were experienced, practicing specialists with unbiased views.

Table 10: Pulmonologists surveyed for the idiopathic pulmonary fibrosis primary research study, 2015

US Japan France Germany Italy Spain UK

Sample size 32 31 32 33 30 31 31

Mean number of years in specialty 12.6 20.3 18.6 15.9 21.3 15.0 14.3

Mean number of patients actively treated by respondents 52.5 40.9 41.5 48.0 29.9 37.6 35.2

Mean number of hours per day spent in clinical practice 9.5 8.1 8.9 8.3 7.6 7.9 8.0

Source: Datamonitor Healthcare’s proprietary idiopathic pulmonary fibrosis survey, July 2015


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The objectives of the main questionnaire for this study were to gain an understanding and insight intothe following:

key epidemiological datasets (diagnosis and treatment rates), both in terms of the conditionas a whole and for specific patient segmentations

patient segmentation by severity

prescribing behavior, including approved pharmacological therapies, off-labelpharmacological therapies, and non-pharmacological treatments, by disease severity

prescribing influences

product comparative performance and valued product attributes

future trends and uptake of new therapies and their impact on the market.

The demographic questions that were asked at the end of Datamonitor Healthcare's survey helped toensure that the sample was broadly representative of the treating physician population in eachcountry.

Pilot interviews (consisting of online self-completion of the questionnaire) and subsequent telephoneinterviews with a Datamonitor Healthcare analyst were conducted with a small number of physiciansin the US and UK. The purpose of piloting was to determine if the questionnaire:

was “fit-for-purpose” and able to gather data that answered the research objectives

was straightforward for the respondents to complete in the allocated time period

covered all relevant aspects of treatment and management for IPF.

After the mainstage fieldwork was completed, the raw data at the respondent level were carefullyreviewed and quality-checked by the research team prior to data processing and analysis.


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Idiopathic pulmonary fibrosis Disease Coverage | Treatment: IdiopathicPulmonary Fibrosis DMKC12770


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Treatment: Idiopathic Pulmonary Fibrosis Executive Summary The overall prognosis of IPF remains poor Despite the growing knowledge of the pathogenesis of idiopathic pulmonary fibrosis (IPF), the

prognosis of patients remains poor. The difficulty in recognizing the early symptoms of IPF delays

diagnosis, further worsening patient outcomes. Additionally, acute exacerbations of IPF continue to

be difficult to predict and treat, making them a focal point of ongoing research.

Esbriet continues to be a cornerstone of treatment Even with the approval of Ofev (nintedanib; Boehringer Ingelheim), first-to-market IPF treatment

Esbriet (pirfenidone; Roche/Shionogi) remains the most widely used pharmacological treatment

across all markets. Esbriet is used in patients of all severities despite reimbursement decisions

restricting it to patients with less advanced disease.

Ofev has gained the most uptake in the US, whereas usage in the EU and Japan continues to be

much lower due to Esbriet’s market advantage.

Off-label medications are still widely used Although the usage of off-label therapies has decreased with the approvals of Esbriet and Ofev, N-

acetylcysteine (NAC) monotherapy and corticosteroid monotherapy still form significant treatment

options. Pooled data for trials studying the effects of NAC monotherapy failed to show any

significant survival benefits, but it remains a cheap and safe alternative for patients ineligible for

branded therapies. Although corticosteroids have been ruled ineffective for the general treatment of

IPF, they are currently a part of the standard treatment for acute exacerbations.

Non-pharmacological therapies are used in

patients of all severities

Both pulmonary rehabilitation and oxygen therapy are readily used in patients with IPF across all

severities. However, usage of pulmonary rehabilitation is lower in patients with advanced disease

who may not be able to participate fully in treatment. Conversely, oxygen therapy is used more

often in severe patients, who are more likely to have higher rates of resting hypoxemia.


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Primary Research Methodology Physician research

Datamonitor Healthcare conducted primary research with a sample of 220 pulmonologists in the US,Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). The research wasconducted in June and July 2015. The sample breakdown by country is shown in the table below,together with some key respondent metrics.

The primary research study was conducted online, with all the respondents self-completing a 30-minute questionnaire in their own language. The questionnaire was divided into three sections:

screening questions

main questionnaire

demographic questions.

Datamonitor Healthcare’s questionnaire was carefully designed and included a number of screeningquestions to ensure the most appropriate targeting of respondents for this study. Respondents neededto have clinical responsibility for the treatment and management of a minimum number of idiopathicpulmonary fibrosis (IPF) patients to ensure that responses were broadly representative of currenttreatment practices. The participating physicians also had to be working in clinical practice daily, havea minimum number of years’ experience in their specialty, and to not work directly for apharmaceutical company, other than involvement in clinical trials. All these criteria aimed to ensure,as far as possible, that respondents were experienced, practicing specialists with unbiased views.

Table 11: Pulmonologists surveyed for the idiopathic pulmonary fibrosis primary research study, 2015


Sample size 32 31 32 33 30 31 31

Mean number of years in specialty 12.6 20.3 18.6 15.9 21.3 15.0 14.3

Mean number of patients actively treated by respondents 52.5 40.9 41.5 48.0 29.9 37.6 35.2

Mean number of hours per day spent in clinical practice 9.5 8.1 8.9 8.3 7.6 7.9 8.0



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The objectives of the main questionnaire for this study were to gain an understanding and insight intothe following:

key epidemiological datasets (diagnosis and treatment rates), both in terms of the conditionas a whole and for specific patient segmentations

patient segmentation by severity

prescribing behavior, including approved pharmacological therapies, off-labelpharmacological therapies, and non-pharmacological treatments, by disease severity

prescribing influences

product comparative performance and valued product attributes

future trends and uptake of new therapies and their impact on the market.

The demographic questions that were asked at the end of Datamonitor Healthcare's survey helped toensure that the sample was broadly representative of the treating physician population in eachcountry.

Pilot interviews (consisting of online self-completion of the questionnaire) and subsequent telephoneinterviews with a Datamonitor Healthcare analyst were conducted with a small number of physiciansin the US and UK. The purpose of piloting was to determine if the questionnaire:

was “fit-for-purpose” and able to gather data that answered the research objectives

was straightforward for the respondents to complete in the allocated time period

covered all relevant aspects of treatment and management for IPF.

After the mainstage fieldwork was completed, the raw data at the respondent level were carefullyreviewed and quality-checked by the research team prior to data processing and analysis.


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Disease Definition and Diagnosis Etiology

Idiopathic pulmonary fibrosis (IPF) is a chronic disease in which scarring and thickening of the lungtissue occurs due to unknown causes, impairing pulmonary function. Several different theories havebeen proposed for the exact pathogenesis of IPF, although the most commonly held hypotheses sharea general flow of events. IPF is thought to begin with repetitive alveolar epithelial cell injury andapoptosis possibly caused by genetic variations, environmental exposures, viral infections, aging,gastroesophageal reflux disease (GERD), or other factors (Camelo et al., 2013). This leads to anaberrant wound healing response and the release of pro-fibrotic cytokines such as transforminggrowth factor-beta and platelet-derived growth factor. Consequently, myofibroblasts accumulate inareas called fibroblast foci through the migration and differentiation of local fibroblasts, recruitmentof circulating fibrocytes, and/or a de-differentiation process called epithelial-to-mesenchymaltransition (Zoz et al., 2011). Myofibroblasts are responsible for the deposition of collagen andextracellular matrix proteins, which in excess not only compromise lung capacity and blood-gasexchange, but also promote further fibrotic activity (Wolters et al., 2014). Diagnosis

Although it is considered a rare disease, IPF is the most common type of interstitial lung disease (ILD)(British Lung Foundation, 2013). ILDs are segmented by their cause, such as environmental exposures,connective tissue diseases, medications, radiation, or other circumstances. Those with unknowncauses, such as IPF, are idiopathic interstitial pneumonias (IIPs). IIPs are typically classified into eightsubtypes, and are differentiated by their radiological and pathological features.


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Due to the complex nature of ILD segmentation, a multidisciplinary approach is recommended in orderto distinguish IPF from several other possible diagnoses. Pulmonologists, radiologists, and pathologistswork together, utilizing high-resolution computed tomography (HRCT) and surgical lung biopsy inorder to confirm diagnoses. The 2011 American Thoracic Society/European RespiratorySociety/Japanese Respiratory Society/Latin American Thoracic Association guidelines state that thefollowing criteria must be met for the diagnosis of IPF (Raghu et al., 2011):

exclusion of other known causes of ILD

presence of a usual interstitial pneumonia (UIP) pattern on HRCT in patients not subjected tosurgical lung biopsy

specific combinations of HRCT and surgical lung biopsy pattern in patients subjected tosurgical lung biopsy.

The first criterion eliminates ILDs of known causes to confirm diagnosis of IIP, whereas the second andthird criteria seek to confirm the specified diagnosis of IPF through the identification of UIP pattern indiagnostic images. Guidelines only require UIP to be observed through HRCT in order to confirm

Table 12: Subtypes of idiopathic interstitial pneumonias

Category Clinical diagnosis Radiologic/pathologic pattern

Chronic fibrosing IP Idiopathic pulmonary fibrosis Usual interstitial pneumonia

Idiopathic nonspecific interstitial pneumonia Nonspecific interstitial pneumonia

Smoking-related IP* Respiratory bronchiolitis-interstitial lung disease Respiratory bronchiolitis

Desquamative interstitial pneumonia Desquamative interstitial pneumonia

Acute/subacute IP Cryptogenic organizing pneumonia Organizing pneumonia

Acute interstitial pneumonia Diffuse alveolar damage

Rare IP Idiopathic lymphoid interstitial pneumonia Lymphoid interstitial pneumonia

Idiopathic pleuroparenchymal fibroelastosis Pleuroparenchymal fibroelastosis

*Desquamative IP can occasionally occur in non-smokers.

IP = interstitial pneumonia

Source: Travis et al., 2013


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diagnosis. However, in cases where HRCT results are inconsistent with UIP pattern or only qualify as apossible UIP pattern, a surgical lung biopsy can be performed to clarify diagnosis. Common features ofUIP pattern in HRCT images include: subpleural, basal predominance; reticular abnormalities; andhoneycombing with or without traction bronchiectasis. Similarly, common histopathological featuresof UIP pattern are: evidence of marked fibrosis/architectural distortion, with or without honeycombingin a predominantly subpleural/paraseptal distribution; presence of patchy involvement of lungparenchyma by fibrosis; and presence of fibroblast foci (Raghu et al., 2011). Symptoms

Patients with IPF commonly display the following symptoms:

dyspnea

cough

bibasilar inspiratory crackles, or “Velcro crackles”

digital clubbing

fatigue

weight loss.

Although dyspnea, the symptom most commonly associated with IPF, is displayed in over 90% ofpatients at the time of diagnosis (Lee et al., 2014), it may be difficult to identify early on as it isinitially only recognized by patients when performing strenuous physical activities. Furthermore, IPFpredominantly occurs in older individuals, who may perceive symptoms like dyspnea and cough to bea part of the natural aging process, delaying diagnosis. In fact, a study consisting of 129 patients withIPF found that the mean duration of time between onset of symptoms and referral to tertiary care was2.2 years (Lamas et al., 2011). Increasing awareness of the disease, as well as the early recognition ofsymptoms – such as Velcro crackles during lung auscultation – by primary physicians will likely helpimprove this delay in diagnosis in the future (Cottin and Cordier, 2012). Risk factors

Although the true cause of IPF is not known, several environmental, medical, genetic, anddemographic characteristics have been commonly found among IPF patients, and are thereforespeculated to contribute to the development of the disease:

The most well-known risk factor for IPF is smoking. Multiple studies have confirmed that eversmoking was associated with an approximate 60% increase in the risk of developing IPF(Baumgartner et al., 1997; Taskar and Coultas, 2006).

Professions which involve exposure to metal dusts, wood dusts, animal/vegetable dusts, orsand/stone/silica dusts have been significantly associated with increased risk for IPF (Meyerand Nathan, 2013; Tasker and Coultas, 2006). Such occupations include farming, raising


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livestock or birds, hairdressing, and stonecutting or polishing (Baumgartner et al., 2000).

Past infections with certain human herpes viruses or hepatitis C are found more commonly inpatients with IPF than in the general population, and such infections are thought topotentially contribute to the epithelial cell injury which initiates fibrotic processes(Molyneaux and Maher, 2013).

Recognized by some as a complication of IPF, GERD has also been speculated to be a potentialcause of IPF due to repeated microaspiration of gastric refluxate (Fahim et al., 2011).

About 5–20% of IPF cases are familial (Kropski et al., 2013); therefore, individuals withrelatives who have IPF have an increased chance of developing it themselves. Mutations insurfactant protein genes-A2 and C as well as the telomerase-related genes, telomerasereverse transcriptase and telomerase RNA, have been associated with familial IPF (Mathai etal., 2015). Additionally, a polymorphism in the promoter of the gene encoding mucin 5B hasbeen linked to both familial and sporadic IPF, indicating that genetic variations likely play arole in the cause of both subtypes. Other genetic variations identified in patients with IPFinclude FAM13A (4p22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13),chromosomal regions 7p22 and 15q14–15, TOLLIP (11p15), and SPPL2C (17q21) (Mathai andSchwartz, 2015).

Both age and sex form significant demographic risk factors for IPF. The disease typicallyaffects the elderly population, with the mean age at diagnosis being 66 years, and occursmore often in males than females (Meltzer and Noble, 2008).

Co-morbidities

Co-morbidities are common in individuals with IPF, and the presence of any additional complicationscan greatly affect patients’ prognosis and quality of life. The following co-morbidities are mostcommonly associated with IPF (Fulton and Ryerson, 2015; Raghu et al., 2015a):

emphysema (often clinically termed “combined pulmonary fibrosis and emphysema”)

pulmonary hypertension

venous thromboembolism

lung cancer

GERD

obstructive sleep apnea

cardiovascular disease

depression

anxiety


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diabetes.

It is difficult to discern if these co-morbidities stem from the pathogenesis of IPF, if they facilitate thedevelopment and progression of IPF, or if they exist simply because they share common risk factorswith IPF such as old age. Therefore, multiple studies have examined how medications used to treatsome of these co-morbidities may impact the survival of IPF patients, whether they exhibit additionalcomplications or not. For example, an early trial showed that treating IPF patients with theanticoagulant warfarin reduced all-cause mortality. However, the study had several design flaws, anda subsequent trial showed that warfarin had a negative impact on the survival of IPF patients (Crooksand Hart, 2015). Therefore, guidelines do not recommend that IPF patients be treated with warfarinunless it is required for an alternate indication. Similarly, evidence supporting the use of pulmonaryhypertension medications sildenafil, bosentan, and macitentan in IPF patients without pulmonaryhypertension was also too weak to gain a positive recommendation. Conversely, observational studieshave shown that supplementing treatment with anti-acids, such as proton pump inhibitors orhistamine-2 blocker receptor antagonists, may improve survival in IPF patients. These data werestrong enough for guidelines to conditionally recommend anti-acid treatment in all IPF patients,regardless of whether they are experiencing symptoms of GERD or not (Raghu et al., 2015b). Prognosis

The natural history of IPF varies greatly by individual; nonetheless, the prognosis remains poor, even incomparison to several types of cancer (du Bois, 2012). Median survival in IPF is 2.5–3.5 years fromdiagnosis, with a five-year survival rate of 20–30% (Ley et al., 2011). An estimated 77% of deaths aredue to respiratory-related issues, with acute exacerbation of IPF being one of the most commoncauses of mortality (Ley et al., 2011; Ryerson et al., 2015). Several clinical, physiologic, diagnostic, andbiomarker predictors have been identified in order to estimate survival, yet the clinical course of IPFremains somewhat unpredictable (Ley et al., 2011). Bibliography

Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA (1997) Cigarette smoking: a risk factorfor idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care, 155(1), 242–8<PMID>9001319</PMID>.

Baumgartner KB, Samet JM, Coultas DB, Stidley CA, Hunt WC, Colby TV, Waldron JA (2000)Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. American Journal of Epidemiology, 152(4), 307–15 <PMID>10968375</PMID>.

British Lung Foundation (2013) Interstitial lung disease (ILD). Available from:https://www.blf.org.uk/Page/interstitial-lung-disease-ILD [Accessed 14 December 2015].

Camelo A, Dunmore R, Sleeman MA, Clarke DL (2013) The epithelium in idiopathic pulmonary fibrosis:breaking the barrier. Frontiers in Pharmacology, 4(173), 1–11<DOI>10.3389/fphar.2013.00173</DOI>.


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Cottin V, Cordier JF (2012) Velcro crackles: the key for early diagnosis of idiopathic pulmonaryfibrosis? European Respiratory Journal, 40(3), 519–21 <DOI>10.1183/09031936.00001612</DOI>.

Crooks MG, Hart SP (2015) Coagulation and anticoagulation in idiopathic pulmonary fibrosis.European Respiratory Journal, 24(137), 392–99 <DOI>10.1183/16000617.00008414</DOI>.

du Bois RM (2012) An earlier and more confident diagnosis of idiopathic pulmonary fibrosis. EuropeanRespiratory Journal, 21(124), 141–46 <DOI>10.1183/09059180.00000812</DOI>.

Fahim A, Crooks M, Hart SP (2011) Gastroesophageal Reflux and Idiopathic Pulmonary Fibrosis: AReview. Pulmonary Medicine, 1–7 <DOI>10.1155/2011/634613</DOI>.

Fulton BG, Ryerson CJ (2015) Managing comorbidities in idiopathic pulmonary fibrosis. InternationalJournal of General Medicine, 8, 309–18 <DOI>10.2147/IJGM.S74880</DOI>.

Kropski JA, Lawson WE, Young LR, Blackwell TS (2013) Genetic studies provide clues on thepathogenesis of idiopathic pulmonary fibrosis. Disease Models and Mechanisms, 5, 9–17<DOI>10.1242/dmm.010736</DOI>.

Lamas DJ, Kawut SM, Bagiella E, Philip N, Arcasoy SM, Lederer DJ (2011) Delayed Access and Survivalin Idiopathic Pulmonary Fibrosis: A Cohort Study. American Journal of Respiratory and Critical CareMedicine, 184(7), 842–7 <DOI>10.1164/rccm.201104-0668OC</DOI>.

Lee AS, Mira-Avendano I, Ryu JH, Daniels CE (2014) The burden of idiopathic pulmonary fibrosis: Anunmet public health need. Respiratory Medicine, 108(7), 955–67<DOI>10.1016/j.rmed.2014.03.015</DOI>.

Ley B, Collard HR, King Jr TE (2011) Clinical Course and Prediction of Survival in Idiopathic PulmonaryFibrosis. American Journal of Respiratory and Critical Care Medicine, 183(4), 431–40<DOI>10.1164/rccm.201006-0894CI</DOI>.

Mathai SK, Schwartz DA (2015) Taking the “I” out of IPF. European Respiratory Journal, 45(6),1539–1541 <DOI>10.1183/09031936.00052715</DOI>.

Mathai SK, Yang IV, Schwarz MI, Schwartz DA (2015) Incorporating genetics into the identificationand treatment of Idiopathic Pulmonary Fibrosis. BMC Medicine, 13(191), 1–6 <DOI>10.1186/s12916-015-0434-0</DOI>.

Meltzer EB, Noble PW (2008) Idiopathic pulmonary fibrosis. Orphanet Journal of Rare Diseases, 3(8),1–15 <DOI>10.1186/1750-1172-3-8</DOI>.

Meyer KC, Nathan SD (2013) Idiopathic Pulmonary Fibrosis: A Comprehensive Clinical Guide. Availablefrom: https://books.google.com/books?id=lt-9BAAAQBAJ&pg=PA10&lpg=PA10&dq=environmental+exposures+IPF&source=bl&ots=ToeVrfa-


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CB&sig=G716v_omiW-3GZRn3x_9P4Cp960&hl=en&sa=X&ved=0ahUKEwjcx7-3vcLJAhXD6CYKHYUjBrQ4ChDoAQhLMAk#v=onepage&q=environmental%20exposures%20IPF&f=false [Accessed 4 December 2015].

Molyneaux PL, Maher TM (2013) The role of infection in the pathogenesis of idiopathic pulmonaryfibrosis. European Respiratory Review, 22(129), 376–381 <DOI>10.1183/09059180.00000713</DOI>.

Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, LaskyJA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Anchochea J, Bouros D, Carvalho C, Costabel U, Ebina M,Hansell DM, Johkoh T, Kim DS, King Jr TE, Kandoh Y, Myers J, Muller NL, Nicholson AG, Richeldi L,Selman M, Dudden RF, Griss BS, Protzko SL, Schunemann HJ (2011) An Official ATS/ERS/JRS/ALATStatement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management.American Journal of Respiratory and Critical Care Medicine, 183(6), 788–824<DOI>10.1164/rccm.2009-040GL</DOI>.

Raghu G, Amatto VC, Behr J, Stowasser S (2015a) Comorbidities in idiopathic pulmonary fibrosispatients: a systemic literature review. European Respiratory Journal, 46, 1113–30<DOI>10.1183/13993003.02316-2014</DOI>.

Raghu G, Rochwerg B, Zhang Y, Cuello Garcia CA, Azuma A, Behr J, Brozek JL, Collard HR, CunninghamW, Homma S, Johkoh T, Martinez FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M, Theodore A,Wells AU, Hoogsteden H, Schunemann HJ (2015b) An Official ATS/ERS/JRS/ALAT Clinical PracticeGuideline: Treatment of Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and CriticalCare Medicine, 192(2), e3–e19 <DOI>10.1164/rccm.201506-1063ST</DOI>.

Ryerson CJ, Cottin V, Brown KK, Collard HR (2015) Acute exacerbation of idiopathic pulmonaryfibrosis: shifting the paradigm. European Respiratory Journal, 46, 512–20<DOI>10.1183/13993003.00419-2015</DOI>.

Taskar VS, Coultas DB (2006) Is idiopathic pulmonary fibrosis an environmental disease? Proceedingsof the American Thoracic Society, 3(4), 293–98 <PMID>16738192</PMID>.

Travis WD, Costabel U, Hansell DM, King Jr TE, Lynch DA, Nicholson AG, Ryerson CJ, Ryu JH, Selman M,Wells AU, Behr J, Bouros D, Brown KK, Colby TV, Collard HR, Cordeiro CR, Cottin V, Crestani B, DrentM, Dudden RF, Egan J, Flaherty K, Hogaboam C, Inoue Y, Johkoh T, Kim DS, Kitaichi M, Loyd J,Martinez FJ, Myers J, Protzko S, Raghu G, Richeldi L, Sverzellati N, Swigris, Valerye D (2013) AnOfficial American Thoracic Society/European Respiratory Society Statement: Update of theInternational Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. AmericanJournal of Respiratory and Critical Care Medicine, 188(6), 733–48 <DOI>10.1164/rccm.201308-1483ST</DOI>.

Wolters PJ, Collard HR, Jones KD (2014) Pathogenesis of Idiopathic Pulmonary Fibrosis. Annual Reviewof Pathology, 9, 157–79 <DOI>10.1146/annurev-pathol-012513-104706</DOI>.


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Zoz DF, Lawson WE, Blackwell TS (2011) Idiopathic Pulmonary Fibrosis: A Disorder of Epithelial CellDysfunction. American Journal of the Medical Sciences, 341(6), 435–8<DOI>10.1097/MAJ.0b013e31821a9d8e</DOI>.


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Patient Segmentation Disease severity

Although staging systems – such as the Gender-Age-Physiology Index and the Japanese stagingsystem – have been proposed in order to segment patients and predict prognosis, no official stagingsystem has been instated for idiopathic pulmonary fibrosis (IPF) (Homma et al., 2015; Ley et al., 2012).However, various guidelines, clinical trials, and reimbursement bodies have historically segmentedpatients according to disease severity. Patients are split into mild, moderate, and severesegmentations based on their forced vital capacity (FVC) and sometimes their diffusing capacity of thelung for carbon monoxide (DLCO). Thresholds for each function test used to segment patients differslightly; however, for the purposes of this analysis, Datamonitor Healthcare has assumed the criteriashown in the table below for the classification of IPF into each severity based on the parameters mostoften observed in literature.

The figure below shows the severity distribution of IPF patients treated by pulmonologists included inDatamonitor Healthcare’s proprietary IPF primary research survey.

Table 13: Datamonitor Healthcare’s definition of idiopathic pulmonary fibrosis severity

Classification Characteristics

Mild FVC >80% of predicted DLCO >60% of predicted

Moderate FVC 50–80% of predicted DLCO 35–60% of predicted

Severe FVC <50% of predicted DLCO <35% of predicted

DLCO = diffusing capacity of the lung for carbon monoxide; FVC = forced vital capacity



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MODERATE IPF IS THE MOST COMMON SEVERITY AMONG DIAGNOSED PATIENTS

The most prevalent disease severity is moderate IPF, making up a mean of 42% of patients across theUS, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). The next mostcommon severity is mild IPF, at a mean of 32%, while severe IPF constitutes the remaining 26% ofpatients. It is important to note that this analysis only consists of diagnosed patients, and that thetrue distribution of the total IPF population is likely to be even more skewed toward the less severeend of the spectrum, as patients with mild disease are more likely to go undiagnosed. Undiagnosed idiopathic pulmonary fibrosis

The following figure shows the estimated proportion of IPF patients who remain undiagnosed acrossthe US, Japan, and five major EU markets.

Figure 10: Distribution of diagnosed idiopathic pulmonary fibrosis patients across the US, Japan, and five major EUmarkets, by severity and country (%)



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OVER HALF OF ALL MILD IPF PATIENTS ARE ESTIMATED TO BE UNDIAGNOSED

Respondents to Datamonitor Healthcare’s IPF primary research survey estimated that approximately52% of the mild IPF population remains undiagnosed. Studies of various IPF cohorts have recorded amean FVC at diagnosis of around 70% of predicted (Cortes-Telles et al., 2014; Oda et al., 2014;Richeldi et al., 2012); therefore, it is likely that a large proportion of patients are not diagnosed withIPF until they have already reached moderate disease severity. This can be explained by the difficultyin recognizing the early symptoms of IPF, such as cough and dyspnea, which may be misinterpreted bypatients as consequences of old age or smoking. Furthermore, mild IPF patients who do present fortreatment are often initially misdiagnosed as having diseases which share common symptoms withIPF, such as bronchitis, asthma, or emphysema (Collard et al., 2007b).

Figure 11: Estimated percentage of idiopathic pulmonary fibrosis patients in each severity who remain undiagnosedacross the US, Japan, and five major EU markets


Table 14: Estimated percentage of idiopathic pulmonary fibrosis patients in each severity who remain undiagnosedacross the US, Japan, and five major EU markets

Severity US Japan France Germany Italy Spain UK

Mild 45.6% 57.3% 51.3% 51.8% 57.8% 52.2% 49.8%

Moderate 29.3% 35.6% 33.1% 33.6% 35.7% 33.8% 30.6%

Severe 16.6% 17.0% 15.3% 17.2% 19.1% 20.2% 16.4%



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Acute exacerbation

The clinical course of patients with IPF can vary drastically depending on a number of known andunknown factors. Some patients may experience a gradual decline in lung function, whereas othersmay experience rapid disease progression from onset. Alternatively, there may be periods with littleprogression, followed by periods of sudden deterioration, known as acute exacerbations. The officialdiagnosis of acute exacerbation requires the following criteria to be met (Collard et al., 2007a):

previous or current diagnosis of IPF

unexplained worsening or development of dyspnea within 30 days

high-resolution computed tomography with new bilateral ground-glass abnormality and/orconsolidation superimposed on a background reticular or honeycomb pattern consistent withusual interstitial pneumonia pattern

no evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage

exclusion of alternative causes, including left heart failure, pulmonary embolism, or otheridentifiable causes of acute lung injury.

The following figure shows the proportion of patients in each severity who experience acuteexacerbation, as estimated by respondents to Datamonitor Healthcare’s IPF primary research survey.


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REAL-WORLD INCIDENCE OF ACUTE EXACERBATION LIKELY TO EXCEED RATES DOCUMENTED INCLINICAL TRIALS

Due to various interpretations of the definition and a frequent lack of adequate patient data, rates ofacute exacerbation observed in the real-world clinical setting are likely much greater than thoserecorded in IPF clinical trials. Respondents to Datamonitor Healthcare’s IPF primary research surveyindicated that an estimated 18%, 36%, and 56% of mild, moderate, and severe patients experienceacute exacerbation, respectively. In contrast, the annual incidence of acute exacerbation observed inthe placebo arms of IPF trials is under 5% (Ryerson et al., 2015). This can partially be attributed to thefact that clinical trials typically exclude patients with more advanced disease, who are more likely toexperience acute exacerbation. Furthermore, trials ordinarily only count cases which fit all diagnosiscriteria, called definite acute exacerbation, whereas real-world analyses also include cases whichcould be acute exacerbation but which do not meet all criteria due to missing information, calledsuspected acute exacerbation (Collard et al., 2013). Lastly, trials often utilize an adjudicated reviewprocess to determine if individual cases qualify for acute exacerbation, while pulmonologists in

Figure 12: Estimated percentage of IPF patients who experience acute exacerbation in the US, Japan, and five major EUmarkets, by severity and country



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clinical practice are likely more liberal in their diagnoses (Ryerson et al., 2015).

Although the current definition describes acute exacerbation as a sudden worsening of dyspnea andlung function due to unknown causes, future updates to this definition may eliminate the need toidentify a cause of the episode. The correct identification of episode triggers currently has littleimpact on the treatment or prognosis of patients with acute exacerbations, and diagnostic proceduresused to identify the cause, such as bronchoalveolar lavage, may actually worsen a patient’s condition.A broader definition would also simplify diagnosis, making it more consistent and reducing thediscrepancy between rates of definite and definite/suspected acute exacerbation (Ryerson et al.,2015). Bibliography

Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King Jr TE, Lasky JA, Loyd JE, Noth I, OlmanMA, Raghu G, Roman J, Ryu JH, Zisman DA, Hunninghake GW, Colby TV, Egan JJ, Hansell DM, JohkohT, Kaminski N, Kim DS, Kondoh T, Lynch DA, Muller-Quernheim J, Myers JL, Nicholson AG, Selman M,Toews GB, Wells AU, Martinez FJ (2007a) Acute exacerbations of idiopathic pulmonary fibrosis.American Journal of Respiratory and Critical Care Medicine, 176(7), 636–643<DOI>10.1164/rccm.200703-463PP</DOI>.

Collard HR, Tino G, Noble PW, Shreve MA, Michaels M, Carlson B, Schwarz MI (2007b) Patientexperiences with pulmonary fibrosis. Respiratory Medicine, 101(6), 1350–4<PMID>17107778</PMID>.

Collard HR, Yow E, Richeldi L, Anstrom KJ, Glazer C (2013) Suspected acute exacerbation of idiopathicpulmonary fibrosis as an outcome measure in clinical trials. Respiratory Research, 14(73), 1–7<DOI>10.1186/1465-9921-14-73</DOI>.

Cortes-Telles A, Forket L, O’Donnell DE, Moran-Mendoza O (2014) Idiopathic pulmonary fibrosis: newinsights on functional characteristics at diagnosis. Canadian Respiratory Journal, 21(3), e55–60<PMID>24712014</PMID>.

Homma S, Sugino K, Sakamoto S (2015) The usefulness of a disease severity staging classificationsystem for IPF in Japan: 20 years of experience from empirical evidence to randomized control trialenrolment. Respiratory Investigation, 53(1), 7–12 <DOI>10.1016/j.resinv.2014.08.003</DOI>.

Ley BL, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, Poletti V, Buccioli M, Elicker BM, JonesKD, King Jr TE, Collard HR (2012) A multidimensional index staging system for idiopathic pulmonaryfibrosis. Annals of Internal Medicine, 156(10), 684–91 <DOI>10.7326/0003-4819-156-10-201205150-00004</DOI>.

Oda K, Ishimoto H, Yatera K, Naito K, Ogoshi T, Yamasaki K, Imanaga T, Tsuda T, Nakao H, Kawanami T,Mukae H (2014) High-resolution CT scoring system-based grading scale predicts the clinical outcomesin patients with idiopathic pulmonary fibrosis. Respiratory Research, 15(10), 1–9


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<DOI>10.1186/1465-9921-15-10</DOI>.

Richeldi L, Ryerson CJ, Lee JS, Wolters PJ, Koth LL, Ley B, Elicker BM, Jones KD, King Jr TE, Ryu JH,Collard HR (2012) Relative versus absolute change in forced vital capacity in idiopathic pulmonaryfibrosis. Thorax, 67(5), 407–11 <DOI>10.1136/thoraxjnl-2011-201184</DOI>.



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Country Treatment Trees Introduction to treatment trees

The treatment trees for idiopathic pulmonary fibrosis (IPF) for the US, Japan, and five major EUmarkets (France, Germany, Italy, Spain, and the UK) are based on Datamonitor Healthcare’s 2015primary research survey of 220 pulmonologists covering the epidemiology, diagnosis, andmanagement of IPF.

The treatment trees provide an approximation of the potential patient populations at each step in thetreatment algorithm and indicate estimated patient numbers; they should not be interpreted asshowing exact patient numbers. For further clarification of these calculations, and to view thetreatment trees, please download the accompanying Excel datapack, available by clicking "DownloadIdiopathic Pulmonary Fibrosis Treatment Algorithm" on the right-hand menu of this page.


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Current Treatment Options There are only two pharmacological treatments currently approved for idiopathic pulmonary fibrosis(IPF), which are detailed in the table below.

In addition to the approved treatments Esbriet (pirfenidone; Roche/Shionogi) and Ofev (nintedanib;Boehringer Ingelheim), several pharmacological therapies have been used off-label for the treatmentof IPF based on evidence from various clinical trials. These off-label treatments are outlined below.

Table 15: Approved treatments available for idiopathic pulmonary fibrosis across the US, Japan, and five major EUmarkets

Brand (molecule) CompanyMost common

therapeutic roleAdministration Currently marketed

Esbriet (pirfenidone) Roche/Shionogi Mild-to-moderate IPF Oral US, Japan, 5EU

Ofev (nintedanib) Boehringer Ingelheim Mild-to-moderate IPF Oral US, Japan, 5EU

5EU = five major EU markets (France, Germany, Italy, Spain, and the UK); IPF = idiopathic pulmonary fibrosis

Source: Pharmaprojects ®, 2015; Citeline


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Table 16: Off-label therapies used in the treatment of idiopathic pulmonary fibrosis across the US, Japan, and five majorEU markets

Molecule or drug class

ambrisentan

Anticoagulants

azathioprine

bosentan

bromhexine hydrochloride

colchicine

Corticosteroids

co-trimoxazole

cyclophosphamide

cyclosporin A

d-penicillamine

etanercept

everolimus

iloprost

imatinib

interferon-gamma-1b

macitentan

N-acetylcysteine

sildenafil

thalidomide


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Numerous non-pharmacological treatments are also used in patients with IPF. The most commonlyused non-pharmacological treatments are listed below.

Updated evidence-based guidelines provide general recommendations for treatment

In 2011, the American Thoracic Society (ATS), European Respiratory Society (ERS), JapaneseRespiratory Society (JRS), and Latin American Thoracic Association (ALAT) collaborated to create acomprehensive set of international, evidence-based guidelines for the diagnosis and management ofIPF. Following on from this, subsequent releases of clinical information on key treatments led thecommittee to publish an update to these guidelines in 2015. These documents have served as animportant tool in order to standardize how IPF is diagnosed, as well as outlining what treatments areviable options.

Unlike guidelines for other diseases, the ATS/ERS/JRS/ALAT guidelines do not compare treatmentsagainst each other to recommend the best course of action for all patients. Rather, each treatment isevaluated independently to determine both its benefit to IPF patients as well as the quality ofevidence supporting its use. This is done through using the GRADE technique, in which the confidencein each treatment’s effect estimates is rated “very low,” “low,” “moderate,” or “high” based on theavailable evidence. A “strong” or “conditional” recommendation is then given for or against using each

Table 16: Off-label therapies used in the treatment of idiopathic pulmonary fibrosis across the US, Japan, and five majorEU markets

Source: Datamonitor Healthcare; Loveman et al., 2015; Raghu et al., 2011; Raghu et al., 2015

Table 17: Non-pharmacological therapies used in the treatment of idiopathic pulmonary fibrosis across the US, Japan,and five major EU markets

Treatment

Lung transplantation (single or double)

Mechanical ventilation

Oxygen therapy

Pulmonary rehabilitation

Source: Datamonitor Healthcare; Adamali et al., 2012; Egan, 2011


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treatment, based on the confidence in effect estimates, outcomes studies, desirable and undesirableconsequences of the treatment, cost of the treatment, implications of the treatment on health equity,and feasibility of the treatment (Raghu et al., 2011; Raghu et al., 2015).


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Figure 13: Overview of the ATS/ERS/JRS/ALAT evidence-based guidelines for the treatment of idiopathic pulmonaryfibrosis


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Bibliography

Adamali HI, Anwar MS, Russell AM, Egan JJ (2012) Non-pharmacological treatment of idiopathicpulmonary fibrosis. Current Respiratory Care Reports, 1(4), 208–215 <DOI>10.1007/s13665-012-0031-z</DOI>.

Egan JJ (2011) Follow-up and nonpharmacological management of the idiopathic pulmonary fibrosispatient. European Respiratory Review, 20(120), 114–117 <DOI>10.1183/09059180.00001811</DOI>.

Loveman E, Copley VR, Colquitt J, Scott DA, Clegg A, Jones J, O’Reilly K, Singh S, Bauswein C, Wells A(2015) The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonaryfibrosis: a systematic review and economic evaluation. Health Technology Assessment, 19(20), 1–336<DOI>10.3310/hta19200</DOI>.


Raghu G, Rochwerg B, Zhang Y, Cuello Garcia CA, Azuma A, Behr J, Brozek JL, Collard HR, CunninghamW, Homma S, Johkoh T, Martinez FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M, Theodore A,Wells AU, Hoogsteden H, Schunemann HJ (2015) An Official ATS/ERS/JRS/ALAT Clinical PracticeGuideline: Treatment of Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and CriticalCare Medicine, 192(2), e3–e19 <DOI>10.1164/rccm.201506-1063ST</DOI>.

Figure 13: Overview of the ATS/ERS/JRS/ALAT evidence-based guidelines for the treatment of idiopathic pulmonaryfibrosis

Source: Raghu et al., 2011; Raghu et al., 2015


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Prescribing Trends Datamonitor Healthcare surveyed 220 pulmonologists across the US, Japan, and five major EU markets(France, Germany, Italy, Spain, and the UK) concerning their prescribing practices for the treatment ofidiopathic pulmonary fibrosis (IPF). The following analysis provides an overview and analysis of themost common treatment regimens used for IPF patients, by severity. For a full breakdown of alltreatment regimens prescribed by respondents in each country, please download the accompanyingExcel datapack, available by clicking "Download Idiopathic Pulmonary Fibrosis Treatment Algorithm"on the right-hand menu of this page. Treatment rate of idiopathic pulmonary fibrosis

The following table shows the proportion of IPF patients in each country who are treatedpharmacologically, non-pharmacologically, with a combination of both modalities, or not treated.


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A SIGNIFICANT PROPORTION OF MILD IPF PATIENTS ARE NOT RECOMMENDED FOR ANYTREATMENT

According to surveyed pulmonologists in the US, Japan, and five major EU markets, a mean of 31% ofpatients diagnosed with mild IPF are not recommended for any type of treatment. This is likely due toa combination of factors involving the adequate performance status of these patients as well as thedisadvantages of the treatments available to them. According to Datamonitor Healthcare’s definition

Figure 14: Percentage of IPF patients who fall into each treatment category in the US, Japan, and five major EUmarkets, by severity and country



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(see the Patient Segmentation chapter), IPF patients with a forced vital capacity (FVC) >80% ofpredicted and a diffusing capacity of the lung for carbon monoxide >60% of predicted are designatedas having mild IPF. However, according to typical spirometry interpretations, any FVC result >80% ofpredicted is considered to be a “normal” level (Petty and Enright, 2003). Therefore, while mild patientshave a radiologically confirmed diagnosis of IPF, some may not exhibit any abnormal or debilitatingsymptoms. As such, pulmonologists occasionally recommend a watch-and-wait treatment approach.Although recent evidence has shown the potential benefits of initiating treatment for IPF as soon aspossible (Albera et al., 2015), the costs and side effects of currently available treatments mayoutweigh their advantages in milder cases. Pharmacological treatment of idiopathic pulmonary fibrosis MILD IPF

The following figure and table show the top regimens prescribed to pharmacologically treated mild IPFpatients in each country.

Figure 15: Top five pharmacological treatment regimens used in mild IPF patients across the US, Japan, and five majorEU markets, by country



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MODERATE IPF

The following figure and table show the top regimens prescribed to pharmacologically treatedmoderate IPF patients in each country.

Table 18: Pharmacological treatment regimens used in mild idiopathic pulmonary fibrosis patients across the US, Japan,and five major EU markets, by country

Treatment regimen All

countries


pirfenidone monotherapy 32.4% 35.6% 33.8% 51.5% 27.1% 37.2% 14.1% 25.2%

N-acetylcysteine (NAC) monotherapy 15.8% 5.9% 5.6% 7.7% 17.1% 7.1% 36.9% 33.6%

corticosteroid monotherapy 15.7% 8.9% 16.5% 13.3% 18.5% 12.2% 20.5% 21.5%

nintedanib monotherapy 6.0% 20.2% 0.0% 5.5% 7.2% 3.8% 3.3% 1.6%

pirfenidone + N-acetylcysteine (NAC) 5.8% 2.4% 8.3% 3.7% 2.4% 10.9% 9.4% 2.7%

pirfenidone + corticosteroid 5.2% 7.2% 11.5% 3.2% 1.7% 6.5% 5.2% 1.1%

azathioprine + corticosteroid 2.1% 2.2% 1.3% 0.5% 2.1% 4.0% 1.5% 3.2%

cyclophosphamide + corticosteroid 2.0% 1.9% 9.2% 0.8% 0.2% 1.5% 0.6% 0.0%

N-acetylcysteine (NAC) + azathioprine +

corticosteroid

1.9% 1.1% 0.4% 0.7% 2.1% 5.0% 1.1% 2.7%

sildenafil 1.7% 1.9% 0.2% 1.2% 5.4% 1.6% 0.7% 0.9%

nintedanib + corticosteroid 1.5% 5.8% 0.0% 2.2% 1.3% 0.6% 0.5% 0.0%

bosentan 1.4% 0.4% 1.7% 0.7% 3.9% 1.5% 0.5% 0.9%

anticoagulant + corticosteroid 1.3% 0.0% 1.3% 0.7% 2.1% 0.8% 0.5% 4.1%

colchicine + corticosteroid 1.0% 0.0% 1.7% 2.1% 0.3% 2.4% 0.2% 0.0%

Note: totals may not sum due to rounding; only treatment regimens used in ≥1.0% of mild idiopathic pulmonary fibrosis patients across all markets

are shown. Please download the accompanying Excel datapack for further information.



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Figure 16: Top five pharmacological treatment regimens used in moderate IPF patients across the US, Japan, and fivemajor EU markets, by country



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SEVERE IPF

The following figure and table show the top regimens prescribed to pharmacologically treated severe

Table 19: Pharmacological treatment regimens used in moderate idiopathic pulmonary fibrosis patients across the US,Japan, and five major EU markets, by country


countries








N-acetylcysteine (NAC) + azathioprine + corticosteroid 3.4% 2.3% 0.3% 0.8% 3.7% 7.0% 4.3% 5.6%



sildenafil 1.9% 1.1% 0.5% 1.1% 6.5% 2.5% 0.8% 0.5%


bosentan 1.3% 0.5% 1.6% 0.6% 2.6% 1.8% 1.4% 0.8%

cyclosporin A 1.1% 0.0% 2.9% 3.0% 0.3% 0.5% 0.8% 0.3%

Other pharmacological treatment 1.1% 0.0% 2.1% 0.8% 0.0% 0.3% 3.5% 1.0%


nintedanib + N-acetylcysteine (NAC) 1.0% 1.6% 0.0% 1.1% 1.2% 0.8% 2.4% 0.0%

Note: totals may not sum due to rounding; only treatment regimens used in ≥1.0% of moderate idiopathic pulmonary fibrosis patients across all

markets are shown. Please download the accompanying Excel datapack for further information.



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IPF patients in each country.

Figure 17: Top five pharmacological treatment regimens used in severe IPF patients across the US, Japan, and five majorEU markets, by country



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TRENDS IN THE PHARMACOLOGICAL TREATMENT OF IPF APPROVED TREATMENTS

The following figure shows the use of Esbriet (pirfenidone; Roche/Shionogi) and Ofev (nintedanib;

Table 20: Pharmacological treatment regimens used in severe idiopathic pulmonary fibrosis patients across the US,Japan, and five major EU markets, by country


countries








N-acetylcysteine (NAC) + azathioprine + corticosteroid 5.1% 3.0% 0.5% 4.5% 2.9% 10.7% 7.9% 7.0%



sildenafil 2.4% 2.7% 0.8% 1.0% 6.2% 3.0% 1.5% 1.1%

bosentan 1.8% 0.3% 1.9% 0.6% 3.6% 3.4% 1.5% 1.0%


Other pharmacological treatment 1.6% 0.0% 2.6% 0.0% 0.5% 0.7% 2.9% 4.8%


nintedanib + N-acetylcysteine (NAC) 1.4% 1.2% 0.0% 1.5% 0.8% 0.9% 5.5% 0.0%

Note: totals may not sum due to rounding; only treatment regimens used in ≥1.0% of severe idiopathic pulmonary fibrosis patients across all

markets are shown. Please download the accompanying Excel datapack for further information.



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Boehringer Ingelheim) in IPF, regardless of use as a monotherapy, in combination with N-acetylcysteine (NAC), or in combination with corticosteroids.

USE OF ESBRIET VARIES BY MARKET AND SEVERITY

Due to aspects such as market timing, approval limitations, and reimbursement status, the usage ofEsbriet varies both by country and disease severity. Esbriet’s highest uptake is in Japan, where overhalf of all patients receiving pharmacological treatment are treated with a regimen containing thedrug. This is likely due to its long-standing market position in Japan, having been approved in 2008based on clinical trials carried out specifically in Japanese patients (Shionogi press release, 2012).Esbriet was subsequently approved for IPF in the EU in 2011 (EMA, 2015), although due to a staggeredlaunch strategy and extensive pricing and reimbursement negotiations, the drug did not launch inSpain until 2014 (BioMedTracker, Copyright 2015, reprinted with permission), likely somewhatreducing its current uptake in relation to other EU markets. Furthermore, the approval of Esbriet in theEU only included mild-to-moderate IPF patients (EMA, 2015), lowering the drug’s usage in severepatients.

Decisions from health technology assessment bodies in Europe also greatly influence the uptake ofEsbriet. French assessment body Haute Autorité de Santé (HAS) ruled that Esbriet provides a minorbenefit in clinical added value (HAS, 2015), allowing 57–58% of pharmacologically treated mild-to-

Figure 18: Use of Esbriet and Ofev, whether alone or in a combination, across the US, Japan, and five major EU markets,by severity and country



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moderate IPF patients in France to receive Esbriet. Conversely, the German Institute for Quality andEfficiency in Health Care (IQWiG; Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen)decided that the drug had no proven added benefit (IQWiG, 2011), which has likely negativelyimpacted Esbriet’s usage in Germany. Reimbursement decisions in Spain were mixed, with Esbriet onlyincluded on formularies by certain regional payers (Sociedad Espanola de Farmacia Hospitalaria,2015). Lastly, the UK’s National Institute for Health and Care Excellence (NICE) gave a positiverecommendation for Esbriet, but only for moderate IPF patients (FVC 50–80% of predicted) (NICE,2013a), decreasing usage in mild patients.

In the US, Esbriet and Ofev were approved simultaneously (FDA, 2014a; FDA, 2014b). However,Esbriet’s prior standing in other markets, as well as its demonstrated mortality benefits, have allowedit to gain significant uptake despite additional competition. The US Food and Drug Administration’s(FDA’s) approval of Esbriet was for all IPF patients regardless of severity, but some insurers have usedprior authorization criteria in order to restrict use in severe patients (Anthem, 2015; Express Scripts,2015) or mild patients (Caremark, 2015). AS EXPECTED, UPTAKE OF OFEV IS HIGHEST IN THE US

Given Esbriet’s significant first-to-market advantage in Japan and the EU, Ofev’s largest uptake wouldbe expected to be in the US, where both drugs were approved in October 2014 (FDA, 2014a; FDA,2014b). Indeed, in the US at least 25% of pharmacologically treated IPF patients in each diseaseseverity are prescribed Ofev. The drug’s use in the EU is comparatively much lower due to Esbriet’smore established position in these markets and Ofev’s later approval (in January 2015, just six monthsbefore Datamonitor Healthcare’s primary research survey was conducted) (Boehringer Ingelheim pressrelease, 2015a). Similarly, Ofev was approved in Japan in July 2015 (the same month as DatamonitorHealthcare’s primary research survey) (Boehringer Ingelheim press release, 2015b), therefore no usageof Ofev was recorded in Japan. COMBINATIONS FEATURING ESBRIET AND OFEV ARE HIGHLY UTILIZED IN ADVANCED PATIENTS

Although each brand is only approved as a monotherapy, regimens featuring Esbriet or Ofev incombination with NAC or corticosteroids are commonly used, especially in severe IPF patients whomay have exhausted their treatment options. According to Datamonitor Healthcare’s primary researchsurvey, 48% of severe patients receiving Esbriet and 31% of severe patients receiving Ofevconcurrently receive NAC or corticosteroids. Real-world studies on the use of Esbriet in clinicalpractice have also reported similar utilization rates in combinations (Harari and Caminati, 2015),despite the lack of robust evidence showing their benefits. Recent studies attempting to discern thesafety and efficacy of such combinations have provided somewhat mixed results. A small case-controlstudy of 34 advanced IPF patients found that the addition of NAC to Esbriet reduced the rate ofannual FVC decline and improved progression-free survival (Sakamoto et al., 2015). Another studyconsisting of 122 patients found that the combination of Esbriet and NAC was well tolerated, butobserved a potentially negative effect of NAC on FVC (Behr et al., 2015).


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OFF-LABEL TREATMENTS MULTIPLE ROLES STILL EXIST FOR CORTICOSTEROID MONOTHERAPY IN THE TREATMENT OF IPF

Despite a negative recommendation in the evidence-based guidelines for the general treatment of IPFproduced by the American Thoracic Society (ATS), European Respiratory Society (ERS), JapaneseRespiratory Society (JRS), and Latin American Thoracic Association (ALAT) in 2011, the use ofcorticosteroid monotherapy remains high due to the treatment’s additional utilities. The results ofDatamonitor Healthcare’s primary research survey show an average of 16%, 15%, and 17% of mild,moderate, and severe patients, respectively, are treated with corticosteroid monotherapy across theUS, Japan, and five major EU markets. A large portion of corticosteroid monotherapy use can likely beattributed to patients being treated for acute exacerbation of IPF. Although guidelines strongly adviseagainst the use of corticosteroids for the general treatment of IPF, they conditionally recommendthem for the treatment of acute exacerbations (Raghu et al., 2011). There is limited evidence for theirefficacy in this setting, although it is hypothesized that corticosteroids may help in treating acutelung injury or organizing pneumonia (Ryerson et al., 2015). Additionally, corticosteroid monotherapymay also be useful in ruling out potential differential diagnoses. It has been shown that other types ofinterstitial lung diseases respond much better to corticosteroid treatment than IPF (Bourke, 2006;Disayabutr et al., 2015). Therefore, if a patient’s initial diagnosis of IPF is questionable, their responseto corticosteroid treatment could provide indicative information.

Figure 19: Percentage use of Esbriet and Ofev as monotherapy and in each combination across the US, Japan, and fivemajor EU markets, by severity



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NAC MONOTHERAPY USE CONTINUES AS POTENTIAL PREDICTIVE BIOMARKER IS IDENTIFIED

The lack of available treatments for IPF and the overall high tolerability of NAC allow it to continue tobe used as a monotherapy in some markets. However, emerging evidence may allow for it toeventually be used more widely. Respondents to Datamonitor Healthcare’s primary research studyindicated that NAC monotherapy continues to be used to treat a significant proportion of IPF patients,especially in Spain and the UK, where 37% and 34% of pharmacologically treated mild IPF patientsare still prescribed the treatment, respectively. Although some studies have shown minor benefits oftreatment, pooled data from three randomized clinical trials showed no significant survival, FVC, orquality of life advantages of NAC monotherapy, earning the treatment a conditional recommendationagainst use in the ATS/ERS/JRS/ALAT international IPF guidelines (Raghu et al., 2015). However,because the therapy is relatively well tolerated, both the Spanish IPF guidelines and NICE IPFguidelines continue to list it as a treatment option (Xaubet et al., 2013; NICE, 2013b). This provides animportant alternative as both Spain and the UK have limited the reimbursement of Esbriet (SociedadEspanola de Farmacia Hospitalaria, 2015; NICE, 2013a).

The future use of NAC monotherapy may be impacted by evidence showing its efficacy in specificsubpopulations of IPF. A recent study found that NAC monotherapy could be an efficacious treatmentfor IPF patients with a specific polymorphism in the TOLLIP gene (Oldham et al., 2015). Nevertheless,further trials will need to be conducted in order to confirm this and apply it to clinical practice. ANTI-GASTROESOPHAGEAL REFLUX MEDICATIONS ANTI-GASTROESOPHAGEAL REFLUX TREATMENTS HAVE BECOME COMMONPLACE IN IPF DUE TOA POSITIVE RECOMMENDATION IN TREATMENT GUIDELINES

Multiple studies have shown the benefits of supplementing treatment with gastroesophageal refluxtherapies in IPF patients. Therefore, the ATS/ERS/JRS/ALAT IPF guidelines have conditionallyrecommended that patients be treated with anti-acids such as proton pump inhibitors and histamine-2 receptor antagonists, regardless of if they display symptoms of gastroesophageal reflux disease(GERD) or not (Raghu et al., 2015). Respondents to Datamonitor Healthcare’s primary research studyindicated that an average of 42%, 53%, and 61% of mild, moderate, and severe patients, respectively,receive supplemental anti-gastroesophageal reflux medications across the US, Japan, and five majorEU markets. The use of GERD therapies in IPF will likely continue to grow as evidence of their benefitscontinues to mount. Currently, the supporting data primarily consist of two retrospectiveobservational studies; one of which demonstrated a survival benefit with anti-acid treatment, whilethe other showed slower FVC decline and fewer acute exacerbations with anti-acid treatment. Thesefindings also support the hypothesis that GERD contributes to disease onset, progression, and/or acuteexacerbation (Lee et al., 2011; Lee et al., 2013).


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Non-pharmacological treatment of idiopathic pulmonary fibrosis MILD IPF

Figure 20: Patients who receive supplemental anti-gastroesophageal reflux medications across the US, Japan, and fivemajor EU markets, by severity and country (%)



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MODERATE IPF

Figure 21: Non-pharmacological treatments used in mild idiopathic pulmonary fibrosis patients across the US, Japan,and five major EU markets, by country



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SEVERE IPF

Figure 22: Non-pharmacological treatments used in moderate idiopathic pulmonary fibrosis patients across the US,Japan, and five major EU markets, by country



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TRENDS IN THE NON-PHARMACOLOGICAL TREATMENT OF IPF PULMONARY REHABILITATION IS THE LEADING FORM OF NON-PHARMACOLOGICAL TREATMENTIN MILD-TO-MODERATE PATIENTS

Pulmonary rehabilitation has become an integral part of the treatment of mild-to-moderate IPF. Theresults of Datamonitor Healthcare’s primary research survey indicate that an average of 62% of mildand 58% of moderate IPF patients who receive non-pharmacological treatment across the analyzedmarkets are prescribed pulmonary rehabilitation therapy. Although the long-term benefits of therapyare not as clear, pulmonary rehabilitation has been shown to improve dyspnea, functional capacity,and patient quality of life over the short term (Ryerson et al., 2014). However, pulmonaryrehabilitation therapy has a slightly reduced role in severe IPF patients, as their performance statusmay not allow them to exercise at a high enough level to see any significant benefits from treatment(Jackson et al., 2014). A LARGE PROPORTION OF SEVERE IPF PATIENTS REQUIRE OXYGEN THERAPY

According to Datamonitor Healthcare’s primary research survey, an average of 75% of severe IPFpatients who are prescribed non-pharmacological treatments across the US, Japan, and five major EU

Figure 23: Non-pharmacological treatments used in severe idiopathic pulmonary fibrosis patients across the US, Japan,and five major EU markets, by country



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markets are treated with oxygen therapy. The international ATS/ERS/JRS/ALAT IPF guidelines stronglyrecommend long-term oxygen therapy to all IPF patients with clinically significant resting hypoxemia(SpO2 <88%) (Raghu et al., 2011). Although there is little evidence supporting its benefits in IPFbeyond patient-reported outcomes, survival advantages related to the addition of long-term oxygentherapy in other respiratory disorders such as chronic obstructive pulmonary disease provide arationale for its use (Duck et al., 2015; Raghu et al., 2011). MECHANICAL VENTILATION IS RARELY USED IN THE UK

Only 1% of severe IPF patients in the UK who are prescribed any non-pharmacological interventionreceive mechanical ventilation, which is much lower than the 15% average observed across theremaining analyzed markets. Although it is clear that the mortality rate associated with mechanicalventilation is high (Raghu et al., 2011), IPF patients experiencing acute respiratory failure often havefew alternative options. Furthermore, non-invasive approaches present an opportunity to improveupon the poor outcomes associated with mechanical ventilation (Vianello et al., 2014; Yokoyama etal., 2010). Nonetheless, NICE guidelines for the treatment of IPF advise not to routinely offermechanical ventilation (including non-invasive mechanical ventilation) to patients experiencingrespiratory failure (NICE, 2013b), stifling use of the treatment. Bibliography

Albera C, Bradford WZ, Costabel U, Fagan EA, Glaspol I, Glassberg MK, Gorina E, Kardatzke D, King JrTE, Lancaster L, Lederer DJ, Nathan SD, Pereira C, Spiriq D, Swigris JJ, Valeyre D, Noble PW (2015)Pirfenidone Is Efficacious In Patients With Idiopathic Pulmonary Fibrosis (IPF) And Mild RestrictiveDisease. Available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2015.191.1_MeetingAbstracts.A1018 [Accessed 15 December 2015].

Anthem (2015) Esbriet Prior Authorization. Available from:https://www.anthem.com/provider/noapplication/f0/s0/t0/pw_e227866.pdf?na=pharminfo [Accessed17 December 2015].

Behr J, Bendstrup E, Crestani B, Gnther A, Olschewski H, Skid M, Wells A, Wuyts W, Koschel D, KreuterM, Wallaert, Tang H, Beck J, Albera C (2015) LATE-BREAKING ABSTRACT: Safety and tolerability of N-acetylcysteine (NAC) with pirfenidone in idiopathic pulmonary fibrosis (IPF): PANORAMA. EuropeanRespiratory Journal, 46(59) <DOI>10.1183/13993003.congress-2015.OA3477</DOI>.

Boehringer Ingelheim press release (2015a) OFEV® (nintedanib*) approved in the EU for the treatmentof IPF. Available from: http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/19_january_2015_ipf.html [Accessed 16December 2015].

Boehringer Ingelheim press release (2015b) New data demonstrate sustained long-term efficacy ofOFEV®* on slowing disease progression and safety in patients with IPF. Available from:http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/29_september_2015_ipf.html [Accessed 16


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Caremark (2015) Esbriet Prior-Approval Requirements. Available from:http://www.caremark.com/portal/asset/FEP_Criteria_Esbriet.pdf [Accessed 16 December 2015].

Disayabutr S, Calfee CS, Collard HR, Wolters PJ (2015) Interstitial lung diseases in the hospitalizedpatient. BMC Medicine, 13(245), 1–8 <DOI>10.1186/s12916-015-0487-0</DOI>.

Duck A, Spencer LG, Bailey S, Leonard C, Ormes J, Caress AL (2015) Perceptions, experiences and needsof patients with idiopathic pulmonary fibrosis. Journal of Advanced Nursing, 71(5), 1055–65<DOI>10.1111/jan.12587</DOI>.

EMA (2015) EPAR summary for the public: Esbriet. Available from:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002154/WC500102979.pdf [Accessed 16 December 2015].

Express Scripts (2015) Drugs That Require Prior Authorization (PA) Before Being Approved forCoverage. Available from: https://www.express-scripts.com/art/medicare15/pdf/prior_authorization_choice.pdf [Accessed 16 December 2015].

FDA (2014a) FDA approves Esbriet to treat idiopathic pulmonary fibrosis. Available from:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418991.htm [Accessed 16December 2015].

FDA (2014b) FDA approves Ofev to treat idiopathic pulmonary fibrosis. Available from:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418994.htm [Accessed 16December 2015].

Harari S, Caminati A (2015) Idiopathic pulmonary fibrosis: from clinical trials to real-life experiences.European Respiratory Journal, 24(137), 420–27 <DOI>10.1183/16000617.0042-2015</DOI>.

HAS (2015) Brief Summary of the Transparency Committee Opinion. Available from: http://www.has-sante.fr/portail/upload/docs/application/pdf/2015-11/esbriet_summary_ct13850.pdf [Accessed 16December 2015].

IQWiG (2011) Pirfenidone: extent of added benefit assessed. Available from:https://www.iqwig.de/en/press/press-releases/press-releases/pirfenidone-extent-of-added-benefit-assessed.2237.html [Accessed 17 December 2015].

Jackson RM, Ramos CF, Cohen MI, Gaunard IA, Cahalin LP, Sol CM, Cardenas D, Gomez-Marin OW(2014) Exercise Limitations and Rehabilitation of IPF Patients. Available from:


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Lee JS, Ryu JL, Elicker BM, Lydell CP, Jones KD, Wolters PJ, King Jr TE, Collard HR (2011)Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathicpulmonary fibrosis. American Journal of Respiratory and Critical and Care Medicine, 184(12), 1390–94<DOI>10.1164/rccm.201101-0138OC</DOI>.

Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts RS, Yow E, Raghu G (2013) Anti-AcidTherapy and Disease Progression in Idiopathic Pulmonary Fibrosis: an analysis of data from threerandomized controlled trials. The Lancet Respiratory Medicine, 1(5), 369–376 <DOI>10.1016/S2213-2600(13)70105-X</DOI>.

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Ryerson CJ, Cayou C, Topp F, Hilling L, Camp PG, Wilcox PG, Khalil N, Collard HR, Carvey C (2014)Pulmonary rehabilitation improves long-term outcomes in interstitial lung disease: A prospectivecohort study. Respiratory Medicine, 108(1), 203–10 <DOI>10.1016/j.rmed.2013.11.016</DOI>.


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Sakamoto S, Muramatsu Y, Satoh K, Ishida F, Kikuchi N, Sano G, Sugino K, Isobe K, Takai Y, Homma S(2015) Effectiveness of combined therapy with pirfenidone and inhaled N-acetylcysteine for advancedidiopathic pulmonary fibrosis: A case–control study. Respirology, 20(3), 445–52<DOI>10.1111/resp.12477</DOI>.

Shionogi press release (2012) Shionogi Provides Pirespa 200mg Tablet to ILDONG PHARMACEUTICALfor the Treatment of Idiopathic Pulmonary Fibrosis in South Korea. Available from:http://www.shionogi.co.jp/en/company/news/2012/pmrltj0000000w2d-att/e_121012.pdf [Accessed16 December 2015].

Sociedad Espanola de Farmacia Hospitalaria (2015) Sumario de los informes publicados por loshospitales en internet. Available from:http://gruposdetrabajo.sefh.es/genesis/genesis/Enlaces/InformesHosp_abc.htm [Accessed 16 December2015].

Vianello A, Arcaro G, Battistella L, Pipitone E, Vio S, Concas A, Paladina L, Gallan F, Marchi MR, Tona F,Iliceto S (2014) Noninvasive ventilation in the event of acute respiratory failure in patients withidiopathic pulmonary fibrosis. Journal of Critical Care, 29(4), 562–67<DOI>10.1016/j.jcrc.2014.03.019</DOI>.

Xaubet A, Ancochea J, Bollo E, Fernandez-Fabrellas E, Franquet T, Molina-Molina M, Montero MA,Serrano-Mollar A (2013) Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis.Available from:http://www.archbronconeumol.org/index.php?p=watermark&idApp=UINPBA00003Z&piiItem=S1579212913001067&origen=bronco&web=bronco&urlApp=http://www.archbronconeumol.org&estadoItem=S300&idiomaItem=en [Accessed 16 December 2015].

Yokoyama T, Kondoh Y, Taniguchi H, Kataoka K, Kato K, Nishiyama O, Kimura T, Hasegawa R, Kubo K(2010) Noninvasive ventilation in acute exacerbation of idiopathic pulmonary fibrosis. InternalMedicine, 49(15), 1509–14 <PMID>20686281</PMID>.


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Idiopathic pulmonary fibrosis Disease Coverage | Epidemiology:Idiopathic Pulmonary Fibrosis DMKC12770


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Epidemiology: Idiopathic Pulmonary Fibrosis Executive Summary Disease background

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible fibrosing interstitial pneumonia of

unknown origin characterized by an underlying histopathological pattern of usual interstitial

pneumonia.

IPF typically occurs in middle-aged to older adults and is associated with high morbidity and

mortality. The median survival of patients diagnosed with IPF ranges from three to five years, and an

individual’s prognosis is difficult to predict at diagnosis.

While IPF is a rare disease, it is the first or second most common interstitial lung disease seen in

pulmonary practices.

Possible risk factors for IPF include gastroesophageal reflux disease, occupational and environmental

exposures, tobacco smoking, and genetic factors. The etiology of the disease remains unknown.

Forecast results Datamonitor Healthcare estimates that in 2015, there were 71,520 incident cases of IPF in the US,

Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). Nearly half of these

cases (44.9%) were in the US alone. By 2035, Datamonitor Healthcare estimates that approximately

101,060 cases of IPF will be diagnosed annually in these markets. As IPF disproportionately affects

the elderly, aging populations in these markets will be responsible for the largest increases in IPF.

More than a third (36.7%) of incident cases in 2015 were in adults aged 75 years and older.

Approximately 56.3% of incident cases in 2015 were in males across the US, Japan, and five major

EU markets (40,240 cases). The proportion ranged from 53.0% to 74.3% depending on the country.

Japan had the smallest number of incident cases of IPF (2,880 cases) in 2015. This disparity may be

due to a combination of ethnic differences and the methods used for diagnosing patients with IPF in

Japan.

In 2015, Datamonitor Healthcare estimates that there were 199,320 prevalent cases of IPF in the US,

Japan, and five major EU markets.

Drivers of patient population Increasing aging populations, particularly adults aged 65 years and older, in the US, Japan, and five

major EU markets will contribute to increasing incident and prevalent IPF patient populations over

the next 20 years.

Improvements in disease definitions and diagnostic criteria for IPF are likely to impact incidence

rates as patients are more likely to be accurately diagnosed.


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Sources and Methodology To provide robust estimates and forecasts for the incidence and prevalence of idiopathic pulmonaryfibrosis (IPF) in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK),studies reporting on the general population prevalence of IPF were searched for in PubMed, GoogleScholar, and reference lists of articles.

As IPF is a relatively rare disease, true population-based studies are challenging and expensive toconduct. As a result, there are a limited number of studies reporting on the prevalence and incidenceof IPF in these markets, none of which are prospective. Changes in definitions of IPF and complexdiagnostic algorithms have also made it challenging to study the disease and compare study findings.Datamonitor Healthcare chose to review and include only studies published after the firstinternational consensus statement on IPF in 2000. Even so, no study truly follows the 2000 and 2011(revision) guidelines where an integrated multidisciplinary approach tends to be warranted in order toconfirm diagnosis. This cannot be completely captured in claims- and hospital records-based studiesdue to the use of retrospective methodologies and non-specific diagnostic and surgical codes. Whenpossible, Datamonitor Healthcare included studies which reviewed subsamples of the population usingmultidisciplinary assessment of patient records.

Details on specific sources used for each country are given in the country-specific sections. Anoverview of sources used is given in the table below.

Table 21: Sources used for idiopathic pulmonary fibrosis data in the US, Japan, and five major EU markets

Market Region Sample size Time period Age (years) Source

US 20 US states 2.2 million* 1996–2000 18+ Raghu et al., 2006

Japan Hokkaido prefecture 5.6 million* 2003–07 All Natsuizaka et al.,

2014

Italy Lazio region 4.7 million* 2005–09 18+ Agabiti et al., 2014

UK Nationally

representative

NS (patients from 446 general practices) 2000–08 40+ Navaratnam et al.,

2011

*Approximate sample size

NS = not specified

Source: various (see above)


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US SOURCE USED

A study by Raghu et al. (2006) was selected to estimate the incidence and prevalence of IPF in the US.Data were obtained from the healthcare claims processing system of a large US health plan from 1January 1996 to 31 December 2000. Claims included in the database are for services provided to planmembers submitted by facilities, healthcare professionals, and retail pharmacies. The plan provideshealthcare services to around 3 million persons living in 20 different states in the US, and nearly 20%of plan members are aged 65 years and older. Data include diagnoses by the InternationalClassification of Diseases, 9th revision, Clinical Modification (ICD-9-CM).

The study sample included all individuals aged 18+ years who were eligible for comprehensive healthbenefits for at least one day of 2000. Persons were established to have a diagnosis of IPF based onone or more medical encounters with an ICD-9-CM 516.3 code (idiopathic fibrosing alveolitis)between 1 January 1996 and 31 December 2000 and no medical encounters with a diagnosis code forany other type of interstitial lung disease on or after the date of their last medical encounter with adiagnosis of IPF. This was considered to be the “broad case definition” of IPF in the study.

As IPF is more accurately diagnosed based on testing (ie high-resolution computed tomography[HRCT], lung biopsy), the authors provided a “narrow case definition” as well. This required individualsto satisfy the broad case definition (described above) and to have had, on or before the date of theirlast medical encounter with a diagnosis of IPF, one or more medical encounters with an ICD-9-CMcode for surgical lung biopsy (33.28, 34.21) or Current Procedural Terminology, fourth edition [CPT-4]code 32095, 32100–32160, 32602; transbronchial lung biopsy (ICD-9-CM 33.27; CPT-4 31628); orcomputed tomography of the thorax (ICD-9-CM 87.41; CPT-4 71250, 71260, 71270) (Raghu et al.,2006). METHODS

It is acknowledged by the study authors that the broad definition for IPF is likely to have includedindividuals who would not have been found to have the disease had consensus statement guidelinesfor IPF diagnosis been applied. For the narrow definition, however, it was noted that surgical lungbiopsy was performed in only a small proportion of patients and ultimately the definition had limitedsensitivity. Because of this, Datamonitor Healthcare epidemiologists suspect that the true prevalenceand incidence lies somewhere in between, and therefore used the average gender- and sex-specificincidence rates to estimate incident and prevalent cases of IPF in the US.

The age- and gender-specific incidence rates were combined with the corresponding age- andgender-specific population estimates from the United Nations (UN) to estimate the number ofincident cases in the 2015–35 forecast period (United Nations, 2013). The UN database was chosen asa reliable population denominator from which to calculate the number of cases: the data includestandard sets of demographic indicators and population by age groups and gender. Japan


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SOURCE USED

A study by Natsuizaka et al. (2014) was selected to estimate the incidence and prevalence of IPF inJapan. This retrospective cohort study was based on the clinical records of patients with IPF who weregiven the Certificate of Medical Benefit (CMB) in Hokkaido prefecture (population: 5.6 million) from 1January 2003 to 31 December 2007. CMBs are issued by the Japanese Ministry of Health, Labour andWelfare to patients who qualify for its medical expense assistance program for diseases of unknowncause, and for diseases for which there is no established treatment. Clinical records, HRCT findings,and the results of pathologic diagnosis (ie lung biopsy) are submitted to the local municipality byphysicians who have made a diagnosis of IPF. Once submitted, a committee of three pulmonologistsexamines each case and grants CMBs to IPF patients who satisfy the diagnostic criteria.

There were 553 patients with IPF included in this study who were identified based on chest HRCTfindings, pathology, and medical records according to the American Thoracic Society/EuropeanRespiratory Society 2000 consensus classification. The cumulative incidence and prevalence rates ofIPF were 2.23 and 10.0 per 100,000 population, respectively, calculated based on July 2008population statistics for Hokkaido (Natsuizaka et al., 2014). METHODS

Natsuizaka et al. (2014) presented age- and gender-specific findings alongside total incidence andprevalence proportions for IPF. Over this period of time, there were no IPF diagnoses in Hokkaidoresidents under the age of 40 years.

Due to a lack of historical data in Japan, incidence proportions were held steady over the forecastperiod. Datamonitor Healthcare combined the age- and gender-specific incidence rates with thecorresponding age- and gender-specific population estimates from the UN to estimate the number ofincident cases in the 2015–35 forecast period (United Nations, 2013). France, Germany, Spain, and the UK SOURCE USED

Datamonitor Healthcare selected a study by Navaratnam et al. (2011) to estimate and forecast theburden of IPF in the UK. To estimate the incidence in the UK, the authors extracted data from TheHealth Improvement Network, a computerized longitudinal primary care database recorded by UKgeneral practitioners as a part of routine clinical care. Patient information is recorded from face-to-face consultations following communication from secondary hospital referrals. The dataset includeddata up until July 2009 from 446 general practices. The Read codes H563.00 (idiopathic fibrosingalveolitis), H563.11 (Hamman-Rich syndrome), H563.12 (cryptogenic fibrosing alveolitis), H563100(diffuse pulmonary fibrosis), and H563z00 (idiopathic fibrosing alveolitis, not otherwise specified[NOS]) were used to identify new diagnoses of what the authors described as "IPF-clinical syndrome(CS)."

Individuals were included in the cohort if they had at least one recorded IPF-CS diagnosis, their firstdiagnosis was recorded at least 12 months after their start date, and they were aged at least 40 years


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when they received their first diagnosis. The age cut-off was used to improve diagnostic specificity.Individuals were excluded if they had one of the following: (1) co-existing diagnosis of connectivetissue diseases, or (2) co-existing diagnosis of extrinsic allergic alveolitis, sarcoidosis, pneumoconiosis,and asbestosis (due to uncertainty about which diagnosis was correct) (Navaratnam et al., 2011). METHODS

Navaratnam et al. (2011) calculated the crude total incidence rates of IPF-CS (per 100,000) annuallyfor the 2000–08 period. Crude incidence rates were also reported by gender, age group, and healthauthority (eg London). Datamonitor Healthcare epidemiologists conducted a trend analysis, usingExcel, based on the nine historical data points. A conservative logarithmic trend was assumed, andincidence rates were projected forward to 2035. Age- and gender-specific ratios calculated from thereported crude incidence rates were assumed to remain constant over the forecast period.

There were no IPF data sources presenting incidence rates for France, Germany, and Spain, thereforeage- and gender-specific incidence rates from the UK were used as a proxy (Navaratnam et al., 2011).These age- and gender-specific incidence rates were then combined with the corresponding age- andgender-specific population estimates from the UN to estimate the numbers of incident cases inFrance, Germany, Spain, and the UK over the forecast period (United Nations, 2013). Italy SOURCE USED

Datamonitor Healthcare epidemiologists selected a recent study by Agabiti and colleagues (2014) toestimate the incidence and prevalence of IPF in Italy. Three databases were used as data sources inthe study, comprising: the regional Hospital Information System (HIS), the regional Mortality Registry,and the Italian National Institute of Statistics database. The HIS database contains admissions recordsfor inpatient and day hospitals, including both private and public hospitals in the Lazio region, allcoded according to the ICD-9-CM. The database contains up to six primary and secondary dischargeICD-9-CM codes and up to six procedure ICD-9-CM codes per patient.

Study subjects were retrospectively identified among the residents (aged 18+ years) of the Lazioregion who were hospitalized in any hospital of the Lazio region for IPF between 1 January 2005 and31 December 2009. In the case of multiple hospitalizations, only the first admission was included inthe study. IPF was defined by a primary or secondary diagnosis with ICD-9-CM 516.3 code.

To test the reporting accuracy of IPF diagnoses, authors selected a random sample of medical records(n=404) from all hospital admissions in six hospitals in Rome which had the ICD-9-CM codes 516.3,516.8 (other specified alveolar and parieto-alveolar pneumonopathies), 516.9 (unspecified alveolarand parieto-alveolar pneumonopathy), and 515 (post-inflammatory pulmonary fibrosis). Thesehospitals accounted for 24% of all 8,827 hospital admissions during the study period and there wereno significant differences in the distribution of demographic and clinical characteristics between thesubsample and the overall population from the database. Hospital charts were reviewed by a group ofpulmonologists, radiologists, and a pathologist for diagnostic accuracy of IPF/usual interstitial


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pneumonia (UIP). Reviewers assigned a degree of confidence to the diagnosis of IPF/UIP as either“confident” (ie HRCT UIP pattern with or without a UIP pattern on lung biopsy) or “possible” (ie HRCTpossible UIP pattern, if associated with a UIP pattern on lung biopsy) (Agabiti et al., 2014). METHODS

Agabiti et al. (2014) presented the number of prevalent and incident cases of IPF by gender and agefor those hospitalized in the Lazio region between 2005 and 2009. These data were from the totalsample. As the subsample hospital chart records were reviewed by a multidisciplinary team, andtherefore are more in line with current IPF guidelines for diagnosis, Datamonitor Healthcare deemedthe prevalence and incidence proportions from the reviewed hospital charts to be more reliable. As thepatients in the subsample did not differ significantly by age, gender, or co-morbidities, DatamonitorHealthcare used the age- and gender-specific ratios calculated from the incident cases in the totalsample, and applied these to the overall incidence reported for the subsample (9.3 per 100,000).

The age- and gender-specific incidence rates were combined with the corresponding age- andgender-specific population estimates from the UN to estimate the number of incident cases in the2015–35 forecast period (United Nations, 2013). Estimating prevalent cases of idiopathic pulmonary fibrosis US METHODS

Datamonitor Healthcare extracted age- and gender-specific prevalence proportions reported by Raghuet al. (2006), defined by the broad definition, to estimate the prevalence of IPF in the US (seedescription of the data source in the section above). Age- and gender-specific prevalence proportionswere combined with the corresponding age- and gender-specific population estimates from the UN toestimate the number of prevalent cases in the US over the 2015–35 forecast period (United Nations,2013). JAPAN

Natsuizaka et al. (2014) was used to estimate the prevalence of IPF in Japan (description of the studycan be found in the section above). Age- and gender-specific prevalence proportions were estimatedfrom Figure 2b and were then applied to the UN population data for Japan over the forecast period toestimate annual prevalent case numbers (United Nations, 2013). FRANCE, GERMANY, ITALY, SPAIN, AND THE UK

There were no IPF data sources presenting prevalence proportions for France, Germany, Spain, and theUK, therefore age- and gender-specific prevalence proportions for Italy from Agabiti et al. (2014) wereused as a proxy (description of the study can be found in the Italy section above). Age- and gender-specific prevalence proportions were then combined with the corresponding age- and gender-specificpopulation estimates from the UN to estimate the numbers of prevalent cases in France, Germany,Italy, Spain, and the UK over the forecast period (United Nations, 2013).


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Bibliography

Agabiti N, Porretta MA, Bauleo L, Coppola A, Sergiacomi G, Cavalli F, Zappa MC, Vignarola R, CarloneS, Mariotta S, et al. (2014) Idiopathic Pulmonary Fibrosis (IPF) incidence and prevalence in Italy.Sarcoidosis, Vasculitis, and Diffuse Lung Diseases, 31(3), 191–197 <PMID>25363218</PMID>.

Natsuizaka M, Chiba H, Kuronuma K, Otsuka M, Kudo K, Mori M, Bando M, Sugiyama Y, Takahashi H(2014) Epidemiologic Survey of Japanese Patients with Idiopathic Pulmonary Fibrosis andInvestigation of Ethnic Differences. American Journal of Respiratory and Critical Care Medicine,190(7), 773–779 <DOI>10.1164/rccm.201403-0566OC</DOI>.

Navaratnam V, Fleming KM, West J, Smith CJP, Jenkins RG, Fogarty A, Hubbard RB (2011) The risingincidence of idiopathic pulmonary fibrosis in the U.K. Thorax, 66(6), 462–467<DOI>10.1136/thx.2010.148031</DOI>.

Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G (2006) Incidence and prevalence of idiopathicpulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 174(7), 810–816<DOI>10.1164/rccm.200602-163OC</DOI>.

United Nations (2013) World Population Prospects Database: the 2012 Revision (Extended dataset: CDversion).


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Forecast In this chapter, Datamonitor Healthcare presents the results of its epidemiologic analyses of thediagnosed incident and prevalent populations of idiopathic pulmonary fibrosis (IPF) patients in the US,Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). Incident cases aresegmented by age and gender, while prevalent cases are also presented:

diagnosed incident cases of IPF, by country, 2015–35

growth in diagnosed incident cases of IPF, by country, 2015–35

age-specific diagnosed incident cases of IPF, by country, 2015

gender-specific diagnosed incident cases of IPF, by country, 2015

diagnosed prevalent cases of IPF, by country, 2015

growth in diagnosed prevalent cases of IPF, by country, 2015–35

age-specific diagnosed prevalent cases of IPF, by country, 2015.

For a further detailed breakdown of numbers, please consult the accompanying datapack. Diagnosed incident cases of idiopathic pulmonary fibrosis

Datamonitor Healthcare estimates that in 2015, there were 71,520 incident cases of IPFdiagnosed in the US, Japan, and five major EU markets.

The US had the largest number of cases (32,140), which comprised 44.9% of the totalincident cases in these markets.

If the five major EU markets were considered to be a single entity, it would represent themajority of IPF cases across the analyzed markets (51.0%; 36,500 cases).

IPF is rarer in Japan than in the other markets, with only 2,880 incident cases diagnosed in2015. This may be attributable to differences in study methodology, differences in thediagnosis of IPF in Japan, or true ethnic differences between Asian and Western countries.


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Table 22: Diagnosed incident cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EU markets, bycountry, 2015–35

Year US Japan France Germany Italy Spain UK 5EU Total

2015 32,140 2,880 8,120 11,950 5,150 3,440 7,840 36,500 71,520

2016 32,790 2,910 8,340 12,220 5,210 3,500 8,030 37,300 72,990

2017 33,440 2,930 8,560 12,520 5,270 3,550 8,230 38,130 74,500

2018 34,100 2,960 8,780 12,830 5,320 3,610 8,430 38,970 76,030

2019 34,780 2,980 9,010 13,130 5,380 3,680 8,630 39,820 77,590

2020 35,480 3,000 9,230 13,410 5,440 3,740 8,830 40,670 79,150

2021 36,160 3,020 9,440 13,650 5,500 3,810 9,020 41,430 80,610

2022 36,870 3,030 9,640 13,880 5,570 3,890 9,200 42,190 82,090

2023 37,590 3,050 9,850 14,120 5,640 3,970 9,400 42,970 83,610

2024 38,320 3,060 10,070 14,370 5,710 4,050 9,600 43,800 85,170

2025 39,060 3,070 10,300 14,640 5,780 4,140 9,820 44,670 86,790

2026 39,780 3,060 10,520 14,880 5,850 4,220 10,010 45,480 88,320

2027 40,500 3,060 10,750 15,140 5,920 4,300 10,220 46,330 89,890

2028 41,240 3,050 10,980 15,400 6,000 4,390 10,430 47,190 91,480

2029 41,960 3,050 11,210 15,660 6,070 4,470 10,630 48,050 93,060

2030 42,680 3,050 11,420 15,930 6,150 4,570 10,820 48,890 94,610

2031 43,310 3,050 11,580 16,150 6,220 4,650 10,980 49,580 95,940

2032 43,920 3,050 11,720 16,380 6,290 4,750 11,120 50,260 97,240

2033 44,520 3,060 11,860 16,600 6,370 4,840 11,260 50,930 98,510

2034 45,130 3,070 12,000 16,800 6,440 4,930 11,410 51,580 99,780

2035 45,750 3,080 12,150 16,980 6,510 5,030 11,560 52,230 101,060



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THE INCIDENT IPF POPULATION IS PREDOMINANTLY ELDERLY AND MALE

In 2015, Datamonitor Healthcare estimates that the single largest proportion of incidentcases of IPF in the US, Japan, and five major EU markets was in those aged 75+ years (36.7%of total cases).

Table 22: Diagnosed incident cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EU markets, bycountry, 2015–35


5EU = five major EU markets (France, Germany, Italy, Spain, and the UK)

Source: Datamonitor Healthcare; Raghu et al., 2006; Navaratnam et al., 2011; Agabiti et al.,2014; Natsuizaka et al., 2014; United Nations, 2013

Figure 24: Growth in incident cases of diagnosed idiopathic pulmonary fibrosis in the US, Japan, and five major EUmarkets, by country, 2015–35



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There was some variation in the age distribution of incident cases across the US, Japan, andfive major EU markets. The US, France, Germany, Italy, and Spain generally showed anincreasing number of cases with every increasing age group, with the highest number in thoseaged 75+ years. In comparison, the single largest proportion of incident cases of IPF in Japanand the UK was in those aged 65–74 years.

Approximately 56. 3% of incident cases of IPF were in males across the US, Japan, and fivemajor EU markets in 2014 (40,240 cases). Within each country, the proportion of incidentcases of IPF that were male ranged from 53.0% to 74.3%.

The greatest gender difference was seen in Japan: the number of male incident cases of IPFwas more than double that of female incident cases (2,140 vs 740 cases).

Table 23: Age-specific diagnosed incident cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EUmarkets, by country, 2015

Age group US Japan France Germany Italy Spain UK 5EU Total

20–44 1,900 30 220 260 160 140 230 1,000 2,930

45–54 3,670 200 90 150 300 230 100 870 4,730

55–64 8,010 630 1,530 2,130 730 530 1,400 6,320 14,970

65–74 8,170 1,140 3,050 4,330 1,680 1,090 3,180 13,330 22,630

75+ 10,390 880 3,240 5,080 2,280 1,450 2,940 14,990 26,260

Total 32,140 2,880 8,120 11,950 5,150 3,440 7,840 36,500 71,520





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Diagnosed prevalent cases of idiopathic pulmonary fibrosis

In 2015, Datamonitor Healthcare estimates that there were 199,320 diagnosed prevalentcases of IPF in the US, Japan, and five major EU markets.

This number is expected to grow to at least 275,860 cases (38.4% increase) by 2035 due toaging populations in the analyzed markets.

Figure 25: Gender-specific diagnosed incident cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EUmarkets, by country, 2015



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Table 24: Diagnosed prevalent cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EU markets, bycountry, 2015–35


2015 118,360 12,980 13,020 18,900 14,000 9,490 12,560 67,980 199,320

2016 120,950 13,010 13,230 19,090 14,150 9,650 12,740 68,870 202,830

2017 123,570 13,040 13,440 19,310 14,300 9,810 12,910 69,770 206,380

2018 126,280 13,060 13,650 19,540 14,450 9,970 13,080 70,680 210,020

2019 129,090 13,090 13,850 19,770 14,600 10,150 13,240 71,610 213,790

2020 132,020 13,130 14,050 20,010 14,750 10,330 13,410 72,550 217,710

2021 134,990 13,160 14,240 20,230 14,900 10,510 13,580 73,450 221,610

2022 138,100 13,200 14,420 20,460 15,050 10,700 13,750 74,380 225,680

2023 141,290 13,240 14,610 20,680 15,210 10,900 13,930 75,330 229,870

2024 144,520 13,280 14,800 20,900 15,380 11,110 14,120 76,310 234,110

2025 147,780 13,300 15,000 21,110 15,560 11,320 14,310 77,300 238,380

2026 150,960 13,280 15,170 21,300 15,730 11,530 14,480 78,210 242,450

2027 154,160 13,250 15,360 21,480 15,910 11,740 14,670 79,150 246,550

2028 157,350 13,210 15,540 21,660 16,100 11,960 14,850 80,100 250,660

2029 160,510 13,180 15,720 21,830 16,290 12,180 15,030 81,060 254,750

2030 163,590 13,180 15,900 22,020 16,480 12,410 15,210 82,010 258,780

2031 166,320 13,170 16,030 22,170 16,640 12,620 15,370 82,840 262,330

2032 168,930 13,170 16,160 22,340 16,810 12,840 15,520 83,680 265,780

2033 171,470 13,190 16,290 22,500 16,970 13,070 15,670 84,500 269,160

2034 174,020 13,210 16,420 22,630 17,130 13,290 15,810 85,280 272,510

2035 176,620 13,220 16,550 22,710 17,290 13,510 15,950 86,010 275,860



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THE MAJORITY OF PREVALENT IPF CASES ARE IN THOSE AGED 65 YEARS AND ABOVE

Age is a significant risk factor for IPF. In 2015, around two thirds (66.6%) of diagnosed IPFcases were in adults aged 65+ years in the US, Japan, and five major EU markets; the highestproportion of IPF cases was in adults aged 75 years and older (35.6%), followed by those aged65–74 years (31.0%).

Table 24: Diagnosed prevalent cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EU markets, bycountry, 2015–35



Source: Datamonitor Healthcare; Raghu et al., 2006; Agabiti et al., 2014; Natsuizaka et al.,2014; United Nations, 2013

Figure 26: Growth in diagnosed prevalent cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EUmarkets, by country, 2015–35



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In 2015, there were 132,790 diagnosed prevalent cases of IPF in the US, Japan, and five majorEU markets in adults aged 65 years and older.

Bibliography


Natsuizaka M, Chiba H, Kuronuma K, Otsuka M, Kudo K, Mori M, Bando M, Sugiyama Y, Takahashi H(2014) Epidemiologic Survey of Japanese Patients with Idiopathic Pulmonary Fibrosis andInvestigation of Ethnic Differences. American Journal of Respiratory and Critical Care Medicine,190(7), 773–779 <DOI>10.1164/rccm.201403-0566OC</DOI>.


Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G (2006) Incidence and prevalence of idiopathicpulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 174(7), 810–816

Table 25: Age-specific diagnosed prevalent cases of idiopathic pulmonary fibrosis in the US, Japan, and five major EUmarkets, by country, 2015

Age group US Japan France Germany Italy Spain UK 5EU Total

20–44 6,230 510 660 800 680 600 680 3,420 10,160

45–54 9,920 1,560 940 1,520 1,060 790 1,000 5,310 16,790

55–64 22,910 3,630 2,610 3,700 2,490 1,820 2,420 13,040 39,580

65–74 33,840 4,710 4,470 6,190 4,800 3,130 4,590 23,190 61,740

75+ 45,460 2,570 4,340 6,690 4,970 3,150 3,880 23,020 71,050

Total 118,360 12,980 13,020 18,900 14,000 9,490 12,560 67,980 199,320





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<DOI>10.1164/rccm.200602-163OC</DOI>.

United Nations (2013) World Population Prospects Database: the 2012 Revision (Extended dataset: CDversion).


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Epidemiologist Insight Datamonitor Healthcare estimates that there were 71,520 diagnosed incident cases of idiopathicpulmonary fibrosis (IPF) in the US, Japan, and five major EU markets (France, Germany, Italy, Spain,and the UK) in 2015, with nearly half of these (44.9%) occurring in the US. As highlighted earlier, IPFis a disease associated with increasing age and the elderly. Therefore, the growing elderly populationsin the analyzed markets over the next 20 years will contribute to an increasing number of annual IPFdiagnoses. Datamonitor Healthcare estimates that in 2015, over a third (36.7%) of cases were aged75+ years, and over two thirds (68.4%) were aged 65 years and older. By 2035, there will be anestimated 101,060 diagnosed incident cases of IPF in these markets.

In the same analyzed markets, there were an estimated 199,320 diagnosed prevalent cases of IPF in2015. Over time, the number of prevalent cases is expected to grow as a function of populationdynamics, specifically a growing elderly population, to approximately 275,860 in 2035. The epidemiology of IPF could change significantly over the next decade

The majority of epidemiological studies currently available that estimate the incidence and prevalenceof IPF have many limitations related to differing methodologies and disease diagnoses. Thesedifferences have led to wide variations in incidence and prevalence estimates, making it challengingto know the true burden of IPF in each country and worldwide. Datamonitor Healthcare predicts thatover the next five to 10 years, researchers will aim to incorporate the diagnostic criteria from the firstinternational consensus statement on IPF (2000) and the revision statement (2011). Both of theseemphasize the importance of multidisciplinary efforts to achieve accurate IPF diagnoses. Ideally,mandatory clinical registries would be initiated in each country, with standardized definitions for IPFand data collection protocols, which would enable researchers to track IPF trends more effectively.Until then, however, researchers should use a combination of International Classification of Diseases-10 codes to initially define the IPF patient sample, and patient data review by multidisciplinary teamsfor diagnostic accuracy, which has only been done in a few studies to date (Agabiti et al., 2014;Fernández Pérez et al., 2010). More country-specific studies are needed to achieve accurate patient number estimates

Datamonitor Healthcare found a very limited number of studies estimating the incidence andprevalence of IPF, many of which did not use the same diagnostic criteria or methodologies.Additionally, there were only studies available for the US, Japan, Italy, and the UK, meaning that datafrom Italy and the UK had to be extrapolated to the other European markets. Most of the limitedstudies available for IPF look at the US and several European markets, which leaves a large gap inknowledge about the epidemiology of IPF in the rest of the world. Studies looking at the epidemiologyof IPF in other parts of the world are needed, particularly as the etiology of the disease remains to beelucidated.

Overall, newer, more methodologically consistent and geographically diverse epidemiological studiesare needed in IPF. Until then, national estimates will continue to be derived from incidence andprevalence proportions reported in older studies of limited geographic area, which may not be


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applicable to all markets. Bibliography


Fernández Pérez ER, Daniels CE, Schroeder DR, St Sauver J, Hartman TE, Bartholmai BJ, Yi ES, Ryu JH(2010) Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis a population-basedstudy. Chest, 137(1), 129–137 <DOI>10.1378/chest.09-1002</DOI>.


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Strengths and Limitations Varying definitions likely impacted the comparability of IPF burden between countries

Ideally, Datamonitor Healthcare would have selected studies which used the same disease definitionand diagnostic criteria to allow for direct comparison of idiopathic pulmonary fibrosis (IPF) burden ineach market. This was the rationale behind only reviewing studies which were published later than2001, after the 2000 American Thoracic Society/European Respiratory Society consensus statementfor the diagnosis and treatment of IPF was published. Despite this parameter, there were limitedstudies which used or referred to the consensus statement as a basis for identifying the IPF patientpopulation. For example, a very recent study by Raghu et al. (2014) looking at US Medicarebeneficiaries aged 65 years and older did not use these guidelines to identify the IPF population. Thisstudy was not included in Datamonitor Healthcare’s analysis, but it demonstrates the persisting lackof uniform diagnostic guidelines and criteria used in epidemiological studies.

The study populations in the US, Italy, and UK studies were from patient databases where researchersidentified the IPF population based on diagnostic codes. There are many potential sources of biasrelated to disease diagnostic codes including misclassification, misdiagnosis, and coding errors. Anadditional source of bias, specific to IPF, is that up until 2013 there was no diagnostic code whichdifferentiated IPF from other interstitial lung diseases.

In the US, Raghu et al. (2006) tried to account for the inherent biases associated with IPF diseasecodes by including a broad definition and a narrow definition of IPF. The true estimate is likelysomewhere in between the two definitions, meaning that the incidence and prevalence of IPF remainunknown (Raghu et al., 2006). In the UK, authors used the term "IPF clinical syndrome" to describeindividuals with IPF in the study. This likely includes patients with other diagnoses; however, theauthors felt this to have limited impact on patient estimates (Navaratnam et al., 2011). In Italy, themethodologies were improved and the authors analyzed a subsample of the originally identified IPFpatient population. Each patient record included in the subsample was reviewed by a multidisciplinaryteam for diagnostic accuracy (Agabiti et al., 2014). Population-based, cross-sectional studies are not ideal samples for rare diseases

While the goal is to use studies that are population-based and representative of a particular market,this is not always the ideal study design for estimating the prevalence of rare diseases. Surveys suchas the US National Health and Nutrition Examination Survey are excellent cross-sectional surveys thatmany researchers analyze to estimate the point prevalence of major diseases and risk factors. Thesesurveys are aimed to be nationally representative of the total population and typically include asample of 5,000 persons. However, this sample size is too small to estimate the prevalence of IPF, andother rare diseases, as it will likely not capture any cases of the disease and lacks precision.Additionally, cross-sectional surveys are not ideal for diseases of short duration, which also pertains toIPF (as median survival is three to five years). The ideal data source would be (mandatory) clinicalregistries in each country using standardized definitions and methodologies. This would enableresearchers to analyze disease trends over time and allow for comparability between individualregistries and countries.


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Retrospective studies may overestimate the incidence and trends of IPF

As described above, cross-sectional studies are not ideal for rare diseases and those with a shortduration. This is why the majority of researchers analyze healthcare databases to estimate IPFincidence and prevalence. These studies are retrospective, meaning the data were collected in the pastand studied at a later time point, and therefore it is sometimes difficult to determine incident versusprevalent cases. Annual incidence is the number of new cases diagnosed in one year, and this numbercan be overinflated when the denominator (ie study sample) is not correctly defined.

Moreover, other factors can contribute to observed increases in incidence trends over time. Theseperceived increases may be due to improved diagnostics and healthcare systems and not actually dueto increasing disease trends. In the UK study, the incidence of IPF increased over the last decade(Navaratnam et al., 2011). Datamonitor Healthcare estimated conservative increases in incidence ratesover time based on these possible biases. Bibliography



Raghu G, Chen S-Y, Yeh W-S, Maroni B, Li Q, Lee Y-C, Collard HR (2014) Idiopathic pulmonary fibrosisin US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11.The Lancet Respiratory Medicine, 2600(14), 1–7 <DOI>10.1016/S2213-2600(14)70101-8</DOI>.

Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G (2006) Incidence and prevalence of idiopathicpulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 174(7), 810–816<DOI>10.1164/rccm.200602-163OC</DOI>.


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Idiopathic pulmonary fibrosis Disease Coverage | Marketed Drugs:Idiopathic Pulmonary Fibrosis DMKC12770


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Marketed Drugs: Idiopathic Pulmonary Fibrosis Executive Summary Esbriet’s demonstrated mortality benefit gives it an

advantage

Both Esbriet (pirfenidone; Roche/Shionogi) and Ofev (nintedanib; Boehringer Ingelheim) have

demonstrated the ability to slow the decline in forced vital capacity commonly observed in

idiopathic pulmonary fibrosis (IPF) patients. However, pooled trial results showed that only Esbriet

was able to significantly reduce the risk of mortality associated with the disease. Although Ofev

performed better in terms of reducing acute exacerbations, Esbriet’s validated survival benefit gives

it a slight edge in terms of efficacy.

Side-effect profiles, dosing frequency, and disease

severity may influence treatment patterns

Given that both drugs have shown comparable efficacy, pulmonologists may rely more on other

factors to guide their treatment decisions. Esbriet and Ofev both induce significant gastrointestinal

(GI) side effects. While GI side effects occur more often with Ofev, Esbriet also causes skin reactions

in some patients. Therefore, patient history and predisposition for certain side effects could help

inform choice of therapy. Furthermore, the dosing frequency and pill burden of Esbriet is much

higher, which could lead some pulmonologists and patients to prefer Ofev. Lastly, due to clinical trial

design, Ofev’s Phase III study population was slightly milder in severity than Esbriet’s, meaning

disease severity could also potentially influence treatment selection.

Further studies will help expand the clinical and

commercial potential of both drugs

The continued assessment of Esbriet and Ofev in multiple ongoing clinical trials will likely lead to the

expanded use of both products. The most significant of these is a clinical trial studying the use of

Ofev as an add-on treatment to Esbriet. Success in this trial would expand Ofev’s patient share by

giving it access to patients currently treated with Esbriet. Esbriet could also see expanded use as a

result of this trial in patients who continue treatment with the combination after disease

progression on Esbriet monotherapy, or in new patients with more severe IPF who urgently need to

halt disease progression.

First-to-market status will help Esbriet over the

short term, but generic competition may hinder

long-term success

Although Esbriet and Ofev were approved simultaneously in the US, Esbriet’s first-to-market status

in the EU and Japan will provide it with a significant commercial advantage in these markets.

Furthermore, the experience that pulmonologists have with Esbriet in other regions may influence

prescribing patterns in the US. However, Esbriet’s primary patents have already expired, and orphan

drug exclusivity will only provide protection until 2018 (Japan) and 2021 (US and EU). Despite being

granted several supplemental patents, Roche is still likely to face significant pressure from generic

competitors attempting to enter the IPF market.


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Product Overview Key marketed drugs for idiopathic pulmonary fibrosis

Table 26: Key marketed drugs for idiopathic pulmonary fibrosis

Brand Molecule Originator

company

Partner Approval date US Approval date EU Approval date

Japan

Esbriet pirfenidone Roche Shionogi October 2014 February 2011 October 2008

Ofev nintedanib Boehringer

Ingelheim

n/a October 2014 January 2015 n/a

Source: BioMedTracker, Copyright 2015, reprinted with permission; Pharmaprojects ®, 2015;Citeline


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Product profile: Esbriet PRODUCT PROFILE Analyst Outlook

As the first therapy to be approved for the treatment of idiopathic pulmonary fibrosis (IPF), Esbriet(pirfenidone; Roche/Shionogi) will likely continue to be the market leader, despite the entrance ofcompeting therapy Ofev (nintedanib; Boehringer Ingelheim). Both treatments have demonstrated theability to slow decay in IPF patients’ forced vital capacity (FVC), but only Esbriet has been shown tosignificantly reduce the risk of all-cause mortality. Nonetheless, the lack of any additional approvedtreatments will mean that both drugs will see substantial uptake, and are likely to be usedsequentially or even concomitantly. Drug Overview

Esbriet is a pyridone analog, which has demonstrated anti-fibrotic, anti-inflammatory, andantioxidant properties. Because of its wide range of activity, the exact mechanism by which Esbrietworks in IPF is not certain. However, the drug’s anti-fibrotic effects are mainly attributed to its abilityto suppress transforming growth factor beta, which induces the proliferation of fibroblasts and causesthe excessive synthesis of collagen. Additionally, Esbriet’s anti-inflammatory traits are thought tostem from its inhibition of tumor necrosis factor alpha, an inflammatory cytokine. As an antioxidant,the drug has demonstrated the capability to reduce the production of reactive oxygen species, whichcan cause cellular injury and further stimulate inflammatory and fibrotic processes (Kim and Keating,2015; Takeda et al., 2014). Other cytokines and growth factors modulated by Esbriet that maycontribute to the drug’s effects in IPF include basic fibroblast growth factor, platelet-derived growthfactor, interleukin-1 beta, interleukin-6, interleukin-10, interleukin-12p40, interleukin-18, stromalcell-derived factor-1 alpha, interferon gamma, and monocyte chemoattractant protein-1 (Gan et al.,2011).


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DEVELOPMENT OVERVIEW

In 1997, Shionogi acquired the rights to develop Esbriet in Japan, Korea, and Taiwan from Marnac and

Table 27: Esbriet drug profile

Molecule pirfenidone

Mechanism of action Antifibrotic

Originator Marnac

Marketing company Roche/Shionogi

Approved indication IPF

Contraindications n/a

Formulation Oral

Pricing strategy Approximately $260 per day

Dosing frequency 801mg three times daily

First approval date for IPF October 2014 (US), February 2011 (5EU), October 2008 (Japan)

Primary patent expiry October 2021 (US)*, February 2021 (5EU)*, October 2018 (Japan)*

Geographic availability US, 5EU, Japan

Alternative names Pirespa (Japan), S-7701, RG6062

2014 global total brand sales $99m**

*Dates represent the end of orphan drug market exclusivity in each region, as Esbriet’s primary patents have already expired.

**2014 sales only include sales reported by Roche in the three months following its acquisition of InterMune and sales reported by Shionogi in

Japan.


Source: Datamonitor Healthcare; BioMedTracker, Copyright 2015, reprinted with permission;Esbriet prescribing information, 2015; Medtrack, October 2015, Copyright Informa UK;Pharmaprojects ®, 2015; Citeline; Roche financial report, 2014; Shionogi annual report, 2015


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KDL (Shionogi press release, 2012). The rights to develop Esbriet in all other markets were licensed toInterMune in 2002 (InterMune 10k, 2012). In 2014, Roche and InterMune reached a mergeragreement in which Roche would fully acquire InterMune for $8.3bn (Roche press release, 2014).

Esbriet was first approved in Japan in October 2008, based on the results of Phase II and Phase IIIstudies in Japanese patients (MHLW, 2008; Shionogi press release, 2012). InterMune was grantedmarketing approval for the drug in the EU in February 2011, based on the results of the Phase IIICAPACITY 1 and 2 trials (EMA, 2015). These same trials were the basis of a New Drug Application(NDA) in the US in 2009. However, because one of the two trials failed to reach its primary endpoint,the US Food and Drug Administration issued InterMune with a complete response letter requestingthat an additional Phase III trial be conducted (InterMune Schedule 14D-9, 2014). After completingthe Phase III ASCEND trial, InterMune resubmitted its NDA for Esbriet in May 2014, and the drugsubsequently gained approval in October 2014 (FDA, 2014). Pivotal trial data

Pivotal trial data that supported approvals of Esbriet in the US, Japan, and EU are summarized in thetable below. See the Appendix section for a comparison of Esbriet’s and Ofev’s Phase III trials in IPF.


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Table 28: Esbriet’s pivotal trial data in idiopathic pulmonary fibrosis

Trial Sample size Target patients Dosing tested and Results Reference

ASCEND

(NCT01366209)

(Phase III)

555 Mild to moderate IPF patients

(FVC 50–90% of predicted;

DLCO 30–90% of predicted)

Arm 1: Esbriet 2,403mg per

day

Arm 2: placebo

Duration: 52 weeks

Percentage of patients

experiencing FVC decline of

≥10% or death*:

Arm 1: 16.5%

Arm 2: 31.8%;

Mean decline from baseline in

FVC*:

Arm 1: 235ml

Arm 2: 428ml;

Percentage of patients with a

decrease of 50m or more in

6MWT distance:

Arm 1: 25.9%

Arm 2: 35.7%;

All-cause mortality:

King et al., 2014


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Arm 1: 4.0%

Arm 2: 7.2%

(Not significant; p=0.10)


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CAPACITY 1

(NCT00287729)

(Phase III)





day

Arm 2: placebo

Duration: 72 weeks

Mean change in predicted

FVC*:

Arm 1: -9.0%

Arm 2: -9.6%

(Not significant; p=0.501);

Mean change in 6MWT

distance:

Arm 1: -45.1m

Arm 2: -76.9m;



6MWT distance:

Arm 1: 33.1%

Arm 2: 46.7%

Noble et al., 2011


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CAPACITY 2

(NCT00287716)

(Phase III)





day


day

Arm 3: placebo

Duration: 72 weeks


FVC*:

Arm 2: -8.0%

Arm 3: -12.4%;

Mean change in 6MWT

distance:

Arm 2: -60.4m

Arm 3: -76.8m




6MWT distance:

Arm 2: 36.5%

Arm 3: 47.1%

Noble et al., 2011


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SP3

(Phase III)

275 IPF patients (oxygen

desaturation of ≥5%

difference between resting

SpO2 and the lowest SpO2

during a 6MET; lowest SpO2

during the 6MET of ≥85%

while breathing air)


day


day

Arm 3: placebo

Duration: 52 weeks

Mean change in VC*:

Arm 1: -90ml

Arm 2: -80ml

Arm 3: -160ml

Taniguchi et al., 2010

SP2

(Phase II)

107 IPF patients (PaO2 ≥70mmHg;

SpO2 ≤90% during exertion

while breathing air)

Arm 1: Esbriet 600mg per day

for the first two days,

1,200mg per day for the

following two days, and then


remainder of the study (as

tolerated)

Arm 2: placebo

Duration: 39 weeks

Mean change from baseline in

lowest SpO2 during 6MET*:

Arm 1: +0.47%

Arm 2: -0.97%


Mean change in VC:

Arm 1: -30ml

Arm 2: -130ml

Azuma et al., 2005


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*Primary endpoint

6MET = six-minute steady-state exercise test; 6MWT = six-minute walk test; DLCO = diffusion capacity of the lung for carbon monoxide; FVC = forced vital capacity; IPF = idiopathic

pulmonary fibrosis; PaO2 = partial pressure of arterial oxygen; SpO2 = oxygen saturation measured by pulse oximetry; VC = vital capacity



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PHASE III CAPACITY TRIALS DEMONSTRATED MIXED RESULTS

The conflicting results of Esbriet’s two registrational trials in IPF are difficult to explain, but the drug’soverall body of evidence supports its use in IPF. In CAPACITY 2, Esbriet provided a significantimprovement in predicted FVC decline in comparison to placebo; however, this result was notreplicated in CAPACITY 1. The primary endpoint analysis in the CAPACITY 1 trial was impacted by theirregular performance of the trial’s placebo arm, which is likely due to the heterogeneous nature of IPFdisease progression.

Apart from the addition of a low-dose arm in CAPACITY 2, the two concurrent trials had the samedesign, and baseline demographics of patients in each trial arm were relatively consistent across bothstudies. One exception was the mean baseline six-minute walk test (6MWT) distance, which was lowerin both arms of the CAPACITY 1 trial (378.0m and 399.1m) than all three arms of the CAPACITY 2 trial(417.5m, 411.1m, and 410.0m). However, the placebo arm of CAPACITY 1 actually performed muchbetter than that of CAPACITY 2, largely disqualifying the differences in baseline 6MWT distance as anexplanation for the diverging trial outcomes. Additionally, a higher percentage of patients in theCAPACITY 1 trial were using supplemental oxygen, but it is likely that this would only have had aminor impact on the differences observed between study control arms (Noble et al., 2011).

Irrespective of the performance of each control group, a comparison of the treatment arms of the twotrials showed that the FVC decline in patients receiving Esbriet was similar across the CAPACITY trialsand was consistent with the previously reported results of Shionogi’s trials in Japanese patients. Thisboosts confidence in the drug’s efficacy, despite the failure of CAPACITY 1 to meet its primaryendpoint (Richeldi and du Bois, 2011). Ongoing late-phase trials

Ongoing late-phase trials are summarized in the table below.


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Table 29: Esbriet ongoing late-phase clinical trials in idiopathic pulmonary fibrosis

Trial Sample size Target patients Dosing Primary endpoints Study start/primary completion

date

RECAP

(NCT00662038)

(Phase III)

603 IPF patients who have completed

either CAPACITY study

Arm 1: Esbriet 2,403mg per day Adverse events August 2008/December 2015

RIFF

(NCT01872689)

(Phase II)

300 IPF patients (FVC ≥40% of predicted;

DLCO 25–90% of predicted; 6MWT

distance ≥100m)

Arm 1: lebrikizumab monotherapy

Arm 2: placebo monotherapy

Arm 3: lebrikizumab plus Esbriet

Arm 4: placebo plus Esbriet

Absolute change from baseline in

predicted FVC

October 2013/May 2017

6MWT = six-minute walk test; DLCO = diffusion capacity of the lung for carbon monoxide; FVC = forced vital capacity; IPF = idiopathic pulmonary fibrosis

Source: ClinicalTrials.gov


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SWOT ANALYSIS

Figure 27: Esbriet for idiopathic pulmonary fibrosis – SWOT analysis

Source: Datamonitor Healthcare; King et al., 2014; Raghu et al., 2015


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CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figure below depicts Datamonitor Healthcare’s drug assessment summary for Esbriet in IPF.

The figure below provides a breakdown of how Datamonitor Healthcare scored Esbriet’s clinical andcommercial attractiveness. The weighting given to each attribute is also shown.

Figure 28: Datamonitor Healthcare’s drug assessment of Esbriet for idiopathic pulmonary fibrosis



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Pooled results of Esbriet’s clinical trials support its use in IPF

Although the results of Esbriet’s individual trials indicate its efficacy in IPF patients, pooled results ofthe drug’s major studies offer more concrete evidence of its benefits. A meta-analysis of the ASCEND,CAPACITY 1, CAPACITY 2, SP3, and SP2 trials showed Esbriet significantly slowed FVC decline incomparison to placebo (odds ratio [OR] = 0.62) (Loveman et al., 2015). Furthermore, in the ASCENDand CAPACITY trials, Esbriet demonstrated the ability to lower the one-year risk of all-cause mortalityby 48% versus placebo (hazard ratio = 0.52; p=0.01) (King et al., 2014). These pooled results overridethe negative impact of the large Phase III CAPACITY 1 study failing to meet its primary endpoint.Furthermore, data provided by these studies have led to Esbriet earning a “conditionalrecommendation” for use in IPF patients in the 2015 American Thoracic Society/European RespiratorySociety/Japanese Respiratory Society/Latin American Thoracic Association guidelines (Raghu et al.,2015). Esbriet and Ofev both offer improvements in outcomes, but in differing endpoints

Esbriet and direct competitor Ofev have both shown themselves to be clinically beneficial treatmentsfor IPF patients. However, which drug is more effective appears to depend on which measurement ofefficacy is used. Pooled analyses of each drug’s relevant trials show that Esbriet was significantlyassociated with a reduction in all-cause mortality (p=0.01), whereas Ofev significantly reduced theoccurrence of confirmed or suspected acute exacerbations (p=0.005) (Boehringer Ingelheim pressrelease, 2014; King et al., 2014). Additionally, both drugs demonstrated the ability to significantlyslow FVC decline. However, when indirectly comparing respective pooled data for each drug usingplacebo as the common comparator, results indicated that Ofev was statistically superior to Esbriet in

Figure 29: Datamonitor Healthcare’s drug assessment of Esbriet for idiopathic pulmonary fibrosis



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slowing FVC decline (OR = 0.67) (Loveman et al., 2015). Although results of indirect comparisons mustbe approached cautiously due to differences in trial inclusion criteria, patient demographics, andendpoint calculations, the lack of any head-to-head trials between the two drugs necessitates suchcomparisons in order to assist with treatment decisions. See the Appendix section for a comparison ofEsbriet’s and Ofev’s Phase III trials in IPF.

While all-cause mortality may seem to be the most important and overarching outcome that all IPFtreatments should seek to improve, levels of efficacy based on other endpoints are certainly still worthconsideration. Change in FVC has been proven to have a strong association with mortality and hasbecome a common surrogate endpoint for both disease progression and mortality in IPF trials as aresult (Zappala et al., 2010). As FVC decline was used as the primary endpoint in Phase III trials ofboth Esbriet and Ofev, these individual studies were powered to show differences in this endpoint, notmortality. Additionally, acute exacerbations have proven to be difficult to predict and treat, so theprevention of these episodes is an important improvement to track, especially given that theoccurrence of acute exacerbations has also been shown to be quite closely associated with mortality(reported 60% mortality rate in the month following an acute exacerbation) (Juarez et al., 2015).Therefore, Ofev’s demonstrated efficacy in terms of FVC decline and the incidence of acuteexacerbations may translate to benefits in all-cause mortality, despite this endpoint not havingreached statistical significance in the INPULSIS trials. Side-effect profiles may help to differentiate Esbriet and Ofev

Because there is no clear leader in terms of efficacy, small differences in the side-effect profiles ofEsbriet and Ofev may help guide treatment decisions in IPF patients. While these factors will notmandate the use of one drug over the other, they may influence patient or physician preference.

In terms of tolerability, both Esbriet and Ofev primarily cause gastrointestinal (GI) side effects.Although Ofev is associated with a much higher rate of diarrhea, Esbriet also demonstrates skin-related side effects that were not observed with Ofev. In the CAPACITY trials, the most commonadverse events associated with Esbriet were (Esbriet versus placebo): nausea (36% versus 17%), rash(32% versus 12%), dyspepsia (19% versus 7%), dizziness (18% versus 10%), vomiting (14% versus4%), and photosensitivity reaction (12% versus 2%) (Noble et al., 2011). On the other hand, the mostcommon side effects associated with Ofev in the INPULSIS trials were (Ofev versus placebo): diarrhea(62% versus 18%), nausea (25% versus 7%), and vomiting (12% versus 3%) (Richeldi et al., 2014).When considering more serious adverse events, both drugs also caused elevations in the level ofalanine or aspartate aminotransferase (of more than three times the upper limit of normal) in 3–5%of patients.

The rate of treatment discontinuation due to adverse events was slightly higher for patients receivingOfev, with 19% of patients discontinuing Ofev in the INPULSIS trials and 15% of patientsdiscontinuing Esbriet in the CAPACITY trials (Noble et al., 2011; Richeldi et al., 2014). The severity ofthe side effects associated with both drugs have been shown to be reduced by administering doses inconjunction with meals, temporarily interrupting treatment, or reducing daily dosages. Furthermore, itis recommended that patients taking Esbriet initiate treatment with a 14-day titration period and


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avoid sun exposure to reduce the risk of adverse events (Costabel et al., 2014). Similarly, the sideeffects of Ofev can be mitigated by supplementing with antidiarrheals such as loperamide, or anti-emetics such as metoclopramide (Ofev, 2015). Esbriet’s higher pill burden could affect patient compliance in the real-world setting

Although it did not prove to be a large issue in clinical trials, Esbriet is at a considerable disadvantageto Ofev when it comes to dosing frequency and pill burden. In the US and EU, the suggested dose ofEsbriet is 801mg three times daily. The drug is dispensed in 267mg capsules, requiring patients to takenine capsules a day (Esbriet prescribing information, 2015). In contrast, Ofev is dosed at 150mg twicedaily, requiring only two capsules per day (Ofev prescribing information, 2015). Mean compliance inpatients receiving the approved dose of Esbriet in the CAPACITY trials was 90% versus 97% inpatients receiving Ofev in the INPULSIS trials (CDER, 2014a; CDER, 2014b). While the level of patientcompliance for Esbriet does not appear to be a major issue based on the rates seen in late-phasestudies, compliance outside of clinical trials is likely to be lower, potentially impacting the efficacy ofthe drug in the real-world setting. First-to-market status gives Esbriet a commercial advantage outside of the US

The approval of Esbriet in the five major EU markets (France, Germany, Italy, Spain, and the UK) andJapan well ahead of Ofev will provide Esbriet with a large commercial advantage in these markets. In2008, Shionogi gained approval for Esbriet in Japan based on the results of the Phase II SP2 and PhaseIII SP3 trials (MHLW, 2008; Shionogi press release, 2012). Subsequently, InterMune gained approvalfor Esbriet in the EU in 2011 based on the CAPACITY trials (EMA, 2015). Initial uptake of Esbriet inthese regions was substantial because it was the only approved treatment. Although approval in theUS was granted at the same time as Ofev, Esbriet’s extensive use for IPF in other geographies willpositively influence uptake in the US market as well. The use of Esbriet will be influenced by disease severity

The design of Esbriet’s clinical trials may moderately diminish its usage in patients with severe or mildIPF. The ASCEND and CAPACITY trials all excluded patients with an FVC of <50% of predicted, who aretypically considered to have severe disease. The trials also excluded patients with an FVC of >90% ofpredicted, making certain mild patients ineligible for treatment as well. Because of this, somepulmonologists and reimbursement bodies may be hesitant to prescribe or reimburse Esbriet for thesepopulations. For example, in the UK, the National Institute for Health and Care Excellence onlyrecommends that Esbriet be used in patients with an FVC between 50% and 80% of predicted, statingthat this group of patients was most clinically relevant for treatment (NICE, 2015). Additionally, theaverage baseline predicted FVC was higher in Ofev’s INPULSIS trials than in Esbriet’s ASCEND andCAPACITY trials (INPULSIS: 79.6%; CAPACITY: 74.7%; ASCEND: 68.2%), potentially leading somepulmonologists to prefer Ofev over Esbriet in patients with milder disease severity (King et al., 2014;Noble et al., 2011; Richeldi et al., 2014). See the Appendix section for a comparison of Esbriet’s andOfev’s Phase III trials in IPF.

Despite these factors, Esbriet will still gain significant uptake in both mild and severe patients due to


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the dearth of effective treatments for IPF. Furthermore, the use of Esbriet in severe patients will likelyincrease as real-world evidence demonstrating the drug’s efficacy in this population continues to becollected. Multiple observational studies have concluded that Esbriet is generally well tolerated inpatients with severe IPF and may also have a similar effect on FVC decline as observed in moderate IPFpatients (Harari et al., 2015; Ogura et al., 2015a). The study of Esbriet in various combinations increases the drug’s long-term potential

As the first approved drug for IPF, many other therapies will likely be tested alongside Esbriet in orderto find synergistic combinations that provide improved outcomes for IPF patients. The success of thesecombinations would help maximize Esbriet’s market penetration, especially in more severe patientswho are in urgent need of effective options and who would be willing to deal with increased sideeffects of treatment.

The most prominent therapy being tested with Esbriet is competing IPF treatment Ofev. The uniquemechanisms of action of the two drugs will undoubtedly elicit the use of these two therapiessequentially; however, it has also sparked an interest in exploring their safety and efficacy when usedin tandem. Concerns of compounded toxicities, namely GI side effects, have slowed the clinicaldevelopment of the combination. Nonetheless, preclinical studies in animal models showed theconcurrent administration of low-dose Esbriet and Ofev did not affect either drug’s pharmacokineticprofile (Pan et al., 2015; Ramesh et al., 2014). Furthermore, a short, one-month trial testing theaddition of Ofev to treatment with Esbriet in 50 Japanese IPF patients showed the combination didnot produce any severe adverse events (Ogura et al., 2015b). A much longer Phase II safety studytesting Ofev as an add-on to Esbriet is currently underway (ClinicalTrials.gov identifier:NCT01417156).

Another combination that has garnered some attention in the treatment of IPF is the addition of N-acetylcysteine (NAC) to Esbriet. While the use of NAC, as a monotherapy or in combination withprednisone and azathioprine, was largely ruled to be ineffective by the PANTHER study, theantioxidant continues to be tested in combination with Esbriet (Martinez et al., 2014). A small casestudy of 34 IPF patients suggested the addition of inhaled NAC to treatment with Esbriet resulted in areduction of FVC decline and prolonged progression-free survival (Sakamoto et al., 2015). However,this study was underpowered and the baseline demographics of the study populations may have beenskewed in favor of the NAC plus Esbriet treatment group. The Phase II PANORAMA study found theaddition of oral NAC to Esbriet was relatively well tolerated, but had a potentially negative effect onFVC (Behr et al., 2015). Further studies are necessary to find if particular subgroups of patientsrespond more to treatment, and whether there is a difference between supplementing Esbriet withoral or inhaled NAC (Velez and Nambiar, 2015).

Additionally, Roche will test its own pipeline IPF therapy lebrikizumab in combination with Esbriet.Lebrikizumab’s Phase II trial will feature four arms: lebrikizumab monotherapy, placebo monotherapy,lebrikizumab plus Esbriet, and placebo plus Esbriet. The study will be more inclusive in its range of IPFpatients than the ASCEND and CAPACITY trials, including patients with predicted FVC of ≥40%.However, patients in the Esbriet trial arms will only be included if they have demonstrated the ability


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to tolerate Esbriet for at least four weeks prior to randomization (ClinicalTrials.gov identifier:NCT01872689). Generics and reformulations will provide substantial competition

As Esbriet’s primary composition patent expired in 2011, the drug will be highly targeted bycompanies developing generic or reformulated pirfenidone. Roche’s only guaranteed protection fromgeneric competitors lies in Esbriet’s orphan drug exclusivity, which will expire in Q4 2018 (Japan), Q12021 (EU), and Q4 2021 (US). However, Roche has been granted several method of use patents whichit will try to use to protect Esbriet through to 2030. These patents cover the methods for dosingtitration upon initiation of therapy, usage in patients who develop elevated liver transaminase levels,managing the effect of food on drug pharmacokinetics, concomitant administration withciprofloxacin, and management of drug interactions with smoking or fluvoxamine (Medtrack, October2015, Copyright Informa UK). While this patent cluster will make it harder for generics to enter themarket, it is likely that competitors will still attempt to launch their products by carving out parts ofEsbriet’s label. Even if “skinny labelled” generics are permitted by regulatory authorities, these methodof use patents will, at the very least, provide Roche with a basis for patent infringement suits, whichcould delay entry of generic competitors significantly.

In addition to generics, Esbriet may also face competition from reformulated versions of pirfenidone.One such competitor is Aerodone, an inhalable formulation of pirfenidone in preclinical developmentby Genoa Pharmaceuticals. Early studies suggest that just 5mg of inhaled pirfenidone provides thesame effective lung dose as 801mg of oral pirfenidone. Theoretically, this would allow pirfenidone tobe delivered at much more effective levels in the lung without being limited by dose-related sideeffects. Furthermore, the improved tolerability would make inhaled pirfenidone a much bettercandidate for potential combination regimens (Genoa Pharmaceuticals press release, 2014). Appendix


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Behr J, Bendstrup E, Crestani B, Gnther A, Olschewski H, Skld M, Wells A, Wuyts W, Koschel D, KreuterM, Wallaert B, Tang H, Back J, Albera C (2015) Safety and tolerability of N-acetylcysteine (NAC) withpirfenidone in idiopathic pulmonary fibrosis (IPF): PANORAMA. Available from:http://abstract.ersnet.org/my-abstract-book-2015/pdf/1443562849003.pdf [Accessed 7 October2015].

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Figure 30: Comparison of Esbriet’s and Ofev’s Phase III registrational trials

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Esbriet prescribing information (2015) Available from:http://www.gene.com/download/pdf/esbriet_prescribing.pdf [Accessed 26 August 2015].

FDA (2014) NDA approval letter. Available from:http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/022535Orig1s000ltr.pdf [Accessed 21August 2015].

Gan Y, Herzog EL, Gomer RH (2011) Pirfenidone treatment of idiopathic pulmonary fibrosis.Therapeutics and Clinical Risk Management, 7, 39–47 <DOI>10.2147/TCRM.S12209</DOI>.

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Harari S, Caminati A, Albera C, Vancheri C, Poletti V, Pesci A, Luppi F, Saltini C, Agostini C, Bargagli E,Sebastiani A, Sanduzzi A, Giunta V, Della Porta R, Bandelli GP, Puglisi S, Tomassetti S, Biffi A, Cerri S,Mari A, Cinetto F, Tirelli F, Farinelli G, Bocchino M, Specchia C, Confalonieri M (2015) Efficacy ofpirfenidone for idiopathic pulmonary fibrosis: An Italian real life study. Respiratory Medicine, 109(7),904–13 <DOI>10.1016/j.rmed.2015.04.010</DOI>.

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pulmonary fibrosis—a review of current and novel pharmacotherapies. Journal of Thoracic Disease,7(3), 499−519 <DOI>10.3978/j.issn.2072-1439.2015.01.17</DOI>.

Kim ES, Keating GM (2015) Pirfenidone: A Review of Its Use in Idiopathic Pulmonary Fibrosis. Drugs,75(2), 219–30 <DOI>10.1007/s40265-015-0350-9</DOI>.

King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM,Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigri JJ, Noble PW(2014) A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. The New EnglandJournal of Medicine, 370, 2083−92 <DOI>10.1056/NEJMoa1402582</DOI>.

Loveman E, Copley VR, Scott DA, Colquitt JL, Clegg AJ, O’Reilly K (2015) Comparing new treatmentsfor idiopathic pulmonary fibrosis – a network meta-analysis. BioMed Central Pulmonary Medicine,15(37), 1−7 <DOI>10.1186/s12890-015-0034-y</DOI>.

Martinez FJ, de Andrade JA, Anstrom KJ, King TE, Raghu G (2014) Randomized Trial of N-acetylcysteine in Idiopathic Pulmonary Fibrosis. The New England Journal of Medicine, 370(22),2093–101 <DOI>10.1056/NEJMoa1401739</DOI>.

MHLW (2008) Report on the Deliberation Results. Available from:http://www.pmda.go.jp/files/000153687.pdf [Accessed 21 August 2015].

NICE (2015) Pirfenidone for treating idiopathic pulmonary fibrosis. Available from:https://www.nice.org.uk/guidance/ta282/chapter/4-Consideration-of-the-evidence [Accessed 30August 2015].

Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE, Lancaster L, SahnSA, Szwarcberg J, Valeyre D, du Bois RM (2011) Pirfenidone in patients with idiopathic pulmonaryfibrosis (CAPACITY): two randomised trials. The Lancet, 377(9779), 1760−9 <DOI>10.1016/S0140-6736(11)60405-4</DOI>.

Ofev (2015) Management of Adverse Events. Available from: http://www.boehringer-ingelheim.com/products/prescription_medicines/respiratory/ipf/ofev/moae [Accessed 30 August 2015].

Ofev prescribing information (2015) Available from: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Ofev/ofev.pdf [Accessed 26 August 2015].

Ogura T, Azuma A, Inoue Y, Taniguchi H, Chida K, Bando M, Niimi Y, Kakutani S, Suga M, Sugiyama Y,Kudo S, Nukiwa T (2015a) All-case post-marketing surveillance of 1371 patients treated withpirfenidone for idiopathic pulmonary fibrosis. Respiratory Investigation, in press<DOI>10.1016/j.resinv.2015.06.001</DOI>.

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K, Klüglich M, Fujimoto T, Okazaki K, Tadayasu Y, Sakamoto W, Sugiyama Y (2015b) Safety andpharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. EuropeanRespiratory Journal, 45(5), 138292 <DOI>10.1183/09031936.00198013</DOI>.

Pan L, Huang Y, Yap S, Liu L, Seiwert SD (2015) Combination Of Pirfenidone And Nintedanib:Pharmacokinetics Upon Co-Administration In Lab Animals. Available from:http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2015.191.1_MeetingAbstracts.A4399[Accessed 31 August 2015].

Raghu G, Rochwerg B, Zhang Y, Cuello Garcia CA, Azuma A, Behr J, Brozek JL, Collard HR, CunninghamW, Homma S, Johkoh T, Martinez FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M, Theodore A,Wells AU, Hoogsteden H, Schunemann HJ (2015) An Official ATS/ERS/JRS/ALAT Clinical PracticeGuideline: Treatment of Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and CriticalCare Medicine, 192(2), e3−e19 <DOI>10.1164/rccm.201506-1063ST</DOI>.

Ramesh A, Gurram N, Garima S, Vasant L, Santhosha D, Rekmini V, Viswanadha S, Routhu KV (2014)Therapeutic Potential Of Pirfenidone In Combination With BIBF 1120 For Treatment Of IdiopathicPulmonary Fibrosis. Available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2014.189.1_MeetingAbstracts.A5438 [Accessed 31 August 2015].

Richeldi L, du Bois RM (2011) Pirfenidone in idiopathic pulmonary fibrosis: the CAPACITY program.Expert Reviews of Respiratory Medicines, 5(4), 473−81 <DOI>10.1586/ERS.11.52</DOI>.

Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM,Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, GirardM, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR (2014) Efficacy and Safety of Nintedanib inIdiopathic Pulmonary Fibrosis. The New England Journal of Medicine, 370(22), 2071–82<DOI>10.1056/NEJMoa1402584</DOI>.

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Sakamoto S, Muramatsu Y, Satoh K, Ishida F, Kikuchi N, Sano G, Sugino K, Isobe K, Takai Y, Homma S(2015) Effectiveness of combined therapy with pirfenidone and inhaled N-acetylcysteine for advancedidiopathic pulmonary fibrosis: a case-control study. Respirology, 20(3), 445–52<DOI>10.1111/resp.12477</DOI>.

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for the Treatment of Idiopathic Pulmonary Fibrosis in South Korea. Available from:http://www.shionogi.co.jp/en/company/news/2012/pmrltj0000000w2d-att/e_121012.pdf [Accessed21 August 2015].

Takeda Y, Tsujino K, Kijima T, Kumanogoh A (2014) Efficacy and safety of pirfenidone for idiopathicpulmonary fibrosis. Patient Preference and Adherence, 8, 361–70 <DOI>10.2147/PPA.S37233</DOI>.

Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A,Takeuchi M, Raghu G, Kudoh S, Nukiwa T (2010) Pirfenidone in idiopathic pulmonary fibrosis.European Respiratory Journal, 35(4), 821−9 <DOI>10.1183/09031936.00005209</DOI>.

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Product profile: Ofev PRODUCT PROFILE Analyst Outlook

Only the second treatment to be approved for idiopathic pulmonary fibrosis (IPF), Ofev (nintedanib;Boehringer Ingelheim) has shown the ability to slow the rate of patients’ forced vital capacity (FVC)decline, as well as reduce the incidence of acute exacerbations. However, pulmonologists have moreexperience using the market-leading treatment Esbriet (pirfenidone; Roche/Shionogi). This, incombination with the drug’s demonstrated mortality benefit, will make Esbriet difficult to surpass interms of patient share. Nonetheless, Ofev will still see substantial uptake, especially in patients ofmilder disease severity, and its potential as an add-on treatment to Esbriet further improves the drug’scommercial prospects. Drug Overview

Ofev is a triple angiokinase inhibitor originally developed for the treatment of various cancers.However, the drug’s ability to inhibit platelet-derived growth factor (PDGF), fibroblast growth factor(FGF), and vascular endothelial growth factor (VEGF) receptors has also led to its use in IPF. PDGF is afibroblast mitogen and plays an important role in mediating other pro-fibrotic growth factors andcytokines. FGF also induces the proliferation of fibroblasts, in addition to airway smooth muscle cellsand alveolar epithelial cells. While VEGF’s specific role in IPF is less apparent, it is heavily involved inangiogenesis, and aberrant neovascularization has been recognized in the lung tissue of patients withIPF (Wollin et al., 2015; Woodcock et al., 2013).


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In October 2014, Ofev was granted approval for the treatment of IPF in the US based on the results ofthe Phase III INPULSIS studies. Shortly after, in January 2015, Boehringer Ingelheim also gainedmarketing authorization for Ofev in Europe (Boehringer Ingelheim press release, 2015). It is likely thatthe INPULSIS trials would also support regulatory approval in Japan; however, the company has yet tosubmit an application in this region.

Table 30: Ofev drug profile

Molecule nintedanib

Mechanism of action Triple angiokinase inhibitor

Originator Boehringer Ingelheim

Marketing company Boehringer Ingelheim

Approved indication IPF


Formulation Oral


Dosing frequency 150mg twice daily

First approval date for IPF October 2014 (US), January 2015 (5EU)

Primary patent expiry February 2024 (US), July 2023 (5EU, Japan)

Geographic availability US, 5EU

Alternative names BIBF-1120, Vargatef (non-small cell lung cancer)

2014 global total brand sales n/a


Source: Datamonitor Healthcare; BioMedTracker, Copyright 2015, reprinted with permission;Medtrack, October 2015, Copyright Informa UK; Ofev prescribing information, 2015;Pharmaprojects ®, 2015; Citeline


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Pivotal trial data

Pivotal trial data that supported approvals of Ofev in the US and EU are summarized in the tablebelow. See the Appendix section for a comparison of Esbriet’s and Ofev’s Phase III trials in IPF.


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Table 31: Ofev pivotal trial data in idiopathic pulmonary fibrosis

Trial Sample size Target patients Dosing tested and duration Results Reference

INPULSIS 1

(NCT01335464)

(Phase III)

513 Mild to moderate IPF patients (FVC

≥50% of predicted; DLCO 30–79%

of predicted)

Arm 1: Ofev 150mg twice daily

Arm 2: placebo

Duration: 52 weeks

Annual rate of decline in FVC:

Arm 1: 114.7ml/year

Arm 2: 239.9ml/year

(p<0.001);

Incidence of acute exacerbation:

Arm 1: 6.1%

Arm 2: 5.4%;

Change in SGRQ scores from

baseline:

Arm 1: 4.3

Arm 2: 4.4

(p=0.97)

Richeldi et al., 2014


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INPULSIS 2

(NCT01335477)

(Phase III)



of predicted)


Arm 2: placebo

Duration: 52 weeks


Arm 1: 113.6ml/year

Arm 2: 207.3ml/year

(p<0.001);

Incidence of acute exacerbation:

Arm 1: 3.6%

Arm 2: 9.6%

(p=0.005);


baseline:

Arm 1: 2.8

Arm 2: 5.5

(p=0.02)



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TOMORROW

(NCT00514683)

(Phase II)



of predicted)

Arm 1: Ofev 50mg once daily




Arm 5: placebo

Duration: 52 weeks


Arm 1: 170ml/year

Arm 2: 210ml/year

Arm 3: 160ml/year

Arm 4: 60ml/year

Arm 5: 190ml/year

(No significant difference between

maximum dose and placebo,

p=0.06);

Decline in predicted FVC from

baseline:

Arm 1: 4.6%

Arm 2: 4.9%

Arm 3: 3.2%



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Arm 4: 1.0%

Arm 5: 6.0%;


baseline:

Arm 1: 4.7

Arm 2: 2.2

Arm 3: 1.5

Arm 4: -0.7

Arm 5: 5.5;

Incidence of acute exacerbations:

Arm 4: 2.4 events/100 patient years

Arm 5: 15.7 events/100 patient

years

DLCO = diffusion capacity of the lung for carbon monoxide; FVC = forced vital capacity; IPF = idiopathic pulmonary fibrosis; SGRQ = St George’s Respiratory Questionnaire


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Ongoing late-phase trials

Ongoing late-phase trials are summarized in the table below.


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Table 32: Ofev ongoing late-phase clinical trials in idiopathic pulmonary fibrosis

Trial Sample size Target patients Dosing Primary endpoints Study start/primary completion

date

Extension trial

(NCT01619085)

(Phase III)


either INPULSIS study

Arm 1: Ofev 150mg twice daily Incidence of overall adverse events June 2012/December 2018

1199.187

(NCT01979952)

(Phase III)


≥50% of predicted; DLCO 30–79% of

predicted)


Arm 2: placebo

Relative change from baseline in

HRCT QLF score

November 2013/December 2016

NCT01417156

(Phase II)


study 1199.31

Arm 1: Ofev 150mg twice daily Incidence of overall AEs September 2011/November 2015

AE = adverse event; DLCO = diffusion capacity of the lung for carbon monoxide; FVC = forced vital capacity; HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary fibrosis; QLF = Quantitative Lung Fibrosis



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SWOT ANALYSIS

Figure 31: Ofev for idiopathic pulmonary fibrosis – SWOT analysis

Source: Datamonitor Healthcare; Boehringer Ingelheim press release, 2014a; BoehringerIngelheim press release, 2014b; Richeldi et al., 2014


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The figure below depicts Datamonitor Healthcare’s drug assessment summary for Ofev in IPF.

The figure below provides a breakdown of how Datamonitor Healthcare scored Ofev’s clinical andcommercial attractiveness. The weighting given to each attribute is also shown.

Figure 32: Datamonitor Healthcare’s drug assessment of Ofev for idiopathic pulmonary fibrosis



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The INPULSIS trials verify Ofev’s efficacy in IPF

The results of the Phase III INPULSIS trials demonstrate the efficacy of Ofev, making it a clear optionfor patients with mild to moderate IPF. Both INPULSIS 1 and 2 met their primary endpoint, reducingthe annual rate of FVC decline by 48% and 55% versus placebo, respectively. Furthermore, patientsreceiving Ofev saw a mean FVC decline of 95ml in both trials versus the 205ml observed in thepatients on placebo (Boehringer Ingelheim press release, 2014a). Pooled results also showed that Ofevdemonstrated the ability to reduce the occurrence of confirmed or suspected acute exacerbations by68% (p=0.005) (Boehringer Ingelheim press release, 2014b). These results have earned Ofev a“conditional recommendation” for use in IPF patients in the 2015 American Thoracic Society/EuropeanRespiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines(Raghu et al., 2015). See the Appendix section for a comparison of Esbriet’s and Ofev’s Phase III trialsin IPF. Esbriet and Ofev both offer improvements in outcomes, but in differing endpoints

Ofev and direct competitor Esbriet have both shown themselves to be clinically beneficial treatmentsfor IPF patients. However, which drug is more effective appears to depend on which measurement ofefficacy is used. Pooled analyses of each drug’s relevant trials show that Esbriet was significantlyassociated with a reduction in all-cause mortality (p=0.01), whereas Ofev significantly reduced theoccurrence of confirmed or suspected acute exacerbations (p=0.005) (Boehringer Ingelheim pressrelease, 2014b; King et al., 2014). Additionally, both drugs demonstrated the ability to significantlyslow FVC decline. However, when indirectly comparing respective pooled data for each drug usingplacebo as the common comparator, results indicated that Ofev was statistically superior to Esbriet in

Figure 33: Datamonitor Healthcare’s drug assessment of Ofev for idiopathic pulmonary fibrosis



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slowing FVC decline (odds ratio = 0.67) (Loveman et al., 2015). Although results of indirectcomparisons must be approached cautiously due to differences in trial inclusion criteria, patientdemographics, and endpoint calculations, the lack of any head-to-head trials between the two drugsnecessitates such comparisons in order to assist with treatment decisions. See the Appendix sectionfor a comparison of Esbriet’s and Ofev’s Phase III trials in IPF.

While all-cause mortality may seem to be the most important and overarching outcome that all IPFtreatments should seek to improve, levels of efficacy based on other endpoints are certainly still worthconsideration. Change in FVC has been proven to have a strong association with mortality and hasbecome a common surrogate endpoint for both disease progression and mortality in IPF trials as aresult (Zappala et al., 2010). As FVC decline was used as the primary endpoint in Phase III trials ofboth Esbriet and Ofev, these individual studies were powered to show differences in this endpoint, notmortality. Additionally, acute exacerbations have proven to be difficult to predict and treat, so theprevention of these episodes is an important improvement to track, especially given that theoccurrence of acute exacerbations has also been shown to be quite closely associated with mortality(reported 60% mortality rate in the month following an acute exacerbation) (Juarez et al., 2015).Therefore, Ofev’s demonstrated efficacy in terms of FVC decline and the incidence of acuteexacerbations may translate to benefits in all-cause mortality, despite this endpoint not havingreached statistical significance in the INPULSIS trials. Side-effect profiles may help to differentiate Esbriet and Ofev

Because there is no clear leader in terms of efficacy, small differences in the side-effect profiles ofEsbriet and Ofev may help guide treatment decisions in IPF patients. While these factors will notmandate the use of one drug over the other, they may influence patient or physician preference.

In terms of tolerability, both Esbriet and Ofev primarily cause gastrointestinal (GI) side effects.Although Ofev is associated with a much higher rate of diarrhea, Esbriet also demonstrates skin-related side effects that were not observed with Ofev. In the CAPACITY trials, the most commonadverse events associated with Esbriet were (Esbriet versus placebo): nausea (36% versus 17%), rash(32% versus 12%), dyspepsia (19% versus 7%), dizziness (18% versus 10%), vomiting (14% versus4%), and photosensitivity reaction (12% versus 2%) (Noble et al., 2011). On the other hand, the mostcommon side effects associated with Ofev in the INPULSIS trials were (Ofev versus placebo): diarrhea(62% versus 18%), nausea (25% versus 7%), and vomiting (12% versus 3%) (Richeldi et al., 2014).When considering more serious adverse events, both drugs also caused elevations in the level ofalanine or aspartate aminotransferase (of more than three times the upper limit of normal) in 3–5%of patients.

The rate of treatment discontinuation due to adverse events was slightly higher for patients receivingOfev, with 19% of patients discontinuing Ofev in the INPULSIS trials and 15% of patientsdiscontinuing Esbriet in the CAPACITY trials (Noble et al., 2011; Richeldi et al., 2014). The severity ofthe side effects associated with both drugs have been shown to be reduced by administering doses inconjunction with meals, temporarily interrupting treatment, or reducing daily dosages. Furthermore, itis recommended that patients taking Esbriet initiate treatment with a 14-day titration period and


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avoid sun exposure to reduce the risk of adverse events (Costabel et al., 2014). Similarly, the sideeffects of Ofev can be mitigated by supplementing with antidiarrheals such as loperamide, or anti-emetics such as metoclopramide (Ofev, 2015). Esbriet’s higher pill burden could affect patient compliance in the real-world setting

Although it did not prove to be a large issue in clinical trials, Esbriet is at a considerable disadvantageto Ofev when it comes to dosing frequency and pill burden. In the US and EU, the suggested dose ofEsbriet is 801mg three times daily. The drug is dispensed in 267mg capsules, requiring patients to takenine capsules a day (Esbriet prescribing information, 2015). In contrast, Ofev is dosed at 150mg twicedaily, requiring only two capsules per day (Ofev prescribing information, 2015). Mean compliance inpatients receiving the approved dose of Esbriet in the CAPACITY trials was 90% versus 97% inpatients receiving Ofev in the INPULSIS trials (CDER, 2014a; CDER, 2014b). While the level of patientcompliance for Esbriet does not appear to be a major issue based on the rates seen in late-phasestudies, compliance outside of clinical trials is likely to be lower, potentially impacting the efficacy ofthe drug in the real-world setting. Studies in combination with Esbriet may help expand Ofev’s patient share

Boehringer Ingelheim is currently testing Ofev as an add-on treatment to Esbriet, which couldsignificantly increase Ofev’s patient share in IPF. As the first approved treatment for IPF, Esbrietcurrently holds a larger market share, especially in regions outside of the US. However, if BoehringerIngelheim can demonstrate that the addition of Ofev to treatment with Esbriet is safe and improvesupon the efficacy of either drug as a monotherapy, Ofev could gain more substantial uptake inpatients who experience disease progression on Esbriet monotherapy, or in previously untreatedpatients who are exhibiting rapid disease progression.

Concerns of compounded toxicities, namely GI side effects, have slowed the clinical development ofthe combination. Nonetheless, preclinical studies in animal models showed the concurrentadministration of low-dose Esbriet and Ofev did not affect either drug’s pharmacokinetic profile (Panet al., 2015; Ramesh et al., 2014). Furthermore, a short, one-month trial testing the addition of Ofevto treatment with Esbriet in 50 Japanese IPF patients showed the combination did not produce anysevere adverse events (Ogura et al., 2015). A much longer Phase II safety study testing Ofev as an add-on to Esbriet is currently underway (ClinicalTrials.gov identifier: NCT01417156). Ofev’s trial design may justify preferential use in mild IPF patients

While both Ofev and Esbriet are considered to demonstrate efficacy in mild to moderate IPF patients,the design of each drug’s Phase III trials may grant Ofev more preferential use in patients of milderdisease severity. The average baseline predicted FVC was higher in Ofev’s INPULSIS trials than inEsbriet’s ASCEND and CAPACITY trials (INPULSIS: 79.6%; CAPACITY: 74.7%; ASCEND: 68.2%) (King etal., 2014; Noble et al., 2011; Richeldi et al., 2014). Therefore, some pulmonologists may choose to useOfev in patients with mild IPF, as their disease status more closely reflects that of the patients in theINPULSIS trials. Moreover, pre-specified analysis of the INPULSIS trials showed that patients aboveand below the 70% predicted FVC threshold experienced similar reductions in absolute FVC decline


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(baseline FVC >70% predicted: 111.3ml versus -220.3ml; baseline FVC ≤70% predicted: -119.7mlversus -233.2ml) (Boehringer Ingelheim press release, 2014c). Additional Phase III trial may help identify patients who respond best to treatment

In addition to the Phase III INPULSIS trials and their corresponding extension study (ClinicalTrials.govidentifier: NCT01619085), Boehringer Ingelheim is also conducting another Phase III trial, which mayhelp pulmonologists decide which patients are likely to respond well to treatment with Ofev. ThePhase III 1199.187 trial will track the disease status of mild to moderate IPF patients receiving aplacebo for six months before being switched to treatment with Ofev. Disease progression will bemonitored primarily by observing relative changes in high-resolution computed tomography (HRCT)Quantitative Lung Fibrosis (QLF) scores; however, changes in a patient’s FVC, six-minute walk testdistance, and St George’s Respiratory Questionnaire score will also be examined (ClinicalTrials.govidentifier: NCT01979952).

By observing patients before treatment is initiated, Boehringer Ingelheim will not only be able to showthe impact Ofev has on disease progression, but also which patients benefit the most from treatment.For example, the trial could reveal that patients who are experiencing more drastic declines in HRCTQLF scores benefit most from treatment. Alternatively, it could show the opposite: that Ofev worksbetter in mild IPF patients experiencing a steady decay in vital capacity. Regardless, the study resultswill likely encourage pulmonologists to initiate treatment with Ofev earlier than they otherwise mighthave, by showing how a six-month delay in treatment could be detrimental to a patient’s health. First-to-market status gives Esbriet a commercial advantage over Ofev outside of the US

The approval of Esbriet in the five major EU markets (France, Germany, Italy, Spain, and the UK) andJapan well ahead of Ofev will provide Esbriet with a large commercial advantage in these markets. In2008, Shionogi gained approval for Esbriet in Japan based on the results of the Phase II SP2 and PhaseIII SP3 trials (MHLW, 2008; Shionogi press release, 2012). Subsequently, InterMune gained approvalfor Esbriet in the EU in 2011 based on the CAPACITY trials (EMA, 2015). Initial uptake of Esbriet inthese regions was substantial because it was the only approved treatment. Although approval in theUS was granted at the same time as Ofev, Esbriet’s extensive use for IPF in other geographies willpositively influence uptake in the US market as well. Appendix


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Bibliography

Boehringer Ingelheim press release (2014a) Phase 3 INPULSIS™ Trials Published in the New EnglandJournal of Medicine Show Investigational Nintedanib Slowed Lung Function Loss in People withIdiopathic Pulmonary Fibrosis. Available from: http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/05-18-14-phase-3-inpulsis-trials-new-england-journal-of-medicine-nintedanib-lung-function-idiopathic-pulmonary-fibrosis.html [Accessed 1 September 2015].

Boehringer Ingelheim press release (2014b) EMA accepts marketing authorisation application fornintedanib in IPF. Available from: http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2014/05_june_2014_ipf.html [Accessed 1September 2015].

Boehringer Ingelheim press release (2014c) New Analysis of Phase III Trials Examines the Impact ofBoehringer Ingelheim’s IPF Therapy Nintedanib on Lung Function Decline Based on Patients’ BaselineSeverity. Available from: http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/09-09-14-new-analysis-phase-iii-trials-examines-impact-boehringer-ingelheims-ipf-therapy-nintedanib-lung-function-decline-patients-baseline-severity.html [Accessed 1 September 2015].

Boehringer Ingelheim press release (2015) OFEV® (nintedanib*) approved in the EU for the treatment

Figure 34: Comparison of Esbriet’s and Ofev’s Phase III registrational trials

Source: CDER, 2014a; CDER, 2014b; King et al., 2014; Loveman et al., 2015; Noble et al.,2011; Richeldi et al., 2014


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of IPF. Available from: http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/19_january_2015_ipf.html [Accessed 1September 2015].

CDER (2014a) Application Number: 205832Orig1s000 (Ofev). Available from:http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205832Orig1s000StatR.pdf [Accessed 26August 2015].

CDER (2014b) Application Number: 022535Orig1s000 (Esbriet). Available from:http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022535Orig1s000MedR.pdf [Accessed 26August 2015].

Costabel U, Bendstrup E, Cottin V, Dewint P, Egan J, Ferguson J, Groves R, Hellstrom PM, Kreuter M,Maher TM, Molina-Molina M, Nordlind K, Sarafidis A, Vancheri C (2014) Pirfenidone in IdiopathicPulmonary Fibrosis: Expert Panel Discussion on the Management of Drug-Related Adverse Events.Advances in Therapy, 31(4), 375−391 <DOI>10.1007/s12325-014-0112-1</DOI>.

EMA (2015) EPAR summary for the public. Available from:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002154/WC500102979.pdf [Accessed 21 August 2015].


Juarez MM, Chan AL, Norris AG, Morrissey BM, Albertson TE (2015) Acute exacerbation of idiopathicpulmonary fibrosis—a review of current and novel pharmacotherapies. Journal of Thoracic Disease,7(3), 499−519 <DOI>10.3978/j.issn.2072-1439.2015.01.17</DOI>.


Loveman E, Copley VR, Scott DA, Colquitt JL, Clegg AJ, O’Reilly K (2015) Comparing new treatmentsfor idiopathic pulmonary fibrosis – a network meta-analysis. BioMed Central Pulmonary Medicine,15(37), 1−7 <DOI>10.1186/s12890-015-0034-y</DOI>.

MHLW (2008) Report on the Deliberation Results. Available from:http://www.pmda.go.jp/files/000153687.pdf [Accessed 21 August 2015].



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Ofev (2015) Management of Adverse Events. Available from: http://www.boehringer-ingelheim.com/products/prescription_medicines/respiratory/ipf/ofev/moae [Accessed 30 August 2015].


Ogura T, Taniguchi H, Azuma A, Inoue Y, Kondoh Y, Hasegawa Y, Bando M, Abe S, Mochizuki Y, ChidaK, Klüglich M, Fujimoto T, Okazaki K, Tadayasu Y, Sakamoto W, Sugiyama Y (2015) Safety andpharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. EuropeanRespiratory Journal, 45(5), 1382–92 <DOI>10.1183/09031936.00198013</DOI>.

Pan L, Huang Y, Yap S, Liu L, Seiwert SD (2015) Combination Of Pirfenidone And Nintedanib:Pharmacokinetics Upon Co-Administration In Lab Animals. Available from:http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2015.191.1_MeetingAbstracts.A4399[Accessed 31 August 2015].

Raghu G, Rochwerg B, Zhang Y, Cuello Garcia CA, Azuma A, Behr J, Brozek JL, Collard HR, CunninghamW, Homma S, Johkoh T, Martinez FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M, Theodore A,Wells AU, Hoogsteden H, Schunemann HJ (2015) An Official ATS/ERS/JRS/ALAT Clinical PracticeGuideline: Treatment of Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and CriticalCare Medicine, 192(2), e3−e19 <DOI>10.1164/rccm.201506-1063ST</DOI>.

Ramesh A, Gurram N, Garima S, Vasant L, Santhosha D, Rekmini V, Viswanadha S, Routhu KV (2014)Therapeutic Potential Of Pirfenidone In Combination With BIBF 1120 For Treatment Of IdiopathicPulmonary Fibrosis. Available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2014.189.1_MeetingAbstracts.A5438 [Accessed 31 August 2015].

Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Raghu G,Brun M, Gupta A, Juhel N, Kluglich M, du Bois RM (2011) Efficacy of a Tyrosine Kinase Inhibitor inIdiopathic Pulmonary Fibrosis. The New England Journal of Medicine, 365, 1079–87<DOI>10.1056/NEJMoa1103690</DOI>.


Shionogi press release (2012) Shionogi Provides Pirespa 200mg Tablet to ILDONG PHARMACEUTICALfor the Treatment of Idiopathic Pulmonary Fibrosis in South Korea. Available from:http://www.shionogi.co.jp/en/company/news/2012/pmrltj0000000w2d-att/e_121012.pdf [Accessed21 August 2015].


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Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb M (2015) Mode of action ofnintedanib in the treatment of idiopathic pulmonary fibrosis. European Respiratory Journal, 45(5),1434–45 <DOI>10.1183/09031936.00174914</DOI>.

Woodcock HV, Molyneaux PL, Maher TM (2013) Reducing lung function decline in patients withidiopathic pulmonary fibrosis: potential of nintedanib. Drug Design, Development and Therapy, 7,503–10 <DOI>10.2147/DDDT.S38833</DOI>.

Zappala CJ, Latsi PI, Nicholson AG, Colby TV, Cramer D, Renzoni EA, Hansell DM, du Bois RM, Wells AU(2010) Marginal decline in forced vital capacity is associated with a poor outcome in idiopathicpulmonary fibrosis. European Respiratory Journal, 35(4), 830−6<DOI>10.1183/09031936.00155108</DOI>.


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Idiopathic pulmonary fibrosis Disease Coverage | Pipeline: IdiopathicPulmonary Fibrosis DMKC12770


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Pipeline: Idiopathic Pulmonary Fibrosis Executive Summary The standardization of clinical trial design will aid

in drug development and commercialization

Clinical trials studying drugs in development for idiopathic pulmonary fibrosis (IPF) continue to

standardize in terms of endpoint selection, measurement, and interpretation, as well as inclusion

criteria. This alignment will help regulatory bodies determine treatment efficacy and use cross-study

comparisons in order to make approval decisions. Furthermore, the standardization of trials will also

aid in the clinical decision-making process by allowing pulmonologists to more easily translate

study outcomes and populations into real-world situations.

Efficacy demonstrated by FG-3019 and PRM-151 in

initial trials are encouraging, but will need to be

validated in larger studies

Early trials studying pipeline agents FG-3019 (FibroGen) and PRM-151 (Promedior/Bristol-Myers

Squibb) show that both drugs have the potential to improve forced vital capacity in patients with

IPF. However, these Phase I and Phase II trials were extremely limited in terms of size and design,

and larger randomized studies must be conducted before the true efficacy of the two therapies can

be discerned. Confirmatory Phase II trials are underway and will have significant implications on the

future of both drugs, especially PRM-151, as Bristol-Myers Squibb will decide whether or not to

exercise its option to acquire Promedior based on these results.


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Clinical Pipeline Overview Pipeline summary

Table 33: Phase II pipeline products in development for idiopathic pulmonary fibrosis

Drug Lead company Target Drug type Phase

FG-3019 FibroGen Connective tissue growth

factor

Monoclonal antibody Phase II

PRM-151 Promedior Anti-fibrotic Recombinant protein Phase II

Source: BioMedTracker, Copyright 2015, reprinted with permission; Pharmaprojects ®, 2015;Citeline


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Target Product Profile Comparator therapies ESBRIET (PIRFENIDONE; ROCHE/SHIONOGI)

Esbriet is a pyridone analog, which has demonstrated anti-fibrotic, anti-inflammatory, andantioxidant properties. Because of its wide range of activity, the exact mechanism by which Esbrietworks in idiopathic pulmonary fibrosis (IPF) is not certain. However, the drug’s anti-fibrotic effects aremainly attributed to its ability to suppress transforming growth factor beta, which induces theproliferation of fibroblasts and causes the excessive synthesis of collagen. Additionally, Esbriet’s anti-inflammatory traits are thought to stem from its inhibition of tumor necrosis factor alpha, aninflammatory cytokine. As an antioxidant, the drug has demonstrated the capability to reduce theproduction of reactive oxygen species, which can cause cellular injury and further stimulateinflammatory and fibrotic processes (Kim and Keating, 2015; Takeda et al., 2014). Other cytokines andgrowth factors modulated by Esbriet that may contribute to the drug’s effects in IPF include basicfibroblast growth factor (FGF), platelet-derived growth factor (PDGF), interleukin-1 beta, interleukin-6, interleukin-10, interleukin-12p40, interleukin-18, stromal cell-derived factor-1 alpha, interferongamma, and monocyte chemoattractant protein-1 (Gan et al., 2011).


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CLINICAL TRIAL DATA

The table below presents a summary of the key findings in pivotal clinical trials for Esbriet.

Table 34: Esbriet drug profile

Molecule pirfenidone

Mechanism of action Anti-fibrotic

Originator Marnac

Marketing company Roche/Shionogi

Primary indication IPF


Formulation Oral


Dosing frequency 801mg three times daily

First launch date October 2014 (US), February 2011 (5EU), October 2008 (Japan)

Primary patent expiry October 2021 (US)*, February 2021 (5EU)*, October 2018 (Japan)*

Alternative brand names Pirespa (Japan), S-7701, RG6062

Geographic availability US, 5EU, Japan

2014 global total brand sales $99m**

*Dates represent the end of orphan drug market exclusivity in each region, as Esbriet’s primary patents have already expired.

**2014 sales only include sales reported by Roche in the three months following its acquisition of InterMune and sales reported by Shionogi in

Japan.


Source: Datamonitor Healthcare; BioMedTracker, Copyright 2015, reprinted with permission;Esbriet prescribing information, 2015; Medtrack, October 2015, Copyright Informa UK;Pharmaprojects ®, 2015; Citeline; Roche financial report, 2014; Shionogi annual report, 2015


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Trial Sample size Target patients Study design Dosing tested and

duration

Results Reference

ASCEND

(NCT01366209)

(Phase III)

555 Mild to moderate IPF

patients (FVC 50–90% of

predicted; DLCO 30–90%

of predicted)

Randomized, double-

blind, parallel-assignment,

placebo-controlled,

safety/efficacy study

Arm 1: Esbriet 2,403mg

per day

Arm 2: placebo

Duration: 52 weeks


experiencing FVC decline

of ≥10% or death*:

Arm 1: 16.5%

Arm 2: 31.8%;

Mean decline from

baseline in FVC*:

Arm 1: 235ml

Arm 2: 428ml;


with a decrease of 50m or

more in 6MWT distance:

Arm 1: 25.9%

Arm 2: 35.7%;

All-cause mortality:

King et al., 2014


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duration

Results Reference

Arm 1: 4.0%

Arm 2: 7.2%

(Not significant; p=0.10)


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150



duration

Results Reference

CAPACITY 1

(NCT00287729)

(Phase III)




of predicted)

Randomized, double-


placebo-controlled,



per day

Arm 2: placebo

Duration: 72 weeks


FVC*:

Arm 1: -9.0%

Arm 2: -9.6%

(Not significant;

p=0.501);

Mean change in 6MWT

distance:

Arm 1: -45.1m

Arm 2: -76.9m;




Arm 1: 33.1%

Arm 2: 46.7%

Noble et al., 2011


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151



duration

Results Reference

CAPACITY 2

(NCT00287716)

(Phase III)




of predicted)

Randomized, double-


placebo-controlled, three-

arm, safety/efficacy study


per day


per day

Arm 3: placebo

Duration: 72 weeks


FVC*:

Arm 2: -8.0%

Arm 3: -12.4%;

Mean change in 6MWT

distance:

Arm 2: -60.4m

Arm 3: -76.8m

(Not significant;

p=0.171);




Arm 2: 36.5%

Arm 3: 47.1%

Noble et al., 2011


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duration

Results Reference

SP3

(Phase III)

275 IPF patients (oxygen

desaturation of ≥5%

difference between

resting SpO2 and the

lowest SpO2 during a

6MET; lowest SpO2 during

the 6MET of ≥85% while

breathing air)

Randomized, double-


placebo-controlled,



per day


per day

Arm 3: placebo

Duration: 52 weeks

Mean change in VC*:

Arm 1: -90ml

Arm 2: -80ml

Arm 3: -160ml

Taniguchi et al., 2010


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duration

Results Reference

SP2

(Phase II)

107 IPF patients (PaO2

≥70mmHg; SpO2 ≤90%

during exertion while

breathing air)

Randomized, double-


placebo-controlled,


Arm 1: Esbriet 600mg per

day for the first two days,


following two days, and

then 1,800mg per day for

the remainder of the

study (as tolerated)

Arm 2: placebo

Duration: 39 weeks

Mean change from

baseline in

lowest SpO2

during 6MET*:

Arm 1: +0.47%

Arm 2: -0.97%

(Not significant;

p=0.0722);

Mean change in VC:

Arm 1: -30ml

Arm 2: -130ml

Azuma et al., 2005

*Primary endpoint

6MET = six-minute steady-state exercise test; 6MWT = six-minute walk test; DLCO = diffusion capacity of the lung for carbon monoxide; FVC = forced vital capacity; IPF = idiopathic

pulmonary fibrosis; PaO2 = partial pressure of arterial oxygen; SpO2 = oxygen saturation measured by pulse oximetry; VC = vital capacity


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155

OFEV (NINTEDANIB; BOEHRINGER INGELHEIM)

Ofev is a triple angiokinase inhibitor originally developed for the treatment of various cancers.However, the drug’s ability to inhibit PDGF, FGF, and vascular endothelial growth factor (VEGF)receptors has also led to its use in IPF. PDGF is a fibroblast mitogen and plays an important role inmediating other pro-fibrotic growth factors and cytokines. FGF also induces the proliferation offibroblasts, in addition to airway smooth muscle cells and alveolar epithelial cells. While VEGF’sspecific role in IPF is less apparent, it is heavily involved in angiogenesis, and aberrantneovascularization has been recognized in the lung tissue of patients with IPF (Wollin et al., 2015;Woodcock et al., 2013).

Table 36: Ofev drug profile

Molecule nintedanib

Mechanism of action Triple angiokinase inhibitor

Originator Boehringer Ingelheim

Marketing company Boehringer Ingelheim

Primary indication IPF


Formulation Oral


Dosing frequency 150mg twice daily

First launch date October 2014 (US), January 2015 (5EU)

Primary patent expiry February 2024 (US), July 2023 (5EU, Japan)

Alternative brand names BIBF-1120, Vargatef (non-small cell lung cancer)

Geographic availability US, 5EU

2014 global total brand sales n/a


Source: Datamonitor Healthcare; BioMedTracker, Copyright 2015, reprinted with permission;Medtrack, October 2015, Copyright Informa UK; Ofev prescribing information, 2015;Pharmaprojects ®, 2015; Citeline


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CLINICAL TRIAL DATA

The table below presents a summary of the key findings in pivotal clinical trials for Ofev.


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157



duration

Results Reference

INPULSIS 1

(NCT01335464)

(Phase III)


(FVC ≥50% of predicted; DLCO

30–79% of predicted)

Randomized, double-blind,

parallel-assignment, placebo-

controlled, safety/efficacy

study


Arm 2: placebo

Duration: 52 weeks


Arm 1: 114.7ml/year

Arm 2: 239.9ml/year

(p<0.001);

Incidence of acute

exacerbation:

Arm 1: 6.1%

Arm 2: 5.4%;


baseline:

Arm 1: 4.3

Arm 2: 4.4

(p=0.97)



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158



duration

Results Reference

INPULSIS 2

(NCT01335477)

(Phase III)







study


Arm 2: placebo

Duration: 52 weeks


Arm 1: 113.6ml/year

Arm 2: 207.3ml/year

(p<0.001);

Incidence of acute

exacerbation:

Arm 1: 3.6%

Arm 2: 9.6%

(p=0.005);


baseline:

Arm 1: 2.8

Arm 2: 5.5



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159



duration

Results Reference

(p=0.02)


160



160



duration

Results Reference

TOMORROW

(NCT00514683)

(Phase II)







study

Arm 1: Ofev 50mg once daily




Arm 5: placebo

Duration: 52 weeks


Arm 1: 170ml/year

Arm 2: 210ml/year

Arm 3: 160ml/year

Arm 4: 60ml/year

Arm 5: 190ml/year

(No significant difference

between maximum dose and

placebo, p=0.06);

Decline in predicted FVC from

baseline:

Arm 1: 4.6%

Arm 2: 4.9%

Arm 3: 3.2%



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161



duration

Results Reference

Arm 4: 1.0%

Arm 5: 6.0%;


baseline:

Arm 1: 4.7

Arm 2: 2.2

Arm 3: 1.5

Arm 4: -0.7

Arm 5: 5.5;

Incidence of acute

exacerbations:


years



162



162



duration

Results Reference

years

DLCO = diffusion capacity of the lung for carbon monoxide; FVC = forced vital capacity; IPF = idiopathic pulmonary fibrosis; SGRQ = St George’s Respiratory Questionnaire



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Bibliography

Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Koichio N, Yoshio T, Nagai S, Itoh H, Ohi M, Sato A,Kudoh S (2005) Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathicpulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 171, 1040−7<DOI>10.1164/rccm.200404-571OC</DOI>.


Gan Y, Herzog EL, Gomer RH (2011) Pirfenidone treatment of idiopathic pulmonary fibrosis.Therapeutics and Clinical Risk Management, 7, 39–47 <DOI>10.2147/TCRM.S12209</DOI>.

Kim ES, Keating GM (2015) Pirfenidone: A Review of Its Use in Idiopathic Pulmonary Fibrosis. Drugs,75(2), 219–30 <DOI>10.1007/s40265-015-0350-9</DOI>.






Roche financial report (2014) Available from: http://www.roche.com/fb14e.pdf [Accessed 3 September


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2015].

Shionogi annual report (2015) Available from: http://www.shionogi.co.jp/en/ir/pdf/pdf_15/all15_e.pdf[Accessed 3 September 2015].

Takeda Y, Tsujino K, Kijima T, Kumanogoh A (2014) Efficacy and safety of pirfenidone for idiopathicpulmonary fibrosis. Patient Preference and Adherence, 8, 361–70 <DOI>10.2147/PPA.S37233</DOI>.

Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A,Takeuchi M, Raghu G, Kudoh S, Nukiwa T (2010) Pirfenidone in idiopathic pulmonary fibrosis.European Respiratory Journal, 35(4), 821−9 <DOI>10.1183/09031936.00005209</DOI>.

Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb M (2015) Mode of action ofnintedanib in the treatment of idiopathic pulmonary fibrosis. European Respiratory Journal, 45(5),1434–45 <DOI>10.1183/09031936.00174914</DOI>.

Woodcock HV, Molyneaux PL, Maher TM (2013) Reducing lung function decline in patients withidiopathic pulmonary fibrosis: potential of nintedanib. Drug Design, Development and Therapy, 7,503–10 <DOI>10.2147/DDDT.S38833</DOI>.


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Clinical Trial Design Clinical trials are imperative to determine the efficacy and safety of all developmental products, andthey are compulsory for gaining marketing approval. Factors such as dosing schedules, patientselection, patient numbers, and trial duration need to be established prior to trial initiation in order togain statistically meaningful results. The aim for most companies is to strike a balance betweendesigning clinical trials to optimize the chances of approval while simultaneously conducting the trialwith economic prudence. Clinical trials COMMONLY USED CLINICAL TRIAL ENDPOINTS FOR IPF

The following table shows the endpoints used in the Phase II and Phase III trials of Esbriet(pirfenidone; Roche/Shionogi) and Ofev (nintedanib; Boehringer Ingelheim), the only therapiescurrently approved for idiopathic pulmonary fibrosis (IPF).


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Figure 35: Primary and secondary endpoints used in Ofev and Esbriet's key late-phase trials

Source: King et al., 2014a; Noble et al., 2011; Richeldi et al., 2011; Richeldi et al., 2014


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FORCED VITAL CAPACITY

Although mortality outcomes are the most clinically significant endpoints in IPF, the use of thesemeasures as primary endpoints is both ethically and commercially impractical (Wells et al., 2012).Therefore, other tests of lung function are used instead as surrogate endpoints. Forced vital capacity(FVC) has emerged as a prominent primary endpoint, as large declines in FVC have been associatedwith disease progression and mortality. FVC is typically tracked as both change in actual FVC (in ml orL) and as a percentage of predicted FVC based on a patient’s demographics such as age, sex, race, andheight. While FVC outcomes can vary slightly, even in stable patients, one study consisting of 1,156clinical trial participants found the minimal clinically important difference (MCID) in predicted FVC tobe 2–6% (du Bois et al., 2011a). Furthermore, it is widely accepted that a decline in predicted FVC ofgreater than 10% is a sign of disease progression (Raghu et al., 2012). While this threshold issomewhat arbitrary, it has been shown that a 10% decline over the course of 24 weeks is associatedwith an almost five-fold increase in the risk of mortality in the following year (du Bois et al., 2011a).Therefore, clinical trials have commonly evaluated the proportion of patients to reach this categoricalchange as a vital endpoint. OTHER LUNG FUNCTION TESTS

A number of other lung function tests besides FVC are utilized as secondary endpoints to monitordisease progression; however, issues with standardization and translatability to treatment effectprevent them from being used as primary endpoints.

Diffusion capacity of the lung for carbon monoxide (DLCO) assesses the ability of gases to diffusebetween alveoli and the bloodstream. Like FVC, DLCO can be measured absolutely (in mlCO/min/mmHg) or can be compared to predicted DLCO based on patient demographics. A decline of≥15% in predicted DLCO is regarded as an indicator of IPF progression and poor prognosis (Maher,2013). However, DLCO testing is inherently variable, not only between different testing centers butalso within the same center on the same subject (Nathan and Meyer, 2014). Guidelines recommendperforming multiple tests (up to five) in each session until two tests come within 3ml CO/min/mmHgof each other (or within 10% of the highest value) and reporting the average of these two results(MacIntyre et al., 2005). Despite this effort to standardize testing, the inconsistency of DLCOmeasurements has kept it from being utilized in primary endpoint analyses.

Another commonly used benchmark of a patient’s lung function is the six-minute walk test (6MWT),in which patients are asked to walk as far as possible within a six-minute time frame, stopping to takea break whenever needed. Theoretically, a decrease in the distance walked during the 6MWT signifiesa reduction in the patient’s ability to perform everyday activities due to disease progression. The MCIDin 6MWT distance is reported to be between 24m and 45m (du Bois et al., 2011b; Swigris et al.,2010a). Other metrics utilizing the 6MWT include recording the lowest oxygen saturation measuredby pulse oximetry during the test, or using the Borg scale to measure any change in the patient’s levelof dyspnea and fatigue following the test (ATS guideline, 2002). Although it has been associated withrisk of mortality, it is difficult to directly relate 6MWT results to treatment effect in IPF, as other


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factors such as co-morbidities can highly influence outcomes. Furthermore, differences in how thetest is administrated, how motivated patients are, and how much the “training” effect impactsperformance can introduce variability in 6MWT results. Finally, the 6MWT may be too difficult forsome patients of poor overall health to perform, causing the issue of missing data points (Maher,2013; Nathan and Meyer, 2014). HRCT ASSESSMENT

High-resolution computed tomography (HRCT) has drastically changed how IPF is diagnosed, so muchso that recent trials have also begun to use longitudinal HRCT assessments to monitor diseaseprogression. HRCT can be used to observe the fibrotic process itself, rather than measuring the impactfibrosis has on lung function through other tests. However, the key issue of quantifying changesobserved in HRCT scans over time has proved a barrier to its widespread use in clinical trials.Quantitative HRCT assessment has ranged from scores given by radiologists based on rating systemsto entirely computer-based scoring systems, but a standard methodology has yet to be established(Maldonado et al., 2014; Oda et al., 2014). Nonetheless, as newer treatments seek to reverse fibrosisrather than just preserve lung function, HRCT will play a larger role in clinical trial endpoints in thefuture. ACUTE EXACERBATION

Acute exacerbation is the sudden worsening of a patient’s disease status due to unknown triggers. Astreatments in development aim to prevent acute exacerbation, or treat it directly, more clinical trialswill incorporate endpoints measuring the occurrence of these episodes. Time to first acuteexacerbation and incidence of acute exacerbation have both been used as endpoints in trials thus far.However, identifying acute exacerbation consistently has been troublesome. Although there is aprecise definition that is commonly used, the full data needed to show that patients meet all criteriaare sometimes unavailable. This has led certain trials to record both “suspected” acute exacerbations,as well as “definite” acute exacerbations. Furthermore, endpoints can vary depending on whetherepisodes are documented by trial investigators at each site or detected by an independentadjudication committee (Collard et al., 2013). MORTALITY

Due to the poor prognosis of IPF patients, the main goal of current therapies in development is toimprove survival. This makes easily defined and encompassing mortality outcomes, such as all-causemortality, ideal endpoints for clinical trials (Raghu et al., 2012). However, many factors prohibitmortality from being used as a primary endpoint. Because enrollment in the majority of current IPFclinical trials is usually limited to mild to moderate patients with stable performance status, themortality rates observed in studies to date are low. Therefore, trials powered to demonstratestatistically significant differences in mortality would need to be exceptionally large and drawn-out,making them logistically and commercially unfeasible. It is estimated that a two-arm randomized trialwould need to enroll 2,582 IPF patients and have a follow-up period of five years in order to have90% power to demonstrate a 25% reduction in all-cause mortality (King et al., 2014b). Furthermore,asking patients to join a potentially life-long study in which they have a significant chance of


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receiving a placebo treatment presents an important ethical issue (Wells et al., 2012). Despite thesefactors preventing its use as a primary endpoint, mortality should still be recorded in all trials aspooled data from multiple studies or the continued treatment of study subjects through an extensiontrial can provide companies with a way to prove a drug’s value in extending survival. HOSPITALIZATION

In IPF, the hospitalization of patients can signify negative events such as drastic disease progression,acute exacerbation, bouts of heightened symptoms, or issues with co-morbidities. Consequently,tracking non-elective hospitalizations in clinical trials can provide a method for inferring atreatment’s positive, or negative, impact on these factors. Like mortality, hospitalizations can besegmented into all-cause, respiratory-related, or IPF-related hospitalizations. All-cause hospitalizationis typically the endpoint of choice due to its straightforward definition; however, it is still limited tobeing a secondary endpoint because of inconsistencies introduced by patients’ varying access tohealthcare and regional practice patterns (Raghu et al., 2012). PROGRESSION-FREE SURVIVAL

Commonly used in oncology, some IPF clinical trials have also used progression-free survival (PFS) as asecondary endpoint. However, progression is less easily defined in IPF, requiring PFS outcomes to bemeasured as a composite endpoint. Typically, PFS is defined as a decline in predicted FVC ≥10% ordeath, but it can also include DLCO, acute exacerbation, and hospitalization components (Maher,2013). However, the use of a composite endpoint creates a number of difficulties. Firstly, one of thecomponents involved in the composite measure can drive the PFS results if it tends to occur moreoften than others, somewhat defeating the purpose of using multiple endpoints. Furthermore, theefficacy of a particular treatment can be easily misinterpreted if the endpoints included in thecomposite outcome have dissenting results. For example, PFS may appear to be low because patientshad a high hospitalization rate, even if the study treatment was effective in preventing FVC declineand acute exacerbations (Raghu et al., 2012). PATIENT-REPORTED OUTCOMES

Questionnaires collecting patient-reported outcomes are commonly used within secondary endpointsin IPF clinical trials as they can demonstrate a drug’s impact on patients’ quality of life, helping tosecure reimbursement (Maher, 2013). The most commonly used tests to measure IPF patients’ overallquality of life are the St George’s Respiratory Questionnaire (SGRQ) and the Short Form (36) HealthSurvey (SF-36). Both tests have been validated in IPF, and the MCID for the SGRQ and SF-36 werefound to be 5–8 and 2–4 points, respectively (Swigris et al., 2010b). Other tests, such as the Universityof California, San Diego Shortness of Breath Questionnaire, focus more on monitoring symptoms ofIPF, namely dyspnea. While there have been recent efforts to design questionnaires specifically meantfor IPF patients, they have yet to gain uptake in clinical trials (Olson et al., 2012). BIOMARKERS

No biomarkers have been validated in IPF yet, although a number of proteins and cell types have beenfound to be statistically associated with poor prognosis in smaller clinical trials. High blood


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concentrations of Krebs von den Lungen 6/mucin-1, CC chemokine ligand-18, surfactant protein A,matrix metalloproteinase-7, intercellular adhesion molecule-1, interleukin-8, circulating fibrocytes,periostin, and semaphoring-7a positive regulatory T cells have all been associated with inferior patientsurvival (Barlo et al., 2010; Maher, 2013; Nathan and Meyer, 2014; Zhang and Kaminski, 2012).However, larger trials studying these potential biomarkers will need to be conducted before they canbe used to stratify patients or measure treatment efficacy in clinical trials. FUTURE DEVELOPMENTS IN CLINICAL TRIAL DESIGN TRIALS WILL LIKELY SHIFT AWAY FROM USING PLACEBO AS A COMPARATOR

With the approval of both Esbriet and Ofev in the US, Datamonitor Healthcare believes that futurerandomized trials are likely to shift away from using placebo as a control arm and instead use one ofthese treatments as an active comparator. During the development of Esbriet and Ofev, there was noestablished, effective standard-of-care treatment available for IPF which they could be compared to.Therefore, it was acceptable to compare them against placebo in all trials. However, now that one orboth of these drugs are widely available in all major markets and their efficacy has been demonstratedin multiple studies, therapies in development for IPF will likely begin to use one or both of these drugsas a comparator. This will prevent patients from having to receive placebo for long periods of time,help with enrollment in trials, and aid in the regulatory approval process if results are positive.However, it will also make it more difficult for treatments to demonstrate efficacy, as they will needto show superiority, or at least non-inferiority, to currently approved drugs rather than placebo. Thetransition away from using placebo in IPF trials is likely to be eased into place by pipeline treatmentsseeking to gain approval as add-on therapies. These combination trials will likely be designed to testthe combination against monotherapy with one or both of its components, eliminating the need for aplacebo arm. ENDPOINTS AND INCLUSION CRITERIA WILL CONTINUE TO BECOME MORE STANDARDIZED

In order to better gauge the effectiveness and applicability of new therapies, clinical trial design willneed to be more standardized across studies, especially in terms of inclusion criteria and endpoints.The majority of current clinical trials are limited to those IPF patients who would commonly beconsidered to be of mild or moderate disease severity; however, the criteria used to define thispopulation in each trial varies slightly. Whether it is through a clear definition of predicted FVC andpredicted DLCO values for severity cutoffs, or establishing an integrated staging system such as theGAP index, a well-defined method of stratifying patients would help to standardize inclusion criteria(Kolb and Collard, 2014). Additionally, solidifying which endpoints should be used, as well as how theyare measured and how missing data are imputed, would aid in comparing or pooling clinical trial data(Raghu et al., 2012). While validating and standardizing these factors will prove to be challenging,these changes would help facilitate both regulatory and clinical decision-making processes for futureIPF treatments. Bibliography

ATS guideline (2002) ATS Statement: Guidelines for the Six-Minute Walk Test. Available from:http://www.atsjournals.org/doi/pdf/10.1164/ajrccm.166.1.at1102 [Accessed 24 September 2015].


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Barlo NP, van Moorsel CH, van den Bosch JM, Grutters JC (2010) Predicting prognosis in idiopathicpulmonary fibrosis. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases, 27(2), 85–95<PMID>21319590</PMID>.

Collard HR, Yow E, Richeldi L, Anstrom KJ, Glazer C (2013) Suspected acute exacerbation of idiopathicpulmonary fibrosis as an outcome measure in clinical trials. Respiratory Research, 14(73), 1–7<DOI>10.1186/1465-9921-14-73</DOI>.

du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, King TE, Lancaster L, NoblePW, Sahn SA, Thomeer M, Valeyre D, Wells AU (2011a) Forced Vital Capacity in Patients withIdiopathic Pulmonary Fibrosis: Test Properties and Minimal Clinically Important Difference. AmericanJournal of Respiratory and Critical Care Medicine, 184(12), 1382–9 <DOI>10.1164/rccm.201105-0840OC</DOI>.

du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, Lancaster L, Noble PW, SahnSA, Szwarcberg J, Thomeer M, Valeyre D, King TE (2011b) Six-minute-walk test in idiopathicpulmonary fibrosis: test validation and minimal clinically important difference. American Journal ofRespiratory and Critical Care Medicine, 183(9), 1231–7 <DOI>10.1164/rccm.201007-1179OC</DOI>.

King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM,Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigri JJ, Noble PW(2014a) A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. The NewEngland Journal of Medicine, 370, 2083−92 <DOI>10.1056/NEJMoa1402582</DOI>.

King TE, Albera C, Bradford WZ, Costabel U, du Bois RM, Leff JA, Nathan SD, Sahn SA, Valeyre D, NoblePW (2014b) All-Cause Mortality Rate in Patients with Idiopathic Pulmonary Fibrosis: Implications forthe Design and Execution of Clinical Trials. American Journal of Respiratory and Critical CareMedicine, 189(7), 825–31 <DOI>10.1164/rccm.201311-1951OC</DOI>.

Kolb M, Collard HR (2014) Staging of idiopathic pulmonary fibrosis: past, present and future.European Respiratory Review, 23(132), 220–4 <DOI>10.1183/09059180.00002114</DOI>.

MacIntyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten C, Brusasco V, Burgos F, Casaburi R,Coates A, Enright P, Gustafsson P, Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pederson OF,Pellegrino R, Wanger J (2005) Standardisation of the single-breath determination of carbon monoxideuptake in the lung. European Respiratory Journal, 26(4), 720–35<DOI>10.1183/09031936.05.00034905</DOI>.

Maher TM (2013) Idiopathic pulmonary fibrosis. European Respiratory Monograph, 62, 37–53<DOI>10.1183/1025448x.10044512</DOI>.

Maldonado F, Moua T, Rajagopalan S, Karwoski RA, Raghunath S, Decker PA, Hartman TE, BartholmaiBJ, Robb RA, Ryu JH (2014) Automated quantification of radiological patterns predicts survival inidiopathic pulmonary fibrosis. European Respiratory Journal, 43(1), 204–12


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<DOI>10.1183/09031936.00071812</DOI>.

Nathan SD, Meyer KD (2014) IPF clinical trial design and endpoints. Current Opinion in PulmonaryMedicine, 20(5), 463–71 <DOI>10.1097/MCP.0000000000000091</DOI>.


Oda K, Ishimoto H, Yatera K, Naito K, Ogoshi T, Yamasaki K, Imanaga T, Tsuda T, Nakao H, Kawanami T,Mukae H (2014) High-resolution CT scoring system-based grading scale predicts the clinical outcomesin patients with idiopathic pulmonary fibrosis. Respiratory Research, 15(1), 1–9 <DOI>10.1186/1465-9921-15-10</DOI>.

Olson AL, Swigris JJ, Brown KK (2012) Clinical trials and tribulations—lessons from pulmonary fibrosis.QJM: An International Journal of Medicine, 105(11), 1043–7 <DOI>10.1093/qjmed/hcs066</DOI>.

Raghu G, Collard HR, Anstrom KJ, Flaherty KR, Fleming TR, King TE, Martinez FJ, Brown KK (2012)Idiopathic Pulmonary Fibrosis: Clinically Meaningful Primary Endpoints in Phase 3 Clinical Trials.American Journal of Respiratory and Critical Care Medicine, 185(10), 1044–8<DOI>10.1164/rccm.201201-0006PP</DOI>.



Swigris JJ, Wamboldt FS, Behr J, du Bois RM, King TE, Raghu G, Brown KK (2010a) The six-minute walkin idiopathic pulmonary fibrosis: longitudinal changes and minimum important difference. Thorax,65(2), 173–7 <DOI>10.1136/thx.2009.113498</DOI>.

Swigris JJ, Brown KK, Behr J, du Bois RM, King TE, Raghu G, Wamboldt FS (2010b) The SF-36 andSGRQ: validity and first look at minimum important differences in IPF. Respiratory Medicine, 104(2),296–304 <DOI>10.1016/j.rmed.2009.09.006</DOI>.

Wells AU, Behr J, Costabel U, Cottin V, Poletti V, Richeldi L (2012) Hot off the breath: Mortality as aprimary end-point in IPF treatment trials: the best is the enemy of the good. Thorax, 67(11), 938–40


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<DOI>10.1136/thoraxjnl-2012-202580</DOI>.

Zhang Y, Kaminski N (2012) Biomarkers in idiopathic pulmonary fibrosis. Current Opinion inPulmonary Medicine, 18(5), 441–6 <DOI>10.1097/MCP.0b013e328356d03c</DOI>.


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Product profile (late stage): FG-3019 PRODUCT PROFILE Analyst Outlook

Early trial results of FibroGen’s FG-3019 in idiopathic pulmonary fibrosis (IPF) were encouraging andwarrant further study of the drug in larger trials. FG-3019 improved fibrosis by measure ofquantitative high-resolution computed tomography (HRCT) in 24% of patients during an initial PhaseII trial. However, due to the limited design of this study, FibroGen will seek to validate these results ina second, larger Phase II study. If successful, the clinical and commercial potential of FG-3019 wouldbe further amplified by the identification of a predictive biomarker. Drug Overview

FG-3019 is a human monoclonal antibody (MAb) targeting connective tissue growth factor (CTGF).Commonly associated with the pathogenesis of IPF, CTGF induces fibroblast proliferation, extracellularmatrix deposition, and chemotaxis (Allen and Spiteri, 2002). In early studies, the inhibition of CTGF byFG-3019 has shown the potential to both reverse established lung fibrosis and prevent furtherscarring (Huber et al., 2010; Mageto et al., 2004).


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In 1998, FibroGen and Medarex entered into a development agreement in which Medarex wouldutilize its proprietary HuMAb-mouse technology to develop human MAbs against targets identified byFibroGen. Subsequently, in 2002, FibroGen exercised its option to license 12 antibodies developedthrough this collaboration, including FG-3019 (FibroGen SEC Filing, 2014).

The tables below summarize the design of FG-3019’s Phase II studies.

Table 38: FG-3019 drug profile

Molecule n/a

Phase of development Phase II

Mechanism of action Anti-CTGF MAb

Originator FibroGen

Marketing company FibroGen

Targeted indication Mild to moderate IPF

Formulation Intravenous

Pricing strategy 10% premium to average cost of Esbriet and Ofev

Dosing frequency 30mg/kg every three weeks

Estimated approval date Q3 2021 (US), Q4 2021 (5EU), Q2 2022 (Japan)

Alternative names n/a

5EU = five major EU markets (France, Germany, Italy, Spain, and the UK); CTGF = connective tissue growth factor; IPF = idiopathic pulmonary

fibrosis; MAb = monoclonal antibody

Source: Datamonitor Healthcare; BioMedTracker, Copyright 2015, reprinted with permission;ClinicalTrials.gov; Medtrack, October 2015, Copyright Informa UK; Pharmaprojects ®, 2015;Citeline


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Table 39: FG-3019 Phase II data in idiopathic pulmonary fibrosis


duration

Results Reference

NCT01262001

(Phase II)

66 First dose cohort: enrolled mild

to severe IPF patients

(predicted FVC 45–85%)

Second dose cohort:

enrollment criteria were

revised to mild to moderate IPF

patients (predicted FVC ≥55%)

Open-label, single-group

assignment, safety/efficacy

study

Arm 1: FG-3019 15mg/kg

every three weeks


every three weeks

Duration: 48 weeks

24% of patients had improved

fibrosis as measured by

quantitative HRCT at week 48

Mean FVC change for all

patients who completed one

year of treatment (n=66) was -

140ml

Mean FVC change for mild to

moderate patients at one year

(n=60) was -110ml

FibroGen press release, 2014

FVC = forced vital capacity; HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary fibrosis

Source: see above


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Table 40: FG-3019 Phase II trial in idiopathic pulmonary fibrosis

Trial Sample size Target patients Study design Treatment arms Primary endpoints Start date/primary

completion date

NCT01890265

(Phase II)


(predicted FVC ≥55%)


parallel-assignment,



every three weeks

Arm 2: placebo

Change in predicted FVC from

baseline to week 48

June 2013/February 2017

FVC = forced vital capacity; IPF = idiopathic pulmonary fibrosis



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SWOT ANALYSIS

Figure 36: FG-3019 for idiopathic pulmonary fibrosis – SWOT analysis

Source: Datamonitor Healthcare; FibroGen press release, 2014


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The figure below depicts Datamonitor Healthcare’s drug assessment summary for FG-3019 in IPF.

The figure below provides a breakdown of how Datamonitor Healthcare scored FG-3019’s clinical andcommercial attractiveness. The weighting given to each attribute is also shown.

Figure 37: Datamonitor Healthcare’s drug assessment of FG-3019 for idiopathic pulmonary fibrosis



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Improvements in fibrosis seen in Phase II trials are encouraging, but require furthervalidation

The results from early trials testing FG-3019 in mild to moderate IPF demonstrated the drug has thepotential to improve fibrosis in patients with IPF; however, larger studies will need to be conducted inorder for FibroGen to confirm the drug’s efficacy. Of the 66 patients completing 48 weeks oftreatment during FG-3019’s initial Phase II trial, 24% had improved fibrosis as measured byquantitative HRCT. Patients who had improved or stable fibrosis experienced a mean forced vitalcapacity (FVC) improvement of 40ml (FibroGen press release, 2014). While this may not seem drastic,FG-3019 is the first drug to show the potential to reverse fibrosis in patients with IPF, resulting inimproved lung function (FibroGen press release, 2012). However, due to the limitations of this study, itis difficult to elucidate the degree of benefit that FG-3019 truly offers. The small sample size of thestudy makes it more susceptible to false positive outcomes due to the heterogeneous nature of IPF.Additionally, the lack of a placebo arm means it is difficult to discern how much of the benefitobserved was actually due to treatment with FG-3019. Therefore, FibroGen will conduct a larger,randomized, double-blind, placebo-controlled Phase II study in order to validate its findings. The trialwill test FG-3019 at 30mg/kg every three weeks versus placebo, using change in predicted FVC as theprimary endpoint and quantitative HRCT as a secondary endpoint (ClinicalTrials.gov identifier:NCT01890265). Identification of a biomarker would largely increase FG-3019’s clinical potential

If FG-3019’s ability to reverse fibrosis in select patients is confirmed in ongoing trials, theidentification of a predictive biomarker or subgroup of patients who respond best to treatment could

Figure 38: Datamonitor Healthcare’s drug assessment of FG-3019 for idiopathic pulmonary fibrosis



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earn it preferential use over Esbriet (pirfenidone; Roche/Shionogi) and Ofev (nintedanib; BoehringerIngelheim). In FG-3019’s prior Phase II study, results in patients who responded well to therapy wereexcellent, but results in the overall population were less impressive. After a full year of treatment, the60 patients who were defined as having mild to moderate disease (FVC ≥55% of predicted) had amean FVC decline of 110ml (FibroGen press release, 2014). Although the lack of a placebo arm in thisstudy makes accurate comparisons across trials implausible, this is somewhat similar to the averageFVC decline observed in patients receiving Ofev and Esbriet in late-phase clinical trials. However, byidentifying patients who would likely respond better to FG-3019, the drug could gain significant usein these select patients. No potential biomarkers have yet been identified, but FG-3019’s second,larger Phase II study will provide a better opportunity to do so. Bibliography

Allen JT, Spiteri MA (2002) Growth factors in idiopathic pulmonary fibrosis: relative roles. RespiratoryResearch, 3(1), 13 <DOI>10.1186/rr162</DOI>.

FibroGen press release (2012) FibroGen Announces Promising Preliminary Data from an Open-labelPhase 2 Study to Evaluate the Safety and Efficacy of FG-3019 in Individuals with IdiopathicPulmonary Fibrosis (IPF) and Provides Program Update. Available from:http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=1983434 [Accessed 11September 2015].

FibroGen press release (2014) FibroGen Announces One-Year Data Supporting the Safety and EfficacyProfile of FG-3019 in Patients with Idiopathic Pulmonary Fibrosis. Available from:http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=1982805 [Accessed 11September 2015].

FibroGen SEC Filing (2014) Fibrogen Form 424B4. Available from:http://investor.fibrogen.com/mobile.view?c=253783&v=202&d=3&id=aHR0cDovL2FwaS50ZW5rd2l6YXJkLmNvbS9maWxpbmcueG1sP2lwYWdlPTk5MDQ0NzQmRFNFUT0xJlNFUT0xODUmU1FERVNDPVNFQ1RJT05fUEFHRSZleHA9JnN1YnNpZD01Nw%3D%3D [Accessed 14 September 2015].

Huber PE, Bickelhaupt S, Peschke P, Tietz A, Wirkner U, Lipson KE (2010) Reversal Of EstablishedFibrosis By Treatment With The Anti-CTGF Monoclonal Antibody FG-3019 In A Murine Model OfRadiation-Induced Pulmonary Fibrosis. Available from:http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2010.181.1_MeetingAbstracts.A1054[Accessed 14 September 2015].

Mageto Y, Flaherty K, Brown K, Fong A, Raghu G (2004) Safety and Tolerability of Human MonoclonalAntibody FG-3019, Anti-Connective Tissue Growth Factor, in Patients with Idiopathic PulmonaryFibrosis. Chest, 126(4), 773S <DOI>10.1378/chest.126.4_MeetingAbstracts.773S-a</DOI>.


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Product profile (late stage): PRM-151 PRODUCT PROFILE Analyst Outlook

Although Promedior’s lead product PRM-151 demonstrated the ability to improve forced vital capacity(FVC) in its small Phase I study, overall results of the trial were somewhat mixed and open tointerpretation. Nonetheless, the results were positive enough for the company to progress it to aPhase II trial. Depending on the results of this study, Bristol-Myers Squibb may choose to exercise itsoption to acquire Promedior and add PRM-151 to its growing portfolio of anti-fibrosis therapies. Thiswould largely improve PRM-151’s commercial prospects and would be likely to expedite itsdevelopment. Drug Overview

PRM-151 is an intravenous formulation of recombinant human pentraxin-2 in development foridiopathic pulmonary fibrosis (IPF) and myelofibrosis. Pentraxin-2, also referred to as serum amyloid P,has been found to inhibit apoptosis, airway inflammation, pulmonary fibrocyte accumulation, andcollagen deposition driven by transforming growth factor beta-1 (Murray et al., 2011). Pentraxin-2also promotes macrophages associated with increased expression of interleukin-10 and interferongamma-induced protein-10, which both possess anti-fibrotic properties (Duffield et al., 2013;Promedior press release, 2011).


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Table 42: PRM-151 Phase I data in idiopathic pulmonary fibrosis


duration

Results Reference

NCT01254409

(Phase I)

20 Diagnosed IPF patients Randomized, double-blind,

parallel-assignment, multiple-

dose, safety study

Arm 1: PRM-151 1mg/kg



Arm 4: placebo

Duration: 57 days


absolute FVC:

Arm 1: 58ml

Arm 2: 60ml

Arm 3: 78ml

Arm 4: -63ml;


predicted DLCO:

Arm 1: 0.2%

Arm 2: -4.0%

Arm 3: -1.5%

Arm 4: -2.3%;


predicted FEV1:

Van Den Blink et al., 2013


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Table 42: PRM-151 Phase I data in idiopathic pulmonary fibrosis


duration

Results Reference

Arm 1: 2.6%

Arm 2: 2.4%

Arm 3: 0.3%

Arm 4: -1.7%;


6MWT distance:

Arm 1: -11.2m

Arm 2: 5.8m

Arm 3: 34.8m

Arm 4: -10.5m

6MWT = six-minute walk test; DLCO = diffusion capacity of the lung for carbon monoxide; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; IPF = idiopathic pulmonary fibrosis

Source: see above


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Table 43: PRM-151 Phase II trial in idiopathic pulmonary fibrosis

Trial Sample size Target patients Study design Treatment arms Primary endpoints Start date/primary

completion date

NCT02550873

(Phase II)

117 Mild to moderate IPF patients (predicted FVC ≥50%

and ≤90%; predicted DLCO ≥25% and ≤90%;

minimum 6MWT distance of 150m; FEV1/FVC ratio

>0.7)


parallel-assignment,



days 1, 3, and 5, then once

every four weeks

Arm 2: placebo

Duration: 28 weeks

Change from baseline in

predicted FVC

August 2015/March 2017

6MWT = six-minute walk test; DLCO = diffusion capacity of the lung for carbon monoxide; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; IPF = idiopathic pulmonary fibrosis



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SWOT ANALYSIS

Figure 39: PRM-151 for idiopathic pulmonary fibrosis – SWOT analysis

Source: Datamonitor Healthcare; Bristol-Myers Squibb press release, 2015; Van Den Blink etal., 2013


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188


The figure below depicts Datamonitor Healthcare’s drug assessment summary for PRM-151 in IPF.

The figure below provides a breakdown of how Datamonitor Healthcare scored PRM-151’s clinical andcommercial attractiveness. The weighting given to each attribute is also shown.

Figure 40: Datamonitor Healthcare’s drug assessment of PRM-151 for idiopathic pulmonary fibrosis



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Despite mixed results, early studies show PRM-151’s potential to improve FVC

Although results of PRM-151’s initial Phase I trial were somewhat mixed, the drug did show thepotential to improve lung function in IPF patients, and therefore warrants further testing in largerPhase II studies. The Phase I trial enrolled 20 IPF patients who were treated with one of three differentdoses of PRM-151 or placebo. Results showed that PRM-151 improved both FVC and six-minute walktest distance in a dose-dependent fashion. Patients receiving PRM-151 also saw marginal increases inpercent-predicted forced expiratory volume in one second; however, patients receiving smaller dosessaw larger improvements, decreasing confidence in this endpoint’s outcome. Changes in percent-predicted diffusion capacity of the lung for carbon monoxide also varied, with two treatment cohortsperforming better than placebo, and the other performing worse. Nonetheless, overall results of theselung function tests trended in favor of PRM-151, especially when data for all treatment cohorts arepooled (Promedior press release, 2013; Van Den Blink et al., 2013). Although imbalanced baselinecharacteristics could have skewed results, the unmet needs within IPF make these results positiveenough to proceed to Phase II trials, which initiated in August 2015 (ClinicalTrials.gov identifier:NCT02550873). The design of Phase II studies will gauge PRM-151’s efficacy in multiple settings

Due to the broad enrollment criteria of its Phase II trial, PRM-151 will be tested in multiple lines oftherapy and in multiple combinations, broadening the drug’s potential range of clinical applications,which can then be explored further in Phase III studies. The Phase II trial will enroll treatment-naïvepatients, as well as patients who have received Esbriet (pirfenidone; Roche/Shionogi) or Ofev(nintedanib; Boehringer Ingelheim) and have stopped treatment at least four weeks prior to initiating

Figure 41: Datamonitor Healthcare’s drug assessment of PRM-151 for idiopathic pulmonary fibrosis



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the study. Therefore, PRM-151 will technically be tested in the first, second, and potentially third linesof therapy. Furthermore, the trial will also include patients currently being treated with Esbriet orOfev who have been on a stable dose for at least three months without an increase in predicted FVCon two consecutive pulmonary function tests. This will test PRM-151’s viability as an add-on therapyfor IPF patients who are not responding particularly well to Esbriet or Ofev alone (ClinicalTrials.govidentifier: NCT02550873).

Although patients in all of these different settings will be included in the study, it remains to be seenwhether Promedior will stratify patients according to all of these segmentations. Furthermore, the sizeof the study (current estimated enrollment of 117 patients) may not be powered to detect significantdifferences in such narrowly defined patient segments (ClinicalTrials.gov identifier: NCT02550873).Nonetheless, if results are positive, this broad approach will be useful in guiding the design of PRM-151’s Phase III program. Bristol-Myers Squibb may add PRM-151 to its growing portfolio of anti-fibrosis drugs

Bristol-Myers Squibb may choose to acquire Promedior in order to add PRM-151 to its growingportfolio of early-stage drugs addressing fibrotic diseases. In August 2015, the two companies reachedan agreement in which Bristol-Myers Squibb paid $150m upfront in exchange for exclusive rights toacquire Promedior. This payment will help Promedior fund Phase II trials in both IPF and myelofibrosis,after which Bristol-Myers Squibb can exercise its option with an additional fee (Bristol-Myers Squibbpress release, 2015). Bristol-Myers Squibb already has a similar agreement with Galecto Biotech AB inorder to gain exclusive rights to its lead product TD139, an inhalable galectin-3 inhibitor in Phase I/IIdevelopment for IPF (Bristol-Myers Squibb press release, 2014). Along with Bristol-Myers Squibb’sown lysophosphatidic acid 1 receptor antagonist, BMS-986020, these three products may allow thecompany to become a key player in the future IPF market. Bibliography

Bristol-Myers Squibb press release (2014) Bristol-Myers Squibb Signs Exclusive Option Agreement toAcquire Galecto Biotech AB and Its Novel Galectin-3 Inhibitor in Development for IdiopathicPulmonary Fibrosis. Available from: http://news.bms.com/press-release/bristol-myers-squibb-signs-exclusive-option-agreement-acquire-galecto-biotech-ab-and-i&t=635506103029481964 [Accessed21 September 2015].

Bristol-Myers Squibb press release (2015) Bristol-Myers Squibb Enters Agreement Providing ExclusiveRight to Acquire Promedior, Inc. and its Novel PRM-151 in Development for Fibrotic Diseases.Available from: http://news.bms.com/press-release/rd-news/bristol-myers-squibb-enters-agreement-providing-exclusive-right-acquire-promed&t=635766082628572412 [Accessed 9 September 2015].

Duffield JS, Lupher M, Thannickal VJ, Wynn TA (2013) Host Responses in Tissue Repair and Fibrosis.Annual Review of Pathology Mechanisms of Disease, 8, 241–76 <DOI>10.1146/annurev-pathol-020712-163930</DOI>.

Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X, Gulati M, Homer RJ, Russell T, van


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Rooijen N, Elias JA, Hogaboam CM, Herzog EL (2011) TGF-beta driven lung fibrosis is macrophagedependent and blocked by Serum amyloid P. International Journal of Biochemistry and Cell Biology,43(1), 154–62 <DOI>10.1016/j.biocel.2010.10.013</DOI>.

Promedior press release (2011) Promedior Announces Publication of New Research DemonstratingPentraxin-2/SAP is a Potent Inhibitor of Pulmonary Fibrosis. Available from:http://www.promedior.com/news/releases/2011%200210%20IPF%20Data.html [Accessed 28September 2015].

Promedior press release (2013) Promedior Presents Encouraging Results from Clinical Study of PRM-151 in Patients with Idiopathic Pulmonary Fibrosis. Available from:http://www.promedior.com/news/releases/2013%200522%20Promedior%20PRM-151%20IBS%20Ph1b%20Results.html [Accessed 21 September 2015].

Promedior press release (2015) Promedior Announces Initiation of a Phase 2 Clinical Study of PRM-151 in Idiopathic Pulmonary Fibrosis (IPF). Available from:http://www.promedior.com/news/releases/2015%200907%20Promedior%20Announces%20Initiation%20of%20Phase%202%20Study%20of%20PRM-151%20in%20IPF.html [Accessed 9 September2015].

Van Den Blink B, Burggraaf J, Morrison LD, Ginns LC, Wijsenbeek MS, Moerland M, Dillingh MR, LupherM (2013) A Phase I Study Of PRM-151 In Patients With Idiopathic Pulmonary Fibrosis. Available from:https://cms.psav.com/cPaper2012/myitinerary/publication-39905.html?congress=ats2013 [Accessed17 September 2015].


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