Crohn's disease pharmascape cv

C h ‘ diCrohn‘s diseasePharmascapepAll information herein is publically availableThis document is meant only to illustrate Oliver Vit’s professional competencesand does not reflect Actelion Pharmaceuticals Ltd’s corporate views

Marketed biologics for Crohn‘s disease

Remicade®, infliximab

Humira®, adalimumabHumira®, adalimumab

Tysabri®, natalizumab

C ®Cimzia®, certolizumab

2 Life Cycle ManagementCompetitive intelligence analysis

Remicade® • Chimeric IgG1κ monoclonal antibody targeting TNF-α• Induction via intravenous infusion of 5mg/kg at week-0 & -2, followed by maintenance regimen of

5mg/kg every 6-weeks for responders at week-2• 1st registration trials based on 12- to 26-week endpoints, followed by label extensions in Crohn‘s

disease acheieved with maintenance therapy in 2 large Phase III trials demonstrating efficacy & steroidsparing effects at 1-year in both severe active & fistulating CD as required by REMs

• Results from 5mg/kg 2-week induction regimen followed by 5mg/kg every 8-weeks – ~60% responder rate to 1st administration (n=573)– 51% higher remission rate (CDAI <150 pts) at week-30 (39% Remicade@ vs 19% placebo)– median time to loss of response (↓ in CDAI score to ≥70 pts and ≥ 25% from baseline) was 27 weeks longer than

placebo (46 weeks Remicade@ vs 19 weeks placebo)56% hi h ti t i d i i th h k 54 (25% R i d @ 11% l b )– 56% higher proportion retained remission through week-54 (25% Remicade@ vs 11% placebo)

• Headache, abdominal pain, URTI & infusion site reactions most common reported AE• Black box warnings: malignancies specifically hepatosplenic T-cell lymphoma in CD patients, serious

infections inclusive of Hepatitis B reactivation, hepatoxicity inclusive of death and liver transplant, cytopenias, hypersensitivity inclusive of anaphylaxis, demyelinating disorders, Lupus-like syndrome & myocardial infarction reported in rare casesmyocardial infarction reported in rare cases

• 6-13% of CD patients test positive for infliximab NABs which are associated with a higher incidence ofinjection site reactions

• Intermittent therapy is not encouraged due to perceived higher immunogenicity risk• Crohn‘s disease was the 1st licensed indication

3

• Annual cost €21,573/$21,166

Life Cycle ManagementCompetitive intelligence analysis

Remicade® – CD development plan1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 20071995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Phase IIISevere active CD

RA PsA UC

Phase III

ACCENT I

Fistulizing active CD

ACCENT I

ACCENT II

Severe active CD

Fistulizing active CD

SONICAzothioprine/Infliximabcombination

4Launch Fistulas

extensionMaintenance

extensionLife Cycle ManagementCompetitive intelligence analysis

Humira® Humanized IgG monoclonal antibody targeting TNF α• Humanized IgG1 monoclonal antibody targeting TNF-α

• Induction via subcutaneous bolus dose of 80mg at week 0 followed by 40 or 80mg at week 2, followed by maintenance regimen of 40mg every other week with a pre-filled syringe orautoinjection pen in Crohn‘s Disease

• Fast acting agent with limited long term respondersg g g p• Results at week-26 maintained through week-56 with 80/40mg induction followed by 40mg EoW

– 44% higher remission rate (CDAI <150 pts) at week-56 (79% Humira®, 50% placebo)

– ~30% of patients achieve corticosteroid-free remission for ≥90 days– 127 days mean time to remission127 days mean time to remission– complete fistula closure achieved in ~30% of patients

• Injection site reaction/irritation most common reported AE• 2 cases of pulmonary tuberculosis and 1 case of MS reported in CHARM trial• Black box warnings: malignancies specifically lymphoma, serious infections inclusive ofac bo a gs a g a c es spec ca y y p o a, se ous ect o s c us e o

bacterial sepsis, TB reactivation, invasive fungal infections reported in rare cases• ≥ 150,000 patients in safety database across all indications as of 2007• 0.4-3.6% of patients test positive for adalimumab NABs• Fourth indication following RA, Psoriatic arthritis & Ankylosing spondylitis

5

g , y g p y• Annual cost €14,700/$20,339


Humira® – CD development plan2000 2001 2002 2003 2004 200 2006 200 2008 2009 2010 2011 20122000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

CLASSIC-I

RA PsA AS Pso JIA

CHARM

CLASSIC-II

GAIN

CHOICEInfliximab failures

EXTENDMucosal healing

CAREQoL outcomes

PYRAMID

6US

Launch

PYRAMIDLong term safety


Tysabri® • Monthly 300mg i.v. infusion of humanized monoclonal antibody against α-4 integrin, reducing

T cell traffic through the endothelium into tissueg• ENACT-1 trial failed to show significant induction effects at week-10, however ENCORE

demonstrated significant results at week-830% higher proportion of clinical response (↓CDAI score by 100 pts) at week-4(39% Tysabri® 300mg, 27% placebo)33% higher proportion of clinical response (↓CDAI score by 70 pts) sustained from week-8 to week-12(48% Tysabri® 300mg 32% placebo)(48% Tysabri® 300mg, 32% placebo)38% higher proportion of clinical remission (CDAI score < 150) sustained from week-8 to week-12(26% Tysabri® 300mg, 16% placebo)

• ENACT-2 demonstrated significant benefit upon long-term treatment54% higher rate of clinical response (↓CDAI score by 70 pts) sustained from week-10 to week-36(61% Tysabri® 300mg, 28% placebo)41% higher rate of clinical remission (CDAI score <150) sustained from week-10 to week-36(44% Tysabri® 300mg, 26% placebo)( % ysab ® 300 g, 6% p acebo)

• Injection site reaction/irritation most common reported AE• Rare malignancies & opportunistic infections cited with long-term exposure• Black box warnings: PML, hypersensitivity specifically anaphylaxis, immunosuppression and

hepatotoxicity reported in rare cases• As of 2010 one PML case reported in Crohn‘s Disease patients; in MS patients a total of 68

PML cases reported, inclusive of 14 deaths• ~10% of patients test positive for natalizumab NABs• Licensed exclusively in the US for Crohn‘s disease

$

7

• Annual cost estimated at $37,000 (based on MS figures)


Tysabri® – CD development plan1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

CD202

CD306

MS Launch Re-launchPML

ENACT-1

ENACT-2

CD306On top of Remicade®

CD305

ENACT 2

ENACT-2 ext

ENCORE

CD305Paediactric

CD352Paediactric

CD INFORMPharmacovigilance long-term safety

8

USLaunch


Cimzia® • Polyethylene glycolated Fab‘ fragment of humanized anti-TNF-α monoclonal antibody delivered by

monthly 400mg subcutaneous injectionmonthly 400mg subcutaneous injection• Phase IIb trial failed to demonstrate a benefit at week-12 in the ITT with 400mg against placebo; post-

hoc analysis suggests a correlation between CRP levels >10mg/L and efficacy• PRECISE 1 & PRECISE 2 trials stratify by CRP levels yet fail to establish a correlation between CRP

levels and efficacy, however reach statistical significance at week-6 and week-26

30% higher proportion of patients with baseline serum CRP levels of at least 10mg/L achievinga reduction of ≥ 100 points in the CDAI score at week-6 (37% Cimzia® 400mg, 26% placebo)

45% higher proportion of patients with baseline serum CRP levels of at least 10mg/L achievinga reduction of ≥ 100 points in the CDAI score at week-26 (62% Cimzia® 400mg, 34% placebo)

• Statistical responses begin at week-2• No explanation accounts for the differences between the increased proportion of patients achieving a

reduction in CDAI scores of ≥ 100 points or remission (CDAI total score <150) in PRECISE 2 (64%/43%) as opposed to PRECISE 1 (35%/22%)

• Maintenance of remission was only achieved in PRECISE 2• Maintenance of remission was only achieved in PRECISE 2• Black box warnings: malignancies specifically lymphoma, serious infections inclusive of bacterial

sepsis, TB reactivation, invasive fungal infections reported in rare cases• ~8% of patients test positive for certolizumab NABs• Licensed for use in Crohn‘s disease exclusively in the US; rejected by EMEA in 2007

9

• Annual costs $18,408


Cimzia® – CD development plan1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

CDP870

PRECISE 1

RA

MUSICMucosal healing

PRECISE 2

PRECISE 3Long-term OL for P1/P2

PRECISE 4Long-term OL for P1/P2 withdrawals due to CD exacerbation

C87042Remicade® failures

COSPAR1Corticosteroid sparing - TERMINATED

SECUREPharmacovigilance long-term safety

C87085Induction study

10US

LaunchUS

NDALife Cycle ManagementCompetitive intelligence analysis

Comparative induction capacity at week-4

Active Placebo Difference

Clinical Response (↓CDAI ≥70)

Remicade®, (5mg) 81% 17% 65%

Remicade®, (5, 10, 20mg) 65% 17% 48%

Humira®, (80/40mg induction) 58% 36% 22%Humira®, (80/40mg induction) 58% 36% 22%

Humira®, (40mg maintenance) 52% 34% 18%

Tysabri®, (300mg, ↑ CRP ENCORE) 51% 37% 15%

Cimzia®, (↑ CRP sub-group analysis) 50% 31% 19%

Cimzia®, (400mg, all patients) 44% 31% 10%

p-values 0.011 - 0.001p values 0.011 0.001


11

Comparative induction capacity at week-4

Active Placebo Difference

Clinical Remission (CDAI ≤150)

Remicade®, (5mg) 48% 4% 44%

Remicade®, (5, 10, 20mg) 36% 4% 28%

Humira®, (80/40mg induction) 33% 12% 24%Humira®, (80/40mg induction) 33% 12% 24%

Humira®, (40mg maintenance) 21% 7% 14%

Tysabri®, (300mg, ↑ CRP ENCORE) 24% 16% 8%

Cimzia®, (↑ CRP sub-group analysis) 20% 10% 10%

Cimzia®, (400mg, all patients) 19% 11% 8%

p-values 0.018 - 0.001p values 0.018 0.001


12

Crohn‘s disease competitors in development

Vedolizumab, MLN0002

Traficet-EN, CCX282-B

CEP-37248

AIN457

Stelara*

Laquinimod

CCX025

CP 690.550

CEP-37247, ART-621

ELND004

Briakinumab, ABT-874**

13

* Rumor: Phase II results positive and support Phase III** Rumor: Clinical development stopped in CD due to negative Phase II results


Crohn‘s disease: clinical development environment

CCR9 antagonistα-4-integrin

CCX025antagonist

ELND004CEP-37247

LaunchedPhase II Phase IIIPhase I

CP 690.550

JAK3 antagonistTraficet-ENVedolizumab

LaunchedPhase II Phase IIIPhase I

Laquinimod

Anti-proliferant/replicativeAIN457Stelara

Briakinumab

Anti-IL-17 CEP-37248oral

Anti-IL-12/IL-23

parenteral


Conclusions

• Remicade® dramatically changed the Crohn‘s disease treatment paradigm; diffcult differentiationbetween Remicade®, Humira®, Tysabri®, and Cimzia® outside of route of administration & rare safetysignals as witnessed by comparable prescription rates

• Response rates are only 30-60% in treatment naϊve patients; discontinuation in the case of inadequateinitial response is recommended in posology label textinitial response is recommended in posology label text

• Although efficacy did not wane during the conduct of the published clinical trials, the presence of NAB titers is associated with a significant loss in efficacy upon extended administration, eg >1yr

• Loss of efficacy & low differentiation drives high switch market between TNF-α agentsConfidential• All registration trials assessed efficacy by ∆CDAI scores, however the index is intrinsically prone tosubjective variability

• Placebo effect appears to be more pronounced over time (up to 47% in Cimzia® trials; average of 19% across 21 randomized CD trials)

Confidential• Alternative efficacy measures available Crohn‘s Disease Endoscopic Index of Severity (CDEIS)• Stellara® & briakinumab both demonstrated fast acting potential in other clinical trials, eg psoriasis• Biosimilars to Remicade® & Tysabri® may be available at the time of launch• Effective competitive oral therapy on the horizonEffective competitive oral therapy on the horizon


Back ups

Crohn‘s Disease Activity Index (CDAI)

Cli i l l b t i bl W i hti f t

Remission of Crohn's disease is defined as a CDAI <150

M d di i d fi d b l f 220 4 0Clinical or laboratory variable Weighting factor

Number of liquid or soft stools each day for seven days x 2

Abdominal pain (graded from 0-3 on severity) x 5

Moderate disease is defined by a value of 220-450

Severre disease is defined as >450

Clinical response is typically defined as a reduction >70

p (g y)each day for seven days x 5

General well being, subjectively assessed from 0 (well) to 4 (terrible) each day for seven days x 7

Presence of complications* x 20

Taking Lomitil or opiates for diarrhea x 30

Presence of an abdominal mass (0 as none, 2 as questionable 5 as definite) x 10

*One point each is added for each set of complications:•the presence of joint pain (arthralgia) or frank arthritis •inflammation of the iris or uveitis•presence of erythema nodosum, pyoderma gangrenosum or aphthous ulcers •Anal fissures fistulae or abscessesquestionable, 5 as definite)

Absolute deviation of Hematocrit from 47% in men and 42% in women x 6

Percentage deviation from standard weight x 1

Anal fissures, fistulae or abscesses•Other fistulae •Fever during the previous week

17 Lifecycle managementCompetitive intelligence analysis

Loss of response to Remicade®






Loss of response to Humira®


Remicade®


Remicade® – US label; indication


Remicade® – US label; warnings


Remicade® – EU label; indication


®Remicade® – EU label; warnings


®Remicade® – EU label; warnings


Remicade® – EU label; warnings


Remicade® – Clinical trials overview• Phase III Induction trial in severe active CD

– 4 week treatment in treatment failures– 5mg/kg, 10mg/kg, 20mg/kg or placebo on top of unsatisfactory background therapy – CDAI endpoints– 108 patients

• Phase III Induction trial in fistulizing active CD (NCT00207662)– 26 week treatment– 5mg/kg, 10mg/kg or placebo– CDAI endpoints– 94 patients

• ACCENT I Phase III Maintenance trial in severe active CD (NCT00207662)– 54 week treatment– 5mg/kg induction followed by 5mg/kg week-2 & 6 followed by 5mg/kg or 10mg/kg every 8-weeks, or placebo– CDAI endpointsp– 573 patients– 11 months recruitment– 6 countries, 55 sites (North America, Europe, IL)

• ACCENT II Phase III Maintenance trial in fistulizing active CD (NCT00207766)– 54 week treatment– 5mg/kg induction followed by 5mg/kg week-2 & 6 followed by 5mg/kg or 10mg/kg every 8-weeks, or placebo– CDAI endpoints

306 patients– 306 patients– 10 months recruitment– 6 countries, 45 sites (BE, CA, CZ, PL, NL, US)

• SONIC Phase III Combination trial with azathiaprine (NCT00094458)– 1 yr trial; 34 week Treatment Period I, 20 week Treatment Period II– 5mg/kg induction followed by 5mg/kg week-2 & 6 followed by 5mg/kg or 10mg/kg every 8-weeks, 2.5mg/kg OD azathioprine or both– CDAI endpoints, mucosal healing, steroid free, clinical response & remission– 508 patients


– 3 years 9 months recruitment

Remicade® – Phase III active CD; design 1998 FDA label

12-week alternative dosing regimens of Remicade® vs placebo on top ofconventional therapies in patients who failed to achieve adequate response(n=108)

Phase I Phase II Phase III

Remicade® 5mg/kg10mg/kg

Week 0 2 4 8 12 20 28 36 48

Phase I Phase II Phase III

20mg/kgPlacebo

10mg/kg*g g

CDAI assessment


* Infliximab treatment failures at the 1° endpointreceived a 2nd infusion of 10mg/kg @ week-4

Remicade® – Phase III active CD; results 1998 FDA label


Remicade® – Phase III fistulizing CD; design 1998 FDA label

22-week alternative dosing regimens of Remicade® vs placebo on top of conventional therapies in patients with inadequate response and fistulas ≥ 3-months(n=94)


Week 0 2 6 10 14 18 22

x x x

x x x

Placebox x x

Fistula assessment

X = administration


Remicade® – Phase III fistulating CD; results 1998 FDA label


Remicade® – Phase III ACCENT I; design 2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial

54-week alternative dosing regimens of Remicade® vs placeboin responders to first 2-week induction therapy(n=573)

Open label Double blind


Week-2 0 2 6 10 14 22 30 38 46 54


Placebo

Rescue Tx 5/10/15mg/kgCDAI assessment

IBDQ

Response assessed as CDAI score reduction at week-2


Response assessed as CDAI score reduction at week-2 from baseline of either:

↓70 points25% total score reduction

Remicade® – Phase III ACCENT I; intent to treat2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial;


Remicade® – Phase III ACCENT I; patient characteristics2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial;


Remicade® – Phase III ACCENT I; endpoints & results 2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial

• Primary endpoints proportion of patients which responded at @ week-2 and in remission

(CDAI<150 points) @ week 30

;

(CDAI<150 points) @ week-30 time to loss of response up to week-54 in responders

• Secondary endpoints ∆ median IBDQ total score from baseline ∆ median CDAI total score from baseline ∆ median CDAI total score from baseline ∆ median CRP levels from baseline

Trial was powered assuming a 60% responder rate to induction to detect a significant difference between dose groups in terms of remission rate at week-30 (95%) and time to loss of response up to week-54 (90%)


met x not met ~trend

Remicade® – Phase III ACCENT I; endpoints & results 2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial;


Remicade® – Phase III ACCENT I; endpoints & results 2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial;


Remicade® – Phase III ACCENT I; safety & tolerability 2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial


Remicade® – Phase III ACCENT II; design

54-week maintenance Remicade® 5mg/kg vs placebo in responders to first

2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease

6-week induction therapy with fistulas ≥ 3-months(n=306)

Week2 0 2 6 10 14 22 30 38 46 54


Remicade® 10mg/kgRemicade® 5mg/kgPlacebo

-2 0 2 6 10 14 22 30 38 46 54

X X

X

PlaceboFistula

assessmentX = re-randomisationX = up-titration possibility

CDAI

IBDQ


Response assessed as 50% reduction from baseline in total number of fistulas at consecutive visits ≥ 4 weeks apart at week-14 visit

Remicade® – Phase III ACCENT II; intent to treat2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease


Remicade® – Phase III ACCENT II; patient characteristics2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease


Remicade® – Phase III ACCENT II; endpoints & results

• Primary endpoints

2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease

• Primary endpoints 36 weeks longer time to loss of response up to week-54 in responders

(40 weeks on Remicade®, 14 weeks on placebo)• Secondary endpoints

50% higher proportion of responders maintained clinical response @ week-54g @(46% on Remicade®, 23% on placebo)

47% higher number of patients with full response at week-54 (36% on Remicade®, 19% on placebo)

84% higher response rate in patients with CDAI scores ≥220 at baseline(36% on Remicade® 6% on placebo)(36% on Remicade®, 6% on placebo)

median decrease of 26 and 25 points in baseline CDAI scores at week-30 and -54(↓42 & ↓40 on Remicade®, ↓16 & ↓15 on placebo)

median increase of 10 and 5 in baseline IBDQ scores at week-30 and -54(↑14 & ↑10 on Remicade®, ↑4 & ↑5 on placebo)

• Crossover treatment results• Following loss initial response in the placebo maintenance regime, re-administration of

5mg/kg re-established clinical response in 61% of patients• Following loss initial response in the 5mg/kg maintenance regime, up-titration to

10mg/kg re-established clinical response in 61% of patients


g g p % p


Remicade® – Phase III ACCENT II; endpoints & results 2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease


Remicade® – Phase III ACCENT II; safety & tolerability 2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease


Remicade® – Phase III ACCENT II; safety & tolerability 2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease


Humira®


Humira® – US label; indication


Humira® – US label; warnings


Humira® – EU label; indication

Humira® – EU label; indication

Humira® – EU label; warnings





Humira® – Clinical trials overview• CLASSIC-I Phase IIb Induction

– 4 week treatment– 160/80mg, 80/40mg, 40/20mg or placebo (1:1:1:1)– CDAI endpoints– 299 patients– 16 months recruitment– 6 countries, 55 sites (BE, CA, CZ, PL, NL, US)

• CLASSIC-II Phase IIb Maintenance– 56 week treatment– 40mg EoW 40mg weekly or placebo– 40mg EoW, 40mg weekly or placebo– CDAI endpoints– 276 patients– 12 months recruitment– 6 countries, 53 sites (BE, CA, CZ, PL, NL, US)

• CHARM Phase III (NCT00077779)– 56 week treatment– 80/40mg on week 0/2 followed by 40mg EoW, 40mg weekly or placebo

CDAI d i t– CDAI endpoints– 778 patients– 14 months recruitment– 8 countries, 92 sites (AU, CA, LT, PL, RO, TR, US, ZA)

• GAIN Phase III (NCT00105300)– 4-week treatment– 160mg/80mg or placebo – CDAI endpointsp– 325 patients– 12 months recruitment– 4 countries, 52 sites (BE, CA, FR, US)

• EXTEND Phase III (NCT00348283)– 1 yr treatment; 12-week Treatment Period I, Week-13 to Week-52 Treatment Period II– 160mg/80mg/40mg or placebo in Treatment Period I, OL Treatment Period II– Mucosal healing 1° endpoint

135 patients


– 135 patients– 2 years recruitment– 8 countries, 21 sites (AT, BE, CA, DE, FR, IT, NL, US)

Humira® – Clinical trials overview• CHOICE Phase IIIb (NCT00338650)

– 4 week treatment– 40mg weekly OL– Safety & QoL endpoints– 1000 patients– 1 countries, 97 sites (US)

• CARE Phase IIIb (NCT00409617)– 20 week treatment– 40mg EoW, 40mg weekly or placebo– Clinical remission CDAI endpoints– Clinical remission, CDAI endpoints– 945 patients– 12 months recruitment– 18 countries, 219 sites (AT, BE, CH, CZ, DE, DK, ES, FI, FR, GR, IR, IT, NO, PT, SE, SK, UK, US)

• PYRAMID Phase IV (NCT00524537)– Long term safety registry study– 5000 patients– 24 countries, 416 sites (AT, AU, BE, CA, CZ, DE, DK, ES, FR, GR, HU, IS, IR, IT, NL, NO, NZ, PT, SE, SK, SL, UK, US, ZA)


Humira® – Phase IIb CLASSIC-I; design 2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in CD: the CLASSIC-I Trial

4-week alternative dosing regimens of Humira® vs placeboAnti-TNF-α treament naϊve patients(n=299)

y ( )

Humira® 160/80 mg80/40 mg

Week Week Week Week Week -2 0 1 2 4

40/20 mgPlacebo

CDAI assessment

administration

IBDQ


Humira® – Phase IIb CLASSIC-I; intent to treat2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in CD: the CLASSIC-I Trialy ( )


Humira® – Phase IIb CLASSIC-I; patient characteristics2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in CD: the CLASSIC-I Trialy ( )


Humira® – Phase IIb CLASSIC-I; endpoints & results 2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in CD: the CLASSIC-I Trialy ( )

• Primary endpoints Induction of remission as measured by CDAI score <150 @ week 4

(36% Humira® 160/80mg 24% Humira® 80/40mg 12% placebo)(36% Humira® 160/80mg, 24% Humira® 80/40mg, 12% placebo)• Secondary endpoints

proportion of patients meeting 70-point reduction @ week 4(59% Humira® 160/80mg, 59% Humira® 80/40mg, 37% placebo)

proportion of patients meeting 100-point reduction @ week 4p p p g p @(50% Humira® 160/80mg*, 40% Humira® 80/40mg, 25% placebo

*statistical significance acheived only with 160/80mg dose group

∆ IBDQ total score from baseline(158 Humira® 160/80mg & 80/40mg, 146 placebo)

Trial was powered (80%) to detect differences between the 80/40mg and 160/80mg dose groups








Humira® – Phase IIb CLASSIC-I; safety & tolerability 2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in CD: the CLASSIC-I Trialy ( )


Humira® – Phase IIb CLASSIC-I; safety & tolerability 2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in CD: the CLASSIC-I Trialy ( )


Humira® – Phase IIb CLASSIC-II; design 2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial

56-week alternative dosing regimens of Humira® vs placeboin patients which acheived remission in CLASSIC-I(n=276)

Humira® 40mg EoW40mg weekly

Week 0 2 4 8 12 16 20 24 32 40 48 56

Placebo

Rescue therapy40mg weekly40mg weekly

CDAI assessment

IBDQ


Humira® – Phase IIb CLASSIC-II; intent to treat2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial

Majority of CLASSIC-I patientsdid not maintain remission and were therefore ineligible for randomization


Humira® – Phase IIb CLASSIC-II; patient characteristics2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial


® C SS C &Humira® – Phase IIb CLASSIC-II; endpoints & results • Primary endpoints

44% higher proportion of patients in remission (CDAI score <150) @ week-56

2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial

g p p p ( ) @(79% Humira® 40mg EoW, 83% Humira® 40mg weekly, 44% placebo)

• Secondary endpoints 40% higher proportion of patients in remission @ week-24

(84% Humira® 40mg EoW, 94% Humira® 40mg weekly, 50% placebo) 12%/9% higher proportion of patients meeting 70 point reduction @ weeks 24 & 56 12%/9% higher proportion of patients meeting 70-point reduction @ weeks-24 & -56

(94%/79% Humira® 40mg EoW, 95%/89% Humira® 40mg weekly, 83%/72% placebo) 27%/29% higher proportion of patients meeting 100-point reduction @ weeks-24 & -56

(84%/79% Humira® 40mg EoW, 94%/89% Humira® 40mg weekly, 61%/56% placebo) 16/9 point higher IBDQ total score from baseline @ weeks-24 & -56

(178/176 H i ® 40 E W 186/192 H i ® 40 kl 162/167 l b )(178/176 Humira® 40mg EoW, 186/192 Humira® 40mg weekly, 162/167 placebo) proportion of patients which discontinued steroids without loss of remission @ weeks-24 & -56

• Open label arm • 46% (93/204) of patients acheived remission• 46% (93/204) of patients acheived remission• 72% (1477204) of patients acheived 70-point reduction• 65% (132/204) of patients acheived 100-point reduction• reduction of mean CDAI score of 158.4 points• 58% (21/36) of patients discontinued steroidal treatment from baseline


( ) pAs an extension of the CLASSIC-I trial, CLASSIC-II was not poweredAll analyses are exploratory, reductions are simply numeric and sample sizes from the RCT are small

Humira® – Phase IIb CLASSIC-II; endpoints & results 2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial


Humira® – Phase IIb CLASSIC-II; endpoints & results 2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial


Humira® – Phase IIb CLASSIC-II; safety & tolerability 2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial


Humira® – Phase III CHARM; design 2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial

56-week alternative dosing regimens of Humira® vs placebofollowing induction with 80mg at week 0 and 40 mg at week 2(n=778)

2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial

Humira® 40mg EoW40mg weekly

Week -2 0 2 4 6 8 12 16 20 26 32 40 48 56 60


40mg weeklyPlacebo

Rescue therapypy40mg EoW

CDAI

IBDQ


Humira® – Phase III CHARM; intent to treat2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial

~ 30-40% do not respondat week-4

~ 50% of respondersdiscontinue

~ 75% of non-respondersdiscontinue


Humira® – Phase III CHARM; patient characteristics2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial


Humira® – Phase III CHARM; endpoints & results 2007 Ad li b f M i t f Cli i l R d R i i i P ti t ith CD Th CHARM T i l

• Primary endpoints 58% higher proportion of patients in remission (CDAI score <150) @ week-26

(40% Humira® 40mg EoW, 47% Humira® 40mg weekly, 17% placebo) 67% higher proportion of patients in remission (CDAI score <150) @ week 56

2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial

67% higher proportion of patients in remission (CDAI score <150) @ week-56(36% Humira® 40mg EoW, 41% Humira® 40mg weekly, 12% placebo)

• Secondary endpoints 41% higher proportion of patients in remission @ week-26

(81% Humira® 40mg EoW, 81% Humira® 40mg weekly, 48% placebo) 48%/58% higher proportion of patients meeting 70-point reduction @ weeks-26/-56

(54/43% Humira® 40mg EoW, 56/49% Humira® 40mg weekly, 28/18% placebo) 49%/61% higher proportion of patients meeting 100-point reduction @ weeks-26/-56

(89/71% Humira® 40mg EoW, 82/75% Humira® 40mg weekly, 45/28% placebo) ∆ IBDQ total score from baseline @ weeks-26/-56∆ IBDQ total score from baseline @ weeks 26/ 56 proportion of patients which discontinued steroids without loss of remission @ weeks-26/-56 proportion of patients with fistula remissiono effects of previous/concomitant use of immunosuppressant or TNF-α antagonist Txo 251 days ↑ median time to remission in responders

(378 d H i ® 40 E W 127 d l b )


(378 days Humira® 40mg EoW, 127 days placebo)met x not met ~trend

Humira® – Phase III CHARM; endpoints & results 2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial








Humira® – Phase III CHARM; safety & tolerability 2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial


Humira® – Phase III CHARM; intent to treatpost-hoc analysis

2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate-to-Severe CD: Results From the CHARM Trial2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate to Severe CD: Results From the CHARM Trial


Humira® – Phase III CHARM; patient characteristicspost-hoc analysis



Humira® – Phase III CHARM; endpoints & resultpost-hoc analysis

2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate-to-Severe CD: Results From the CHARM Trial


(51% Humira® 40mg EoW, 49% Humira® 40mg weekly, 38% placebo)• Secondary endpoints• Secondary endpoints

proportion of patients in remission @ week-24(51% Humira® 40mg EoW, 49% Humira® 40mg weekly, 38% placebo)

proportion of patients meeting 70-point reduction @ weeks-24/-56 proportion of patients meeting 100-point reduction @ weeks -24/-56 ∆ IBDQ total score from baseline @ weeks -24/-56 proportion of patients which discontinued steroids without loss of remission @

weeks -24/-56

• Open label arm• Open label arm • 46% (93/204) of patients acheived remission• 72% (1477204) of patients acheived 70-point reduction• 65% (132/204) of patients acheived 100-point reduction• reduction of mean CDAI score of 158.4 points


p• 58% (21/36) of patients discontinued steroidal treatment from baseline

Humira® – Phase III CHARM; endpoints & resultspost-hoc analysis



Humira® – Phase III CHARM; endpoints & resultspost-hoc analysis



Humira® – Phase III CHARM; safety & tolerabilitypost-hoc analysis



Humira® – Phase III GAIN; design 2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab

4-week Humira® vs placebo in Remicade® treatment failures following induction with 160mg at week-0 and 80 mg at week-2(n=387)

2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab

Humira® 160mg/80mgWeek Week Week Week Week

-2 0 1 2 4

Humira® 160mg/80mgPlacebo

CDAI assessment

IBDQ


Humira® – Phase III GAIN; intent to treat2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab


Humira® – Phase III GAIN; patient characteristics2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab


Humira® – Phase III GAIN; endpoints & results 2007 Ad li b I d ti Th f CD P i l T t d ith I fli i b


(21% Humira® 160/80mg, 7% placebo)S d d i t

2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab

• Secondary endpoints proportion of patients in remission 40%/36%/35% higher proportion of patients meeting 70-point ↓ @ week-1/-2/-4

(35%/52%/52% Humira® 160/80mg, 21%/33%/34% placebo) 40%/44%/34% higher proportion of patients meeting 100-point ↓ @ week-1/-2/-440%/44%/34% higher proportion of patients meeting 100 point ↓ @ week 1/ 2/ 4

(20%/37%/38% Humira® 160/80mg, 12%/18%/25% placebo) ∆ CDAI total score from baseline 11 point ↑ mean IBDQ score from baseline @ week-4

(150 Humira® 160/80mg, 139 placebo) 50% increase in IBQD score from baseline @ week 4 50% increase in IBQD score from baseline @ week-4

(30 Humira® 160/80mg, 15 placebo) ↓ CRP levels from baseline @ week-4

(5.0 mg/L Humira® 160/80mg, 7.0 mg/L placebo)x ↓ number of draining fistulas


x Fistula remission met x not met ~trend

Humira® – Phase III GAIN; endpoints & results 2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab


Humira® – Phase III GAIN; endpoints & results 2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab


Humira® – Phase III GAIN; safety & tolerability 2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab


Tysabri®


Tysabri® – US label; indication


Tysabri® – US label; warnings


Tysabri® – Clinical trials overview• CD202 Phase IIb (N0192080633)

– 8 week treatment– 3mg/kg, 2 x 3mg/kg, 2 x 6mg/kg or placebo (1:1:1:1)– CDAI endpoints– 248 patients– 11 months recruitment– 8 countries, 35 sites (BE, CZ, DE, DK, IL, NL, SE, UK)

• CD306 Phase II (NCT00055536)12 week treatment– 12 week treatment

– 300mg & Remicade®, or placebo & Remicade® (2:1)– CDAI endpoints– 79 patients– 11 months recruitment– 1 countries, 17 sites (US)

• ENACT-1 Phase III (NCT00032799)ENACT 1 Phase III (NCT00032799)– CDAI (220 -450)– 12 week treatment– 300mg monthly, or placebo (4:1)– CDAI endpoints– 905 patients– 18 months recruitment– 15 countries, 133 sites (AU, CA, CZ, BE, DE, DK, ES, FR, IL, NL, NZ, RSA, SE, UK, US)

• ENACT-2 Phase III (NCT00032786)– CDAI (0-220)– Up to 56 week treatment– 300mg monthly, or placebo (1:1)– CDAI endpoints– 339 patients– Extension of ENACT-1; no recruitment


– 15 countries, 133 sites (AU, CA, CZ, BE, DE, DK, ES, FR, IL, NL, NZ, RSA, SE, UK, US)

Tysabri® – Clinical trials overview• ENCORE Phase III (NCT00078611)( )

– 12 week treatment– 300mg monthly, or placebo (1:1)– CDAI endpoints– 509 patients– 12 months recruitment– 8 countries, 114 sites (AU, BE, CA, CZ, DE, HU, NZ, US)

CD INFORM Phase IV (NCT00707512)• CD INFORM Phase IV (NCT00707512)– Pharmacovigilance long term PML monitoring program– 2000 patients– 1 country, (US)

• CD305 Phase II induction paediatric (NCT00055367)– 8 week treatment

3mg/kg– 3mg/kg – PCDAI endpoints– 38 patients– 9 months recruitment– 3 countries, 18 sites (AU, UK, US)

• CD352 Phase II maintenance paediatric (NCT00055367)– 2 year treatment– 3mg/kg – PCDAI endpoints– 24 patients– Extension of CD305; no recruitment– 3 countries, 18 sites (AU, UK, US)


Tysabri® – Phase IIb CD202; design 2003 Natalizumab for Active Crohn‘s Disease

12-week alternative dosing regimens of Tysabri® vs placeboCD patients (CDAI 220-450)(n=248)

Tysabri® 3mg/kg + placebo2 x 3mg/kg

Week 0 2 4 6 8 12

2 x 6mg/kgPlacebo

CDAI assessment

IBDQ

CRP levels


IBDQ

Tysabri® – Phase IIb CD202; patient characteristics2003 Natalizumab for Active Crohn‘s Disease


Tysabri® – Phase IIb CD202; endpoints & results


2003 Natalizumab for Active Crohn‘s Disease

• Primary endpointsx higher rate of remission (CDAI score <150) @ week-6

(16% Tysabri® 2 x 6mg/kg, 29% Tysabri® 2 x 3mg/kg, 20% Tysabri® 1 x 3mg/kg , 17% placebo)

• Secondary endpoints higher proportion of patients acheiving clinical response at week-4/-6/-8/-12*

(155 Tysabri® 2 x 6mg/kg, 163 Tysabri® 2 x 3mg/kg, 155 Tysabri® 1 x 3mg/kg, 145 placebo)

higher IBDQ scores at week-6 (155 Tysabri® 2 x 6mg/kg, 163 Tysabri® 2 x 3mg/kg, 155 Tysabri® 1 x 3mg/kg, 145 l b )145 placebo)

~ higher IBDQ scores at week-12*(155 Tysabri® 2 x 6mg/kg, 161 Tysabri® 2 x 3mg/kg, 149 Tysabri® 1 x 3mg/kg, 145 placebo)

lower CRP levels*

*exclusively in dose groups with multiple infusions 3 or 6mg/kg



Tysabri® – Phase IIb CD202; endpoints & results 2003 Natalizumab for Active Crohn‘s Disease


Tysabri® – Phase IIb CD202; safety & tolerability 2003 Natalizumab for Active Crohn‘s Disease


Tysabri® – ENACT-1/2; design 2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease

10-week induction with Tysabri® vs placebo CD patients (CDAI 220-450), followed by re-randomisation for patients sustaining response between

k 10 d k 12 (CDAI 220)

py

week-10 and week-12 (CDAI ≤220)(n=905/339)

Week 0 4 8 10 12 16 20 24 28 32 36 40 44 48 54

ENACT-1 ENACT-2

Tysabri® 300 mgPlacebo

CDAI assessment


Tysabri® – ENACT-1/2; intent to treat2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease


Tysabri® – ENACT-1/2; patient characteristics2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease


Tysabri® – ENACT-1/2; endpoints & results 2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease

ENACT 1• Primary endpoints at week-10

x higher proportion of patients achieving clinical response (↓CDAI score by 70 pts)(56% Tysabri® 300mg, 49% placebo)

ENACT-1

• Secondary endpoints at week-10x higher rate of clinical remission (CDAI score <150)

(37% Tysabri® 300mg, 30% placebo)

• Primary endpoints at week-3654% higher proportion of patients achieving clinical response (↓CDAI score by

70 pts)

ENACT-2

70 pts) (61% Tysabri® 300mg, 28% placebo)

• Secondary endpoints scores at week-36 41% higher rate of clinical remission (CDAI score <150)


41% higher rate of clinical remission (CDAI score <150)(44% Tysabri® 300mg, 26% placebo)






Tysabri® – ENACT-1/2; safety & tolerability 2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease


Tysabri® – ENACT-1/2; safety & tolerability 2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease


Tysabri® – ENCORE; design 2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial

12-week induction trial Tysabri® vs placebo CD patients (CDAI 220-450)(n=509)

;

Screening Double-blind Follow-up

Tysabri® 300 mgPlacebo

Week -2 0 4 8 12 20

CDAICDAI assessment

CRP levels

IBDQ

SF-36


Tysabri® – ENCORE; intent to treat2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial


Tysabri® – ENCORE; patient characteristics2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial


Tysabri® – ENCORE; endpoints & results


2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial

• Primary endpoints33% higher proportion of patients acheiving clinical response (↓CDAI score by

70 pts) sustained from week-8 to week-12(48% Tysabri® 300mg, 32% placebo)

• Secondary endpoints 38% higher proportion of patients acheiving clinical remission (CDAI score <

150) sustained from week-8 to week-12(26% Tysabri® 300mg, 16% placebo)

27% higher proportion of patients acheiving clinical response (↓CDAI score by27% higher proportion of patients acheiving clinical response (↓CDAI score by 70 pts) @ week-12(60% Tysabri® 300mg, 44% placebo)

35% higher proportion of patients acheiving clinical remission (↓CDAI score by 150 pts) @ week-12(38% Tysabri® 300mg 25% placebo)(38% Tysabri® 300mg, 25% placebo)



Tysabri® – ENCORE; endpoints & results

• Tertiary endpoints % C

2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial

44% higher proportion achieving a 100-point decrease in baseline CDAI score at both week-8 and -12(39% Tysabri® 300mg, 22% placebo)

27% higher proportion achieving a clinical response (↓CDAI score by 70 pts) at both week-4 and -8(51% Tysabri® 300mg 37% placebo)(51% Tysabri® 300mg, 37% placebo)

proportion achieving a clinical remission (CDAI score < 150) at both week-4 and -8 26 day reduction in time to clinical response, defined as a 70-point decrease in baseline

CDAI score(31 days Tysabri® 300mg, 57 days placebo)

~ time to clinical remission defined as a CDAI score of 150time to clinical remission, defined as a CDAI score of 150(86 days Tysabri® 300mg, undeterminable for placebo)

proportion achieving a clinical response (↓CDAI score by 70 pts) at week-8 mean change from baseline CDAI score at week-4, -8, and -12

(83 pt mean decrease at week-4 Tysabri® 300mg) mean change from baseline platelet count at week-4 -8 and -12 mean change from baseline platelet count at week-4, -8, and -12

(55% Tysabri® 300mg, 25% placebo restored to normal levels) ↓ mean change from baseline CRP level at week-4, -8, and -12

(15 mg/L Tysabri® 300mg, 24.7mg/L placebo at week-12) 11.5 increase mean change in IBDQ from baseline at week-12

(26.7 pts Tysabri® 300mg, 15.2 pts placebo)


(26.7 pts Tysabri® 300mg, 15.2 pts placebo)- mean change in the SF-36 or its components from baseline at week-12

met x not met ~trend – not reported

Tysabri® – ENCORE; endpoints & results 2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial


Tysabri® – ENCORE; endpoints & results 2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial


Tysabri® – ENCORE; safety & tolerability 2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial


Cimzia®


Cimzia® – US label; indication


Cimzia® – US label; warnings


Cimzia® – Clinical trials overview• Phase IIb

– 12 week treatment– 100mg, 200mg, 400mg, or placebo (1:1:1:1)– CDAI endpoints– 291 patients– 10 months recruitment– 10 countries, 58 sites (BE, CA, DE, DK, IR, RS, RU, SE, UK, ZA)

• PRECISE 1 (NCT000152490)– 26 week treatment– 400mg monthly or placebo (1:1)– CDAI endpoints– 662 patients– 12 months recruitment– 22 countries, 157 sites (AT, AU, BE, BG, BY, CA, CZ, DE, DK, ET, GE, HK, HU, IT, LV, NO, PL, RU, SI, SE, UA, US, ZA)

PRECISE 2 (NCT000152425)• PRECISE 2 (NCT000152425)– CDAI (220 -450)– 26 week treatment– 400mg monthly, or placebo (1:1)– CDAI endpoints– 668 patients– 10 months recruitment– 15 countries, 147 sites (AU, DE, DK, ES, HU, IR, IL, LI, NO, NZ, PL, UA, US)

• C87042 (NCT00308581)– Remicade® failures– 26 week treatment– 400mg every other month, 200mg every two weeks, or placebo (1:1:1)– CDAI endpoints– 539 patients– 18 months recruitment


– 18 months recruitment– 14 countries, 107 sites (AT, BE, CA, CH, DE, DK, ES, FR, IT, NL, NO, SE, UK, US)

Cimzia® – Clinical trials overview• C87085 (NCT00552058)

– 6 week treatment– 400mg or placebo (1:1)– CDAI endpoints– 439 patients– 16 months recruitment– 20 countries, 116 sites (AT, AU, BE, BR, CA, CL, CZ, DE, ET, FI, HK, HU, IL, IT, LV, NZ, PL, RO, RU, UA, US)

• MUSIC (NCT00297648)– Mucosal healing– 54 week treatment– 400mg monthly– CDEIS endpoints– 89 patients– 10 months recruitment– 3 countries, 20 sites (BE, DE, FR)

• COSPAR1 (NCT00349752)– Corticosteroid sparing– 38 week treatment– 400mg monthly or placebo– 174 patients– Terminated due to low recruitment– 3 countries, 68 sites (CA, DE, US)

SECURE (NCT00844285)• SECURE (NCT00844285)– Long term safety– 4000 patients

• Japanese studies– NCT00291668 – NCT00329550– NCT00329420


– NCT00329420

Cimzia® – Clinical trials overview• PRECISE 3 (NCT00160524)

– 84 month treatment– 400mg– Long-term safety– 595 patients– 20 countries, 168 sites (AT, AU, BE, BG, BY, CA, CZ, DE, DK, ET, GE, HK, HU, IT, LV, NO, PL, RU, SI, SE, UA, US, ZA)

• PRECISE 4 (NCT00160706)– 84 month treatment for PRECISE 1 or 2 withdrawals due to CD exacerbation– 400mg monthly– Long-term safety– 310 patients– 20 countries, 127 sites (AT, AU, BE, BG, BY, CA, CZ, DE, DK, ET, GE, HK, HU, IT, LV, NO, PL, RU, SI, SE, UA, US, ZA)

• COSPAR1 (NCT00349752)– Corticosteroid sparing

38 week treatment– 38 week treatment– 400mg monthly or placebo– 174 patients– Terminated due to low recruitment– 3 countries, 68 sites (CA, DE, US)

• SECURE (NCT00844285)– Long term safety– 4000 patients

• Japanese studies– NCT00291668 – NCT00329550– NCT00329420


Cimzia® – Phase IIb; design 2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease

12-week alternative dosing regimens of Cimzia® vs placeboCD patients (CDAI 220-450)(n=291)

, g ( )

Cimzia® 100mg200mg

Week -2 0 2 4 6 8 10 12

400mgPlacebo

CDAI assessment

IBDQ

CRP levels


IBDQ

Cimzia® – Phase IIb; intent to treat2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease


Cimzia® – Phase IIb; patient characteristics2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease


Cimzia® – Phase IIb; patient characteristics2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease, g ( )


Cimzia® – Phase IIb; endpoints & results


2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease

• Primary endpointsx higher proportion of patients achieving clinical response (↓CDAI score ≥100 or

remission) @ week-12(44.4% Cimzia® 400mg, 36.1% Cimzia® 200mg, 36.5% Cimzia® 100mg , 35.6% placebo)

• Secondary endpointshigher proportion of patients acheiving clinical response at week-2/-4/-6/-8/-10

(33.3% Cimzia® 400mg, 30.6% Cimzia® 200mg, 29.7% Cimzia® 100mg , 15.1% placebo at week-2; 52.8% Cimzia® 400mg, 30.1% placebo at week-10)

x higher remission rate (CDAI score ≤ 150) at week 12x higher remission rate (CDAI score ≤ 150) at week-12(26.4% Cimzia® 400mg, 19.4% Cimzia® 200mg, 27% Cimzia® 100mg , 23.3% placebo)

lower mean CDAI scores15.9 points higher mean IBDQ scores at week-12p g

(156.4 pts Cimzia® 400mg, 140.5 pts placebo) lower CRP levels



Cimzia® – Phase IIb; endpoints & results 2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease


Cimzia® – Phase IIb; endpoints & results2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease


Cimzia® – Phase IIb; safety & tolerability 2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease2005 A Randomized, Placebo Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn s Disease


Cimzia® – Phase IIb; safety & tolerability 2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease


Cimzia® – Precise 1; design 2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease

26-week induction & maintenance study of Cimzia® 400mg vs placeboCD patients (CDAI 220-450)(n=662)

g

Cimzia® 400mgWeek

-2 0 2 4 6 8 12 16 20 24 26

Placebo

CDAI assessment

IBDQ

CRP levels


Cimzia® – Precise 1; intent to treat2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease


Cimzia® – Precise 1; patient characteristics2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease


Cimzia® – Precise 1; endpoints & results 2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease


30% higher proportion of patients with baseline serum CRP levels of at least 10mg/L acheiving a reduction of ≥ 100 points in the CDAI score at week-6 (37% Cimzia® 400mg 26% placebo)(37% Cimzia® 400mg, 26% placebo)

45% higher proportion of patients with baseline serum CRP levels of at least 10mg/L acheiving a reduction of ≥100 in CDAI score at both week-6 and week-26(22% Cimzia® 400mg, 12% placebo)

• Secondary endpoints

23% higher proportion of patients regardless of baseline serum CRP levels acheiving a reduction of ≥ 100 points in the CDAI score at week-6 and at both week-6 and week-26(35% Cimzia® 400mg 27% placebo)(35% Cimzia® 400mg, 27% placebo)

x Higher proportion of patients with baseline serum CRP levels of at least 10mg/L acheiving a remission at week-6 and at both week-6 and week-26

x Higher proportion of patients regardless of baseline serum CRP levels acheiving remission at at week-6 and at both week-6 and week-26







Cimzia® – Precise 1; safety & tolerability 2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease


26 k i d ti & i t t d f Ci i ® 400 l b

Cimzia® – Precise 2; design 2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease

26-week induction & maintenance study of Cimzia® 400mg vs placeboCD patients (CDAI 220-450)(n=668)

Screening Open label Double-blind

Cimzia® 400mgWeek

-2 0 2 4 6 8 12 16 20 24 26

g p

Placebo

CDAI assessment

IBDQ

CRP levels


Cimzia® – Precise 2; intent to treat2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease


Cimzia® – Precise 2; patient characteristics2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease


• Efficacy at week-6

Cimzia® – Precise 2; endpoints & results 2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease

• 33% higher proportion of patients acheiving a reduction of ≥ 100 points in the CDAI score at week-6 (64% Cimzia® 400mg, 43% placebo)

P i d i t• Primary endpoints45% higher proportion of patients with baseline serum CRP levels of at least

10mg/L acheiving a reduction of ≥ 100 points in the CDAI score at week-26(62% Cimzia® 400mg, 34% placebo)

• Secondary endpoints43% higher proportion of patients regardless of baseline serum CRP levels

acheiving a reduction of ≥ 100 points in the CDAI score at week-26(63% Cimzia® 400mg, 36% placebo) ( g, p )

40% higher remission rate (total CDAI score < 150) in patients regardless of baseline serum CRP levels at week-26(48% Cimzia® 400mg, 29% placebo)

28% higher IBDQ response rate at week-26(60% Ci i ® 400 43% l b )


(60% Cimzia® 400mg, 43% placebo)met x not met ~trend

Cimzia® – Precise 2; endpoints & results 2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease


Cimzia® – Precise 2; safety & tolerability 2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease


Cimzia® – Precise 2; safety & tolerability 2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease


Documents

Crohn's disease pharmascape cv