Galvus Product Analysis - Informa€¦ · Primary patent expiry Q4 2022 (EU), Q4 2024 (Japan) Geographic availability Japan, 5EU Alternative names Equa (Japan), Jalra (Germany) 2015

Galvus Product Analysis

Ref Code: DMKC0080871Publication Date: 12/07/2016Author: Rajan Sharma

Datamonitor HealthcarePharma intelligence |


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Galvus Product Analysis DMKC0080871 | Published on 12/07/2016

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Reference: DMKC0080871 First published: 12/07/2016

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TABLE OF CONTENTS

LIST OF FIGURES

LIST OF TABLES

4 PRODUCT PROFILES4 Galvus : Diabetes type 2

8 Figure 1: Galvus brand franchise for type 2 diabetes – SWOT analysis10 Figure 2: Datamonitor Healthcare drug assessment of Galvus10 Figure 3: Datamonitor Healthcare drug assessment scorecard for Galvus compared to Januvia

4 Table 1: Galvus franchise products4 Table 2: Galvus drug profile5 Table 3: Eucreas drug profile6 Table 4: Overview of pivotal trial data for Galvus franchise in diabetes


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PRODUCT PROFILES Galvus : Diabetes type 2 PRODUCT PROFILE Analyst Outlook

Galvus (vildagliptin; Novartis) was the second-to-market dipeptidyl peptidase-IV (DPP-IV) inhibitor inmany countries, but was unable to show superiority to Januvia (sitagliptin; Merck & Co). Non-superiorefficacy and liver safety signals caused registration delays and lack of approval in the US market.However, fixed-dose combination Eucreas (vildagliptin/metformin; Novartis) launched before thecompetitor Janumet (sitagliptin/metformin; Merck & Co) in some European markets, and has attractedmore sales there than Merck & Co's drug.

Novartis offers vildagliptin as Galvus franchise products, which are listed below.

Drug Overview

Galvus is a member of the DPP-IV inhibitor class. DPP-IV is an enzyme responsible for the rapiddegradation of the incretin hormone glucagon-like peptide-1 (GLP-1), which is released postprandiallyfrom the gut (Mest and Mentlein, 2005). Inhibition of DPP-IV augments the amount of active GLP-1,which in turn triggers increased insulin secretion from the pancreas in a glucose-dependent mannerand suppresses the release of glucagon, resulting in lowered blood glucose levels (Mentlein, 1999;Ahrén, 2005).

The franchise product Eucreas addresses the fact that Galvus is generally used as a second- or third-line treatment option as an add-on to metformin.

Table 1: Galvus franchise products

Product name Combination preparation

Galvus vildagliptin

Eucreas vildagliptin + metformin

Source: Datamonitor Healthcare


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Table 2: Galvus drug profile

Molecule vildagliptin

Mechanism of action DPP-IV inhibitor

Originator Novartis

Marketing company Novartis

Approved indication Type 2 diabetes

Target patient population Monotherapy or add-on to metformin and/or sulfonylurea, or

thiazolidinedione, or insulin

Contraindications Hypersensitivity; moderate and severe renal or hepatic impairment;

diabetic ketoacidosis; type 2 diabetes

Formulation Oral; 50mg tablet

Pricing strategy $59 for one month’s supply in UK (ex-factory)

Dosing frequency Twice daily

First launch date 2008 (5EU), 2010 (Japan)

Primary patent expiry Q4 2022 (EU), Q4 2024 (Japan)

Geographic availability Japan, 5EU

Alternative names Equa (Japan), Jalra (Germany)

2015 global total franchise sales $1,140m

5EU = five major EU markets (France, Germany, Italy, Spain, and the UK); DPP-IV = dipeptidyl peptidase-IV

Source: Medtrack


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DEVELOPMENT OVERVIEW

The table below shows pivotal trial data for the Galvus franchise.

Table 3: Eucreas drug profile

Molecule vildagliptin + metformin

Mechanism of action DPP-IV inhibitor + biguanide

Originator Novartis

Marketing company Novartis

Approved indication Type 2 diabetes

Target patient population Monotherapy or add-on to sulfonylurea or insulin

Contraindications Hypersensitivity; renal or hepatic impairment, dehydration, sepsis,

lactic acidosis; diabetic ketoacidosis; type 1 diabetes

Formulation Oral; 50/850mg, 50/1,000mg tablets

Pricing strategy $59 for one month’s supply in UK (ex-factory)

Dosing frequency Twice daily

First launch date 2008 (5EU), 2010 (Japan)

Primary patent expiry Q4 2022 (EU)

Geographic availability 5EU

Alternative names Icandra (Germany), Zomarist (Spain)

5EU = five major EU markets (France, Germany, Italy, Spain, and the UK); DPP-IV = dipeptidyl peptidase-IV

Source: Medtrack


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Table 4: Overview of pivotal trial data for Galvus franchise in diabetes

Phase Sample size Target

patients

Study design Dosing

tested and

duration

Results Source

III 632 Type 2

diabetes, drug-

naïve

Double-blind,

placebo-

controlled,

dose-ranging

RCT

50mg or

100mg once

daily or 50mg

twice daily, for

24 weeks

Vildagliptin (50mg once daily): HbA1c -0.8%

Vildagliptin (50mg twice daily): HbA1c -0.8%


Placebo: HbA1c -0.3%

Dejager et al.,

2007

III 544 Type 2

diabetes,

uncontrolled

on metformin

Double-blind,

placebo-

controlled, RCT

50mg or

100mg once

daily for 24

weeks

Vildagliptin (50mg) relative to placebo: HbA1c

-0.7%, FPG -0.8mmol/l, PPG -1.9mmol/l, beta-

cell function +5.2pmol/min/m/mmol/l, weight

±0.0kg

Vildagliptin (100mg) relative to placebo:

HbA1c -1.1%, FPG -1.7mmol/l, PPG -

2.3mmol/l, beta-cell function

+5.7pmol/min/m/mmol/l, weight +1.2kg

Bosi et al.,

2007

III 463 Type 2

diabetes, drug-

naïve

Double-blind,

active

comparator,

RCT

100mg once

daily, or 2g

metformin, for

104 weeks

Vildagliptin from baseline: HbA1c -1.0%,

weight +0.5kg, AE in 82.2% patients,

gastrointestinal AE in 25.0% patients

Metformin from baseline: HbA1c -1.5%,

weight -2.5kg, AE in 87.3% patients,

gastrointestinal AE in 45.6% patients

Göke et al.,

2008

III 576 Type 2

diabetes,

uncontrolled

on metformin

Double-blind,

active

comparator,

RCT

50mg twice

daily, or 30mg

pioglitazone,

for 24 weeks

Vildagliptin + metformin from baseline: HbA1c

-0.9%, FPG -1.4mmol/l, weight -1.6kg, serious

AE in 2.0% patients

Pioglitazone + metformin from baseline:

HbA1c -1.0%, FPG -2.1mmol/l, weight +1.9kg,

serious AE in 4.6% patients

Bolli et al.,

2007


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Galvus development showed liver safety signals

A liver signal in patients taking the 100mg, once-daily dose of vildagliptin was reported in clinicaltrials and resulted in delays to registration (Ligueros-Saylan et al., 2010; Smith, 2007). The livertoxicity issues meant that a European marketing authorization was only granted for the lower 50mgdose and warnings about the hepatotoxicity were added to the label (EMA, 2013a). The authorizationwas granted for the 50mg dose after a meta-analysis from Phase II and Phase III clinical trialsindicated no increased risk of hepatic events or enzyme elevations indicative of drug-induced livertoxicity (Ligueros-Saylan et al., 2010). SWOT ANALYSIS

Table 4: Overview of pivotal trial data for Galvus franchise in diabetes

Phase Sample size Target

patients

Study design Dosing

tested and

duration

Results Source

III 2,789 Type 2

diabetes,

HbA1c

6.5–8.5% on

metformin

Double-blind,

non-inferiority,

RCT

50mg twice

daily, or

titrated

glimepiride, for

52 weeks

Vildagliptin + metformin from baseline: HbA1c

-0.44%, FPG -1.01mmol/l, weight -0.23kg,

1.7% patients experienced hypoglycemic

events, serious AE in 7.1% patients

Glimepiride + metformin from baseline: HbA1c

-0.53%, FPG -1.14mmol/l, weight +1.56kg,

16.2% patients experienced hypoglycemic

events, serious AE in 9.5% patients

Ferranini et al.,

2009

III 632 Type 2

diabetes, drug-

naïve

Double-blind,

placebo-

controlled,

dose-ranging

RCT

50mg or

100mg once

daily or 50mg

twice daily, for

24 weeks


Vildagliptin (50mg twice daily): HbA1c -0.8%


Placebo: HbA1c -0.3%

Dejager et al.,

2007

AE = adverse events; FPG = fasting plasma glucose; HbA1c = glycated hemoglobin; PPG = postprandial glucose (measured after 2 hours); RCT

= randomized controlled trial

Source: various (see above)


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CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figure below depicts Datamonitor Healthcare's drug assessment summary for Galvus in relation to

Figure 1: Galvus brand franchise for type 2 diabetes – SWOT analysis



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the other marketed non-insulin antidiabetic products.

The figure below shows Galvus's drug assessment scorecard compared to Januvia.

Figure 2: Datamonitor Healthcare drug assessment of Galvus



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Twice-daily dosing and safety profile have hindered uptake

Galvus shows no efficacy benefit over Januvia, and its twice-daily dosing along with some negativesafety signals make the drug less attractive than other DPP-IV inhibitors. A warning was added toGalvus's label as a result of the liver safety signal in trials and monitoring of liver enzymes isrecommended in patients using vildagliptin (Ligueros-Saylan et al., 2010). This means increased costsfor payers and decreased convenience for patients using Galvus compared to other DPP-IV inhibitors.Liver toxicity is an unacceptable side effect for antihyperglycemic therapeutics, and Novartis dealtwith this issue by replacing the 100mg once-daily dose with twice-daily 50mg doses that did notshow hepatic toxicity in clinical studies. However, a twice-a-day dosing regimen is less convenientand decreases patient compliance, putting Galvus at a disadvantage compared to once-daily DPP-IVinhibitors. Galvus is unable to capitalize on its broad indication

Galvus does have a broad indication, but is unable to fully capitalize because more favorablealternatives are available. In December 2011, Galvus received an indication expansion for use in type2 diabetes patients with moderate or severe renal impairment (EMA, 2013a). This patientsubpopulation comprises up to one quarter of type 2 diabetes patients, so the indication expansionsignificantly broadened the target market for Galvus (Keane et al., 2003; Ritz et al., 1999). However,most other DPP-IV inhibitors also have indication expansions for use in renally impaired patients.Datamonitor Healthcare believes that Tradjenta (linagliptin; Boehringer Ingelheim/Eli Lilly) will be themore successful DPP-IV inhibitor in this niche market, as it does not need dose adjustment or liver

Figure 3: Datamonitor Healthcare drug assessment scorecard for Galvus compared to Januvia



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enzyme monitoring and its once-daily dosing is more convenient. Eucreas has had some success in the EU markets

Twice-daily Eucreas is the main driver of Galvus franchise sales in Europe (Novartis, 2013). Kombiglyze(saxagliptin/metformin; AstraZeneca) and Jentadueto (linagliptin/metformin; Boehringer Ingelheim/EliLilly) are Eucreas’s main competitors but, like Eucreas, these drugs are only available as twice-dailyformulations. Thus, Eucreas is not at a disadvantage to its main competitors. Its first-to-market fixed-dose combination status in some European countries has helped the drug to gain market share, andDatamonitor Healthcare expects physician familiarity to continuously drive brand sales in line withthe growth of the type 2 diabetic population. Galvus is not available in the US

Galvus is not marketed in the US, and not having access to the biggest antidiabetic marketsignificantly restricts its commercial success. A New Drug Application (NDA) was submitted to the USFood and Drug Administration (FDA) in March 2006, but in February 2007 the FDA requested thatNovartis undertake a study in patients with renal impairment (Smith, 2007). In July 2008 Novartiswithdrew its US application entirely, and it is assumed that no launch will take place there, cutting itoff from the most lucrative market (Johnson and Winslow, 2008). Safety issues will affect growth to a small extent

The use of DPP-IV inhibitors and GLP-1 agonists potentially increases the risk for acute pancreatitisand may be related to changes in pancreatic tissue, which Datamonitor Healthcare predicts will havea small detrimental effect on the growth of Galvus’s market share. Singh et al. (2013) published astudy derived from administrative patient data, stating that the risk of acute pancreatitis was nearlytwice as high in patients taking incretin mimetics such as DPP-IV inhibitors and GLP-1 agonists. InMarch 2013, the FDA and European Medicines Agency announced that they would launch aninvestigation into the safety of incretin mimetics, largely triggered by a study from a group ofresearchers who found precancerous cellular changes in the pancreases of patients using DPP-IVinhibitors or GLP-1 agonists (FDA, 2013; EMA, 2013). Shortly after, in July 2013, both agenciesannounced that their safety reviews did not show an unfavorable risk/benefit ratio and that incretinmimetics continued to be a safe treatment option (EMA, 2013c). The FDA also stated thatepidemiological studies and close monitoring of adverse events were ongoing (Scrip, 2013).

Datamonitor Healthcare expects physicians to be slightly more reluctant to prescribe incretinmimetics because of these unconfirmed findings, despite the regulatory agencies’ affirmation of thedrug classes' safety. However, in the absence of many alternatives, the effect on class growth will besmall. Bibliography

Ahrén B (2005) What mediates the benefits associated with dipeptidyl peptidase-IV inhibition?Diabetologia, 48, 605–7 <DOI>10.1007/s00125-005-1706-6</DOI>.


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Bolli G, Dotta F, Rochotte E, Cohen SE (2007) Efficacy and tolerability of vildagliptin vs. pioglitazonewhen added to metformin: a 24-week, randomized, double-blind study. Diabetes, Obesity andMetabolism, 10(1), 82–90 <DOI>10.1111/j.1463-1326.2007.00820.x</DOI>.

Bosi A, Camiasca RP, Collober C, Rochotte E, Garber AJ (2007) Effects of vildagliptin on glucosecontrol over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin.Diabetes Care, 30, 890–5 <DOI>10.2337/ dc06-1732</DOI>.

Dejager S, Razac S, Foley E, Schweizer A (2007) Vildagliptin in drug-naïve patients with type 2diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. Hormoneand Metabolic Research, 39(3), 218–23 <DOI>10.1055/s-2007-970422</DOI>.

EMA (2013a) EMA Galvus Product Information. Available from:http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000771/human_med_000803.jsp&mid=WC0b01ac058001d124 [Accessed 7 May 2013].

EMA (2013b) European Medicines Agency investigates findings on pancreatic risks with GLP-1-basedtherapies for type 2 diabetes. Available from:http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/03/news_detail_001753.jsp&mid=WC0b01ac058004d5c1 [Accessed 26 March 2013].

EMA (2013c) Investigation into GLP-1 based diabetes therapies concluded. Available from:http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001856.jsp&mid=WC0b01ac058004d5c1 [Accessed 30 July 2013].

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Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahrén B, Byiers S, Shao Q, Dejager S (2009) Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitusinadequately controlled on metformin monotherapy. Diabetes, Obesity and Metabolism, 11, 157–66<DOI>10.1111/j.1463-1326.2008.00994.x</DOI>.

Göke B, Hershon K, Kerr D, Pascuel AC, Schweizer A, Foley J, Shao Q, Dejager S (2008) Efficacy andsafety of vildagliptin monotherapy during 2-year treatment of drug-naïve patients with type 2diabetes: comparison with metformin. Hormone and Metabolic Research, 40(12), 892–5<DOI>10.1055/s-0028-1082334</DOI>.

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Keane WF, Brenner BM, Zeeuw D De, Grunfeld J-P, McGill J, Mitch WE, Ribeiro AB, Shahinfar S,Simpson RL, Snapinn SM (2003) The risk of developing end-stage renal disease in patients with type 2diabetes and nephropathy: the RENAAL study. Kidney International, 63, 1499–507<DOI>10.1046/j.1523-1755.2003.00885.x</DOI>.

Ligueros Saylan M, Foley J, Schweizer A, Couturier A, Kothny W (2010) An assessment of adverseeffects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin andin patients with impaired renal function from a large pooled database of Phase II and III clinical trials.Diabetes, Obesity and Metabolism, 12, 495–509 <DOI>10.1111/j.1463-1326.2010.01214.x</DOI>.

Mentlein R (1999) Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides.Regulatory Peptides, 85, 9–24 <DOI>10.1016/S0167-0115(99)00089-0</DOI>.

Mest H-J, Mentlein R (2005) Dipeptidyl peptidase inhibitors as new drugs for the treatment of type 2diabetes. Diabetologia, 48, 616–20 <DOI>10.1007/s00125-005-1707-5</DOI>.

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Ritz E, Rychlík I, Locatelli F, Halimi S (1999) End-stage renal failure in type 2 diabetes: A medicalcatastrophe of worldwide dimensions. American Journal of Kidney Diseases, 34, 795–808<DOI>10.1016/S0272-6386(99)70035-1</DOI>.

Scrip (2013) Scripintelligence - FDA CONCURS: No confirmation of new GLP-1, DPP-4 pancreaticconcerns. Available from: http://www.scripintelligence.com/home/FDA-CONCURS-No-confirmation-of-new-GLP-1-DPP-4-pancreatic-concerns-345359 [Accessed 30 July 2013].

Singh S, Chang H-Y, Richards TM, Weiner JP, Clark JM, Segal JB (2013) Glucagonlike Peptide 1-basedtherapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Internal Medicine, 173, 534–9<DOI>10.1001/jamainternmed.2013.2720</DOI>.

Smith A (2007) FDA holds Novartis’ Galvus back from U.S. market. Available from:http://money.cnn.com/2007/02/26/news/companies/novartis_merck/index.htm [Accessed 13 May2013].

Documents

Galvus Product Analysis - Informa€¦ · Primary patent expiry Q4 2022 (EU), Q4 2024 (Japan) Geographic availability Japan, 5EU Alternative names Equa (Japan), Jalra (Germany) 2015