Crohn's disease pharmascape cv

Crohn‘s disease
C h ‘ di
Pharmascape
p
All information herein is publically available
This document is meant only to illustrate Oliver Vit’s professional competences
and does not reflect Actelion Pharmaceuticals Ltd’s corporate views

Marketed biologics for Crohn‘s disease

Remicade®, infliximab

Humira®, adalimumab

Tysabri®, natalizumab

Cimzia®, certolizumab
C ®

2 Life Cycle Management
Competitive 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 & steroid
sparing 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 proportion retained remission th
higher ti t i d i i through week-54 (25% R i d @ vs 11% placebo)
h k 54 Remicade@ l b )
• 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 cases
• 6-13% of CD patients test positive for infliximab NABs which are associated with a higher incidence of
injection site reactions
• Intermittent therapy is not encouraged due to perceived higher immunogenicity risk
• Crohn‘s disease was the 1st licensed indication
• Annual cost €21,573/$21,166

Remicade® – CD development plan
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
RA PsA UC

Phase III
Severe active CD

Phase III
Fistulizing active CD

ACCENT I
Severe active CD

ACCENT II
Fistulizing active CD

SONIC
Azothioprine/Infliximab
combination

Maintenance Fistulas
Launch
extension extension

Humira®
• Humanized IgG1 monoclonal antibody targeting TNF α
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 or
autoinjection pen in Crohn‘s Disease
• Fast acting agent with limited long term responders
g 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 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 bo warnings: malignancies specifically lymphoma, serious infections inclusive of
ac box 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
g , y g p y
• Annual cost €14,700/$20,339


Humira® – CD development plan
2000 2001 2002 2003 2004 200
2005 2006 200
2007 2008 2009 2010 2011 2012
RA PsA AS Pso JIA

CLASSIC-I

CLASSIC-II

CHARM

GAIN

CHOICE
Infliximab failures

CARE
QoL outcomes

EXTEND
Mucosal healing

PYRAMID
Long term safety

US
6 Life Cycle Management Launch

Tysabri®
• Monthly 300mg i.v. infusion of humanized monoclonal antibody against α-4 integrin, reducing
T cell traffic through the endothelium into tissue
g
• ENACT-1 trial failed to show significant induction effects at week-10, however ENCORE
demonstrated significant results at week-8
30% 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
300mg
38% higher proportion of clinical remission (CDAI score < 150) sustained from week-8 to week-12

• ENACT-2 demonstrated significant benefit upon long-term treatment
54% higher rate of clinical response (↓CDAI score by 70 pts) sustained from week-10 to week-36
41% higher rate of clinical remission (CDAI score <150) sustained from week-10 to week-36
( % 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
• Annual cost estimated at $ $37,000 (based on MS figures)


Tysabri® – CD development plan
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
MS Launch PML Re-launch

CD202
CD306
On top of Remicade®

ENACT-1

ENACT 2
ENACT-2
ENACT-2 ext

ENCORE

CD305
Paediactric

CD352
Paediactric

CD INFORM
Pharmacovigilance long-term safety

US
Launch

Cimzia®
• Polyethylene glycolated Fab‘ fragment of humanized anti-TNF-α monoclonal antibody delivered by
monthly 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 achieving
a 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 achieving
a 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
• 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
• Annual costs $18,408


Cimzia® – CD development plan
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
CDP870 RA

MUSIC
PRECISE 1 Mucosal healing

PRECISE 2

PRECISE 3
Long-term OL for P1/P2

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

COSPAR1
Corticosteroid sparing - TERMINATED

C87042
Remicade® failures

C87085
Induction study

SECURE
Pharmacovigilance long-term safety

US US
10 Life Cycle Management NDA Launch

Comparative induction capacity at week-4

Clinical Response (↓CDAI ≥70)
Active Placebo Difference

Remicade®, (5mg) 81% 17% 65%

Remicade®, (5, 10, 20mg) 65% 17% 48%

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
p-values 0.011 - 0.001


Comparative induction capacity at week-4

Clinical Remission (CDAI ≤150)
Active Placebo Difference

Remicade®, (5mg) 48% 4% 44%

Remicade®, (5, 10, 20mg) 36% 4% 28%

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
p-values 0.018 - 0.001


Crohn‘s disease competitors in development

Vedolizumab, MLN0002 CEP-37248

Traficet-EN, CCX282-B AIN457

Stelara* CCX025

Laquinimod

CP 690.550

CEP-37247, ART-621

ELND004

Briakinumab, ABT-874**
* 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 antagonist
α-4-integrin
antagonist CCX025

CEP-37247
ELND004

Traficet-EN JAK3 antagonist
Vedolizumab

CP 690.550

Phase I Phase II Phase III Launched

Laquinimod

AIN457
Stelara Anti-proliferant/replicative

Briakinumab

Anti-IL-17 CEP-37248
oral
parenteral

Anti-IL-12/IL-23

Conclusions
• Remicade® dramatically changed the Crohn‘s disease treatment paradigm; diffcult differentiation
between Remicade®, Humira®, Tysabri®, and Cimzia® outside of route of administration & rare safety
signals as witnessed by comparable prescription rates
• Response rates are only 30-60% in treatment naϊve patients; discontinuation in the case of inadequate
initial 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

Confidential
• Loss of efficacy & low differentiation drives high switch market between TNF-α agents
• All registration trials assessed efficacy by ∆CDAI scores, however the index is intrinsically prone to
subjective variability
• Placebo effect appears to be more pronounced over time (up to 47% in Cimzia® trials; average of 19%
across 21 randomized CD trials)
• 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 horizon


Crohn‘s Disease Activity Index (CDAI)
Remission of Crohn's disease is defined as a CDAI <150

Clinical laboratory variable
Cli i l or l b t i bl Weighting factor
W i hti f t Moderate di
M d disease i d fi d by a value of 220-450
is defined b l f 220 4 0

Number of liquid or soft stools each day for seven Severre disease is defined as >450
x2
days
Clinical response is typically defined as a reduction >70

Abdominal pain (g
p (graded from 0-3 on severity)
y)
x5
each day for seven days

General well being, subjectively assessed from 0
x7
(well) to 4 (terrible) each day for seven days

Presence of complications* x 20 *One point each is added for each set of complications:
•the presence of joint pain (arthralgia) or frank arthritis
Taking Lomitil or opiates for diarrhea x 30 •inflammation of the iris or uveitis
•presence of erythema nodosum, pyoderma gangrenosum or
Presence of an abdominal mass (0 as none, 2 as aphthous ulcers
x 10
questionable,
questionable 5 as definite) •Anal fissures, fistulae or abscesses
Anal fissures
•Other fistulae
•Fever during the previous week
Absolute deviation of Hematocrit from 47% in
x6
men and 42% in women

Percentage deviation from standard weight x1

17 Lifecycle management

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® – 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)
– 5mg/kg induction followed by 5mg/kg week-2 & 6 followed by 5mg/kg or 10mg/kg every 8-weeks, or placebo
– CDAI endpoints
p
– 573 patients
– 11 months recruitment
– 6 countries, 55 sites (North America, Europe, IL)
• ACCENT II Phase III Maintenance trial in fistulizing active CD (NCT00207766)
– 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
– 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 of
conventional therapies in patients who failed to achieve adequate response
(n=108)

Phase I Phase II Phase III
Week
0 2 4 8 12 20 28 36 48
Remicade® 5mg/kg
10mg/kg
20mg/kg
Placebo
10mg/kg*
g g

CDAI
assessment

* Infliximab treatment failures at the 1° endpoint
received 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
Remicade® 5mg/kg x x x

10mg/kg x x x
Placebo x 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 placebo
in 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
Remicade® 5mg/kg
10mg/kg
Placebo

Rescue Tx 5/10/15mg/kg
CDAI assessment

IBDQ

Response assessed as CDAI score reduction at week-2
from baseline of either:
↓70 points
34 Lifecycle management 25% total score reduction

Remicade® – Phase III ACCENT I; intent to treat
;


Remicade® – Phase III ACCENT I; patient characteristics
;


Remicade® – Phase III ACCENT I; endpoints & results
;

• Primary endpoints
 proportion of patients which responded at @ week-2 and in remission
(CDAI<150 points) @ week 30
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 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; safety & tolerability


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

54-week maintenance Remicade® 5mg/kg vs placebo in responders to first
6-week induction therapy with fistulas ≥ 3-months
(n=306)

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

Remicade® 10mg/kg
X
Remicade® 5mg/kg
X X
Placebo
Fistula
X = re-randomisation assessment
X = 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 treat


Remicade® – Phase III ACCENT II; patient characteristics


Remicade® – Phase III ACCENT II; endpoints & results

 36 weeks longer time to loss of response up to week-54 in responders
(40 weeks on Remicade®, 14 weeks on placebo)
 50% higher proportion of responders maintained clinical response @ week-54
g
(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)
Remicade®,
 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


Remicade® – Phase III ACCENT II; safety & tolerability


Humira®


Humira® – US label; indication


Humira® – US label; warnings


Humira® – EU label; indication

Humira® – EU label; warnings

Humira® – Clinical trials overview
• CLASSIC-I Phase IIb Induction
– 160/80mg, 80/40mg, 40/20mg or placebo (1:1:1:1)
– CDAI endpoints
– 299 patients
• CLASSIC-II Phase IIb Maintenance
– 40mg EoW 40mg weekly or placebo
EoW,
– CDAI endpoints
– 276 patients
• CHARM Phase III (NCT00077779)
– 80/40mg on week 0/2 followed by 40mg EoW, 40mg weekly or placebo
– CDAI endpoints
d i t
– 778 patients
– 8 countries, 92 sites (AU, CA, LT, PL, RO, TR, US, ZA)
• GAIN Phase III (NCT00105300)
– 4-week treatment
– 160mg/80mg or placebo
– CDAI endpoints
p
– 325 patients
– 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
– 2 years recruitment
– 8 countries, 21 sites (AT, BE, CA, DE, FR, IT, NL, US)


Humira® – Clinical trials overview
• CHOICE Phase IIIb (NCT00338650)
– 40mg weekly OL
– Safety & QoL endpoints
– 1000 patients
– 1 countries, 97 sites (US)
• CARE Phase IIIb (NCT00409617)
– 40mg EoW, 40mg weekly or placebo
– Clinical remission CDAI endpoints
remission,
– 945 patients
– 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 (
y (Adalimumab) in CD: the CLASSIC-I Trial
)

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

Week Week Week Week Week
-2 0 1 2 4
Humira® 160/80 mg
80/40 mg
40/20 mg
Placebo
CDAI assessment

IBDQ

administration


Humira® – Phase IIb CLASSIC-I; intent to treat
)


Humira® – Phase IIb CLASSIC-I; patient characteristics
)


Humira® – Phase IIb CLASSIC-I; endpoints & results
)

 Induction of remission as measured by CDAI score <150 @ week 4
(36% Humira® 160/80mg, 24% Humira® 80/40mg, 12% placebo)
160/80mg 80/40mg
 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 4
p 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
)


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

in patients which acheived remission in CLASSIC-I
(n=276)

Week
0 2 4 8 12 16 20 24 32 40 48 56
Humira® 40mg EoW
40mg weekly
Placebo

Rescue therapy
40mg weekly
CDAI
assessment

IBDQ


Humira® – Phase IIb CLASSIC-II; intent to treat

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


Humira® – Phase IIb CLASSIC-II; patient characteristics


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

 44% higher proportion of patients in remission (CDAI score <150) @ week-56
g p p p ( )
(79% Humira® 40mg EoW, 83% Humira® 40mg weekly, 44% placebo)
 40% higher proportion of patients in remission @ week-24
 12%/9% higher proportion of patients meeting 70 point reduction @ weeks 24 & -56
70-point 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 ® 40mg E W 186/192 H i ® 40mg weekly, 162/167 placebo)
Humira® 40 EoW, Humira® 40 kl l b )
 proportion of patients which discontinued steroids without loss of remission @ weeks-24 & -56

• 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
• 58% (21/36) of patients discontinued steroidal treatment from baseline
( ) p
As an extension of the CLASSIC-I trial, CLASSIC-II was not powered
All analyses are exploratory, reductions are simply numeric and sample sizes from the RCT are small

Humira® – Phase IIb CLASSIC-II; endpoints & results


Humira® – Phase IIb CLASSIC-II; safety & tolerability


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

following induction with 80mg at week 0 and 40 mg at week 2
(n=778)
Week
-2 0 2 4 6 8 12 16 20 26 32 40 48 56 60
Humira® 40mg EoW
40mg weekly
Placebo

Rescue therapy
py
40mg EoW
CDAI

IBDQ


Humira® – Phase III CHARM; intent to treat

~ 30-40% do not respond
at week-4
~ 50% of responders
discontinue
~ 75% of non-responders
discontinue


Humira® – Phase III CHARM; patient characteristics


Humira® – Phase III CHARM; endpoints & results
2007 Ad li
Adalimumab f M i t
b for Maintenance of Cli i l Response and Remission in Patients with CD: The CHARM T i l
f Clinical R d R i i i P ti t ith CD Th Trial

 67% higher proportion of patients in remission (CDAI score <150) @ week 56
week-56
 41% higher proportion of patients in remission @ week-26
 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
weeks 26/ 56
 proportion of patients which discontinued steroids without loss of remission @ weeks-26/-56
 proportion of patients with fistula remission
o effects of previous/concomitant use of immunosuppressant or TNF-α antagonist Tx
o 251 days ↑ median time to remission in responders
(378 d
days H i ® 40mg E W 127 d
Humira® 40 EoW, days placebo)
l b )

Humira® – Phase III CHARM; safety & tolerability


Humira® – Phase III CHARM; intent to treat
post-hoc analysis
2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate to Severe CD: Results From the CHARM Trial
Moderate-to-Severe


Humira® – Phase III CHARM; patient characteristics
post-hoc analysis
Moderate-to-Severe


Humira® – Phase III CHARM; endpoints & result
post-hoc analysis
2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate-to-Severe CD: Results From the CHARM Trial

 proportion of patients in remission @ week-24
 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
• 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

post-hoc analysis
Moderate-to-Severe


Humira® – Phase III CHARM; safety & tolerability
post-hoc analysis
Moderate-to-Severe


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)

Week Week Week Week Week
-2 0 1 2 4
Humira® 160mg/80mg
Placebo

CDAI assessment

IBDQ


Humira® – Phase III GAIN; intent to treat


Humira® – Phase III GAIN; patient characteristics


Humira® – Phase III GAIN; endpoints & results
2007 Ad li
Adalimumab I d ti Th
b Induction Therapy f CD P i
for Previously T
l Treated with I fli i b
t d ith Infliximab

(21% Humira® 160/80mg, 7% placebo)
• S
Secondary endpoints
d d i t
 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/-4
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
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; safety & tolerability


Tysabri®


Tysabri® – US label; indication


Tysabri® – US label; warnings


Tysabri® – Clinical trials overview
• CD202 Phase IIb (N0192080633)
– 3mg/kg, 2 x 3mg/kg, 2 x 6mg/kg or placebo (1:1:1:1)
– CDAI endpoints
– 248 patients
– 8 countries, 35 sites (BE, CZ, DE, DK, IL, NL, SE, UK)

• CD306 Phase II (NCT00055536)
– 300mg & Remicade®, or placebo & Remicade® (2:1)
– CDAI endpoints
– 79 patients
– 1 countries, 17 sites (US)

• ENACT 1
ENACT-1 Phase III (NCT00032799)
– CDAI (220 -450)
– 300mg monthly, or placebo (4:1)
– CDAI endpoints
– 905 patients
– 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
– 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)
( )
– CDAI endpoints
– 509 patients
– 8 countries, 114 sites (AU, BE, CA, CZ, DE, HU, NZ, US)

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

• CD305 Phase II induction paediatric (NCT00055367)
– 3mg/kg
– PCDAI endpoints
– 38 patients
– 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 placebo
CD patients (CDAI 220-450)
(n=248)

Week
0 2 4 6 8 12
Tysabri® 3mg/kg + placebo
2 x 3mg/kg
2 x 6mg/kg
Placebo
CDAI assessment

CRP levels

IBDQ


Tysabri® – Phase IIb CD202; patient characteristics


Tysabri® – Phase IIb CD202; endpoints & results

x 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)
 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
145 placebo)
l b )
~ higher IBDQ scores at week-12*
145 placebo)
 lower CRP levels*
*exclusively in dose groups with multiple infusions 3 or 6mg/kg


Tysabri® – Phase IIb CD202; endpoints & results


Tysabri® – Phase IIb CD202; safety & tolerability


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

10-week induction with Tysabri® vs placebo CD patients (CDAI 220-450),
followed by re-randomisation for patients sustaining response between
week-10 and week-12 (CDAI ≤220)
k 10 d k 12 220)
(n=905/339)
ENACT-1 ENACT-2
Week
0 4 8 10 12 16 20 24 28 32 36 40 44 48 54

Tysabri® 300 mg
Placebo
CDAI
assessment


Tysabri® – ENACT-1/2; intent to treat


Tysabri® – ENACT-1/2; patient characteristics


Tysabri® – ENACT-1/2; endpoints & results

ENACT-1
ENACT 1
• Primary endpoints at week-10
x higher proportion of patients achieving clinical response (↓CDAI score by 70 pts)

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

ENACT-2
• Primary endpoints at week-36
 54% higher proportion of patients achieving clinical response (↓CDAI score by
70 pts)

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

Tysabri® – ENACT-1/2; safety & tolerability


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
Week
-2 0 4 8 12 20

Tysabri® 300 mg
Placebo
CDAI
assessment

CRP levels

IBDQ

SF-36


Tysabri® – ENCORE; intent to treat


Tysabri® – ENCORE; patient characteristics


Tysabri® – ENCORE; endpoints & results

 33% higher proportion of patients acheiving clinical response (↓CDAI score by
70 pts) sustained from week-8 to week-12

 38% higher proportion of patients acheiving clinical remission (CDAI score <
150) sustained from week-8 to week-12
 27% higher proportion of patients acheiving clinical response (↓CDAI score by
70 pts) @ week-12
 35% higher proportion of patients acheiving clinical remission (↓CDAI score by
150 pts) @ week-12
(38% Tysabri® 300mg 25% placebo)
300mg,



• Tertiary endpoints
 44% higher proportion achieving a 100-point decrease in baseline C
% CDAI score at both week-
8 and -12
 27% higher proportion achieving a clinical response (↓CDAI score by 70 pts) at both week-4
and -8
300mg
 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 150
remission,
(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
week-4, -8,
(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)
- mean change in the SF-36 or its components from baseline at week-12
120 Lifecycle management met x not met ~trend – not reported

Tysabri® – ENCORE; safety & tolerability


Cimzia®


Cimzia® – US label; indication


Cimzia® – US label; warnings


Cimzia® – Clinical trials overview
• Phase IIb
– 100mg, 200mg, 400mg, or placebo (1:1:1:1)
– CDAI endpoints
– 291 patients
– 10 countries, 58 sites (BE, CA, DE, DK, IR, RS, RU, SE, UK, ZA)

• PRECISE 1 (NCT000152490)
– 400mg monthly or placebo (1:1)
– CDAI endpoints
– 662 patients
– 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)
– CDAI (220 -450)
– CDAI endpoints
– 668 patients
– 15 countries, 147 sites (AU, DE, DK, ES, HU, IR, IL, LI, NO, NZ, PL, UA, US)

• C87042 (NCT00308581)
– Remicade® failures
– 400mg every other month, 200mg every two weeks, or placebo (1:1:1)
– CDAI endpoints
– 539 patients
– 14 countries, 107 sites (AT, BE, CA, CH, DE, DK, ES, FR, IT, NL, NO, SE, UK, US)


• C87085 (NCT00552058)
– 400mg or placebo (1:1)
– CDAI endpoints
– 439 patients
– 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
– 400mg monthly
– CDEIS endpoints
– 89 patients
– 3 countries, 20 sites (BE, DE, FR)

• COSPAR1 (NCT00349752)
– Corticosteroid sparing
– 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


• PRECISE 3 (NCT00160524)
– 84 month treatment
– 400mg
– Long-term safety
– 595 patients

• PRECISE 4 (NCT00160706)
– 84 month treatment for PRECISE 1 or 2 withdrawals due to CD exacerbation
– 400mg monthly
– Long-term safety
– 310 patients

• COSPAR1 (NCT00349752)
– Corticosteroid sparing
– 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
, g ( )

12-week alternative dosing regimens of Cimzia® vs placebo
(n=291)

Week
-2 0 2 4 6 8 10 12
Cimzia® 100mg
200mg
400mg
Placebo
CDAI
assessment

CRP levels

IBDQ


Cimzia® – Phase IIb; intent to treat


Cimzia® – Phase IIb; patient characteristics


Cimzia® – Phase IIb; patient characteristics
, g ( )


Cimzia® – Phase IIb; endpoints & results

x 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)
 higher 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-12
week 12
(26.4% Cimzia® 400mg, 19.4% Cimzia® 200mg, 27% Cimzia® 100mg , 23.3%
placebo)
 lower mean CDAI scores
 15.9 points higher mean IBDQ scores at week-12
p g
(156.4 pts Cimzia® 400mg, 140.5 pts placebo)
 lower CRP levels


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


Cimzia® – Phase IIb; safety & tolerability


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

26-week induction & maintenance study of Cimzia® 400mg vs placebo
(n=662)

Week
-2 0 2 4 6 8 12 16 20 24 26
Cimzia® 400mg

Placebo

CDAI
assessment

CRP levels

IBDQ


Cimzia® – Precise 1; intent to treat


Cimzia® – Precise 1; patient characteristics


Cimzia® – Precise 1; endpoints & results


 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)
400mg,
10mg/L acheiving a reduction of ≥100 in CDAI score at both week-6 and week-26
(22% Cimzia® 400mg, 12% placebo)

 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)
400mg,
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


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

26-week i d ti & maintenance study of Ci i ® 400mg vs placebo
26 k induction i t t d f Cimzia 400 l b
(n=668)

g
Screening Open label
p Double-blind
Week
-2 0 2 4 6 8 12 16 20 24 26
Cimzia® 400mg

Placebo

CDAI
assessment

CRP levels

IBDQ


Cimzia® – Precise 2; intent to treat


Cimzia® – Precise 2; patient characteristics



• Efficacy at week-6
• 33% higher proportion of patients acheiving a reduction of ≥ 100 points in the
CDAI score at week-6

• Pi
Primary endpoints
d i t
10mg/L acheiving a reduction of ≥ 100 points in the CDAI score at week-26

 43% higher proportion of patients regardless of baseline serum CRP levels
acheiving a reduction of ≥ 100 points in the CDAI score at week-26
(
g, p )
 40% higher remission rate (total CDAI score < 150) in patients regardless of
baseline serum CRP levels at week-26
 28% higher IBDQ response rate at week-26
(60% Ci i ® 400
Cimzia® 400mg, 43% placebo)
l b )

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