Psoriasis pharmascape cv

PharmascapePharmascapePsoriasis therapy: today & tomorrow

All information herein is publically availableThis document is meant only to illustrate Oliver Vit’s professional competences and does not reflect Actelion Pharmaceuticals Ltd’s corporate viewsand does not reflect Actelion Pharmaceuticals Ltd s corporate views

Psoriasis; approved biologics

Etanercept, Enbrel®

Adalimumab, Humira ®

Infliximab, Remicade ®

Ustekinumab, Stelara ®

2 Life Cycle ManagementCompetitive intelligence analysis

Psoriasis therapies; EU market protection estimates

Compound Parent patent #

Parent patentfiling

1st

IndicationMarket

authorisation(estimated)

Parent patentexpiry

Use in psoriasis

patentexpiry

SPC(estimated)

Marketexclusivity(estimated)Compound Parent patent # filing (estimated) expiry expiry (estimated) (estimated)

Enbrel EB 0418014 10-Sep-90 03-Feb-00 10-Sep-10 31-Jan-15 03-Feb-10

Remicade EP 0610201 18-Mar-92 13-Aug-99 18-Mar-12 12-Aug-14 13-Aug-09

Humira EP 0929578 10-Feb-97 08-Sep-03 10-Feb-17 16-Apr-18 08-Sep-13

S 1309692 0 01 16 09 0 21 1 24 16 19Stelara EP 1309692 07-Aug-01 16-Jan-09 07-Aug-21 15-Jan-24 16-Jan-19

Briakinumab EP 1175446* 24-Mar-00 (Apr-11) 24-Mar-20 (24-Mar-25) (Apr-21)

* may not be granted


Psoriasis therapies; US market protection estimates

Compound Parent patent #

Parent patentfiling

Use in psoriasis patent #

Use in psoriasis

patentfiling

1st

IndicationMarket

authorisation(estimated)

Parent patentexpiry

Use in psoriasis

patentexpiry

PT extension

(estimated)Compound Parent patent # filing patent # filing (estimated) expiry expiry (estimated)

Enbrel Re.36,755 10-May-90 US 5,605,690 08-Feb-95 02-Nov-98 07-Mar-12 25-Feb-14 23-Oct-12

Remicade US 6284471 04-Feb-94 24-Aug-98 04-Sep-18 none

Humira US 6090382 09-Feb-96 31-Dec-02 09-Feb-16 31-Dec-16

St l US 6902734 01 A 01 (O t 09) 24 J l 22 (O t 23)Stelara US 6902734 01-Aug-01 (Oct-09) 24-Jul-22 (Oct-23)

Briakinumab US 6914128 24-Mar-00 (Apr-11) 24-Mar-20 (Aug-23)


Licensed indicationsRheumatoid

A th itiCrohn‘s Juvenile

PsoriasisPsoriatic Ulcerative Ankylosing

S d litiArthritis disease ArthritisPsoriasis

Arthritis Colitis Spondylitis

Enbrel®

(≥2 yrs US;

(etanercept) (≥2 yrs, US;≥4 yrs, EU)

(≥8 yrs, EU)

Remicade®

(≥6 yrs (infliximab)

( yEU& US)

Humira®

(≥4 yrs, US; (adalimumab) ≥13 yrs, EU)

Stelara®

(EU & CA onl )

5

(ustekinumab) only)

Life Cycle ManagementCompetitive intelligence analysis

Dosing regimens for adults US & EU

Rheumatoid Arthritis*

Psoriatic Arthritis

Ankylosing Spondylitis

Plaque Psoriasis

Enbrel® 25 mg twice weekly

or

(etanercept) subcutaneous

injections

25 mg twice weekly or

50 mg weekly

50 mg weekly or

50 mg twice weekly for 12 weeksfollowed by 50 mg weeklyinjections y g y

(max 24 weeks in EU)

Annual cost per patient €13,400

$20,190€19,326*$24,848**

(ex-factory price) Annual global sales

(2008) $3.6 bio

6

* Average of FR & DE prices & based on 1 yr continuous use** Wholesale Acquisition Cost (WAC)Life Cycle Management

Competitive intelligence analysis


Rheumatoid Arthritis*

Psoriatic Arthritis


Crohn‘sDisease

Ulcerative Colitis

Plaque Psoriasis

Remicade®3 mg/kg induction

3 mg/kg weeks 2 & 6Remicade® (infliximab)

intravenous infusion

g g3 mg/kg every 8

weeksIncomplete

responders up to 7 5mg/kg

5 mg/kg induction5 mg/kg weeks 2 & 6

5 mg/kg every 8 weeks

7.5mg/kg

Annual cost per patient (ex-factory price)

€17,400$19,510

€21,573*$21,166**

Annual global sales (2008)

$3.7 bio

7

* Average of FR & DE prices & based on 1 yr continuous use** Wholesale Acquisition Cost (WAC)



Rheumatoid ArthritisPsoriatic Arthritis


Crohn‘sDisease

Plaque Psoriasis

Humira® ( )

80 mg induction80 i d ti(adalimumab)

subcutaneous injections

40 mg every other week(12 week maximum exposure for Pso.Ar. & A.S.)

g40 mg at week 3

40 mg every other week

80 mg induction40 mg every other week

Annual costAnnual cost per patient

(ex-factory price)

€14,200$18,886

€3,300$18,886

€14,700$20,339

€15,898*$18,886**

Annual global sales (2008)

$4.5 bio

* Average of FR & DE prices & based on 1 yr continuous use

8

g p y** Wholesale Acquisition Cost (WAC)


Prescribing paradigm

E b l® i li d f h i th i th US & ≤ 24 k i th EU• Enbrel® is licensed for chronic therapy in the US & ≤ 24 weeks in the EU• Remicade® is licensed for chronic therapy in both the US & EU• Humira® is licensed for chronic therapy in both the US & EU• Stelara® is licensed for chronic therapy in the EU

• Treatment of psoriasis may vary from the label & is dependent upon• Treatment of psoriasis may vary from the label & is dependent upon – visible efficacy – long term side effects; both perceived & real

d t ti t l ti hi– doctor-patient relationship

• Awareness of malignancies & serious opportunistic infections is on the rise


• Dimeric fusion protein which binds TNFα and lowers the concentration of free TNFαleft in circulation

Enbrel® (etanercept)

left in circulation• Dosing regimens vary geographically with a 24 week maximum treatment period in

the EU and no cap in the US; yearly treatment with 50 mg weekly subcutaneousinjections is on the rise

• 34% of 25 mg twice weekly patients reached PASI 75 @ week 12 with continued34% of 25 mg twice weekly patients reached PASI 75 @ week 12 with continuedimprovement to 44% @ week 24 in Study-2

• SAEs: malignancies (breast and lung carcinomas, lymphomas, non-melanoma skincancers), demyelinating disorders, fatal haematological reactions, fatal bacterial, viral & fungal opportunistic infections including TB and hepatitis B reactivation

• 7% of patients tested positive for anti-etanercept antibodies after 1 year• Contraindicated with Anakinra®, abatacept, sulfasalazine, cyclophosphoamides,

congestive heart failure, alcoholic hepatitis, Wegener‘s granulomatosis and live vaccines

• No signals from developmental toxicity study in rats & rabbits; long termobservational pregnancy registry in place

• No head-to-head comparative trials• Abandoned indications: idiopathic pulmonary fibrosis asthma uveitis cachexia

10

Abandoned indications: idiopathic pulmonary fibrosis, asthma, uveitis, cachexia, myelodysplastic syndrome, congestive heart failure, Wegener‘s granulomatosis


Enbrel® – Development overview1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

PsARA AS PsoMAMA

Rheumatoid Arthritis Study I / II / III3 Phase III registration trials

MA MA

Psoriatic Arthritis NCT00317499single Phase III registration

Ankylosing spondylitisAnkylosing spondylitissingle Phase III registration

PsoriasisStudy I / II2 Phase III registration trials


Enbrel® – Psoriasis development1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Study-120021632

Study-2 20021639

NCT00111449 50 mg twice weekly

NCT00121615 OL ext

NCT00110981UVB combination Tx

NCT00333034 50 mg once weekly

12

MAA MA Launch


• Chimeric monoclonal antibody targeting TNFα delivered by i.v. infusion 5 mg/kg at weeks 0, 2 & 6 followed by maintainance infusions every 8 weeks

Remicade® (infliximab)

• 80% of patients in EXPRESS I acheived PASI 75 with 5 mg/kg by week 10 sustained at 82% PASI 75 @ week 24, p<0.001;

• EXPRESS II demonstrates better efficacy of chronic over cyclical therapy• SAEs include malignancies, serious infections (bacterial, viral, fungal) &SAEs include malignancies, serious infections (bacterial, viral, fungal) &

cardiovascular events• Most common AEs: arthralgia, nasopharyngitis, URT infections, cough, injection site

reactions, headache• Black box warning: serious & fatal fungal, viral & bacterial infections inclusive of TB,Black box warning: serious & fatal fungal, viral & bacterial infections inclusive of TB,

and hepatosplenic T-cell lymphomas• ~20% of patients develop infliximab antibodies and efficacy wanes over time• Contraindicated with mild-to-severe heart failure and live vaccines

No developmental toxicity results available; administration to pregnant women• No developmental toxicity results available; administration to pregnant women limited by medical need

• Early development strategy was to use pivotal Phase IIb trial data in conjunction with single Phase III trial experience with multiple label extensions per indicationAbandoned indications: congestive heart failure asthma COPD sarcoidosis

13

• Abandoned indications: congestive heart failure, asthma, COPD, sarcoidosis, multiple myeloma


Remicade® – Development overview1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Crohn‘sMA

Crohn‘s disease ACCENT I

i l Ph III i t ti

RAMA

ASMA

PsAMA

UCMA

PsoMA

single Phase III registration

Rheumatoid Arthritis ATTRACTsingle Phase III registration

Ankylosing spondylitisNCT00207701single Phase III registration

Psoriatic ArthritisNCT00051623single Phase III registration

Ulcerative ColitisUCI NCT00096655 & UC II NCT000364392 Phase III trials

14

PsoriasisEXPRESS I NCT00106834 EXPRESS II NCT00106847 2 Phase III trials


Remicade® – Psoriasis development1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

SPIRITPhase IIb

EXPRESS I

EXPRESS IIEXPRESS II

NCT00687401Standard Tx & biologic Tx failures

NCT00251641MTX head-to-head

NCT00358670

NCT00527072Etanercept Tx failures

NCT00833053 dose optimization

NCT00358670OL ext

NCT00686595Etanercept switch

Long term observation, registry & cross-indication surveillance

p

15

MAA MA Launch


• Fully humanized TNFα inhibitor

Humira® (adalimumab)

• Dosing regimen of subcutaneous injection of 40 mg every other week• 71% of patients acheive PASI 75 by week 12 in Study Ps-I • 28% of patients lose adequate response by week 52 as defined by a 50% p q p y y

reduction from baseline improvement witnessed at week 33• SAEs include malignancies, cardiovascular events & serious infections• Most common AEs: infections, injection site reactions, headache, & rashj• Black box warning: TB, invasive fungal infections & other occassionally fatal

opportunistic infections • Contraindicated with Anakinra® and live vaccines• No signals from perinatal toxicity study in cynomolgus monkey; long term

observational pregnancy registry in place • Development abandoned in asthma


Humira® – Development overview2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

RAMA

Rheumatoid Arthritis Studies I / II / III / IV / V5 Phase III registration trials

ASMA

PsAMA

CDMA

PsoMA

JIAMA

UCMA

5 Phase III registration trials

Ankylosing spondylitisNCT00085644

Psoriatic Arthritis Study PsA-I, NCT00646386NCT00646178 2 Phase III registration trials

NCT00085644single Phase III registration trial

Crohn‘s DiseaseCD-II, NCT00105300CD-III, NCT000777792 Phase III registration trials

PsoriasisPs-I, NCT00237887single Phase III registration trial

Juvenile Idiopathic ArthritisNCT00237887

17

single Phase III registration trial

Ulcerative ColitisNCT00408629 & NCT00385736 2 Phase III registration trials


Humira® – Psoriasis development2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

NCT00646191

NCT00645905NCT00645892

Study Ps-II

Study Ps-I

NCT00645892OL extention

Study Ps I

CHAMPIONMTX & placebo controlled

NCT00195676Phase III catch-all OL extention

NCT00566722OL in suboptimal response patients

ESPRIT, NCT0079987710 year post marketing safety study

Phase III catch-all OL extention

NCT00735787Hands & Feet

18

MAA MA Launch


Ustekinumab

• Fully humanized anti IL antibody delivered by subcutaneous injection via• Fully humanized anti-IL-12/23 antibody delivered by subcutaneous injection via induction at weeks 0 & 4 followed by quarterly maintainance regimen

• 67% of patients in both PHOENIX trials acheived PASI 75 with 45 mg, the lower dose, by week 12, p<0.0001; maximum effect 75% PASI 75 @ week 20 with 45 mgy @ g

• SAEs include malignancies, serious infections (bacterial, viral, fungal) & cardiovascular events

• Most common AEs: arthralgia, nasopharyngitis, URT infections, cough, injection site reactions, headache

• Marketed as Stelara® in EU, US & CA for psoriasis• Additional indications

– Psoriatic arthritis– Crohn‘s disease– previously abandoned MS

U ki b ifi ib di d i % f i

19

• Ustekinumab specific antibodies noted in 5% of patients


Ustekinumab – Development overview2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 20172005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

NCT00267956 xPsoriatic arthritis

NCT00771667Crohn‘s disease

(pivotal IIb/III)

PHOENIX I

Crohn‘s disease (confirmatory III)

P i i

PHOENIX II

Psoriasis

Psoriasis

20

MAA MA Launch MAA MA Launch


Ustekinumab – Psoriasis development2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 20142002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

NCT00320216 x

PHOENIX I

PHOENIX II

NCT00454584Enbrel® controlled

x

PHOENIX 5yr OL

NCT00723528 JP

NCT00747344 KR TW

21

MAA MA Launch


Efficacy & median time to relapseHalf life

(t1/2)Elimination

(5 x t1/2)PASI 75 Median time to relapse

(50%≤PASI 50)(t1/2) (5 x t1/2) (50%≤PASI 50)

Enbrel 0.6 weeks 3 weeks 34% @ week 12 12 weeks1

(etanercept)@

Remicade ~ 1.5 weeks ~ 7.5 weeks 80% @ week 10 >20 weeks2

(infliximab)

Humira ~ 2 weeks ~ 10 weeks 71% @ week 12 ~ 24 weeks3

(adalimumab)

Stelara ~ 3 weeks ~ 15 weeks 67% @ week 12 ~ 24 weeks4

22

(ustekinumab)1 http://www.wyeth.com/news/archive?nav=display&navTo=/wyeth_html/home/news/pressreleases/2004/1145887154280.html2 SPIRIT trial, http://www.mims.co.uk/news/891873/Remicade-approved-use-psoriasis/3 Study Ps-I, Extrapolated from graph4 Phoenix I, trial Etrapolated from graph


Psoriasis therapy: competitive environment

TNFα inhibitor

ART621

IL-12/IL-23 inhibitorCNTO 1959

LaunchedPhase II Phase IIIPhase I

Briakinumab

LaunchedPhase II Phase IIIPhase I

BMS-582949

p38 kinaseJAK inhibitor

CP-690.550R348

23

p38 kinase inhibitor


Compounds in clinical development for psoriasis

Briakinumab, ABT874

ART621

BMS-582949

CP-690.550

R348

CNTO 1959


Briakinumab

• Fully humanized anti-IL 12/23 antibodyFully humanized anti IL-12/23 antibody• Monthly subcutaneous injection with 200 mg induction at weeks 0 & 4 followed by

100 mg monthly maintainance regimen; t½ ~ 8- 10 days• Positive results from 180 patient Phase IIb trial• 90% reach PASI 75 by week 12, p<0.001 and 3 months following cessation 85%

maintain at least PASI 50 with one 200 mg injection/week for 4 weeks• Patients were allowed to relapse in a 12 week blinded withdrawal period; 69%

regain PASI 75 within 12 weeks following retreatmentregain PASI 75 within 12 weeks following retreatment• Well tolerated; no SAEs, most common AEs: injection site reactions,

nasopharyngitis, URT infections• Comparator trials versus Enbrel® and MTX (ongoing)• Phase III results expected 04Q09; filing in 2010• Additional indications

– Crohn‘s diseasepreviously abandoned MS & RA programs

25

– previously abandoned MS & RA programs


Briakinumab – Psoriasis development2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 20142002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

NCT00292396

NCT00570986

NCT00691964

NCT00710580

Enbrel® head-to-headplacebo controlled

NCT00626002

NCT00710580

NCT00679731MTX controlled

Enbrel® head-to-headplacebo controlled

NCT00626002 OL catch-all ext.

NCT00870948Bioavailability for CMC process

26

MAA MA Launch


ART621

S b t ti TNF l l tib d i t d i• Subcutaneous anti-TNFα monoclonal antibody; incorporates domain antibodies (dAb) which being smaller improves manufacturing yield, lowers immunogenicity and improves tissue penetrationPoC• PoC

– factorial-design, randomised, double-blind, placebo-controlled, dose optimisation, pharmacokinetics, safety, efficacy study

lti l d d i i t ti f ART621– multiple dose administration of ART621.– 1 site in NZ– results from Mar09; well tolerated and exhibiting a safety profile

i t t ith ti TNF ti itconsistent with anti-TNF activity • IND filed in Rheumatoid Arthritis


O l d il 38 it ti t d t i (MAP) ki i hibit

BMS-582949

• Oral once daily p38 mitogen-activated protein (MAP) kinase inhibitor promising to halt the inflammatory cytokine cascade

• 99 patient 12 week PoC in psoriasis completed in Apr09• previously abandoned Eczema/dermatitis• other p38MAP kinases abandoned due to toxicity

– Johnson & Johnson, talmapimodp– Vertex, VX-745


CP-690550 • Selective oral JAK-3 inhibitor (IL-2,4,7,9,15,21 receptors only) which limits the

effects to T and NK cell development and B-cell functioneffects to T and NK cell development and B cell function• Preclinical models show efficacy

– arthritisasthma– asthma

– transplant • Additional indications: Crohn‘s disease, Rheumatoid Arthritis, psoriasis,

l t l trenal transplant• NK cell levels reduced with no reduction in CD4

+ or CD8+ levels

Results from 58 patient PoC


CP-690550 • Phase II trials

– Dose dependent increase in HDL & LDL levels– Increased ALT & AST levels > 3 x ULN– 3 sudden cardiac deaths3 sudden cardiac deaths

• 1 in 12 week study• 2 in long term follow-up 6-12 months

– 9 serious infections in 9 patients9 serious infections in 9 patients• Bacterial• Viral• FungalFungal


R348

O l d l JAK 3 & S k i hibit• Oral dual JAK-3 & Syk inhibitor• EIM Jan08; combi SAD/MAD• Preclinical models show efficacy

– arthritic symptoms, bone destruction & swelling– psoriasis– transplant p

• Planned clinical programs– psoriasis

Rheumatiod Arthritis– Rheumatiod Arthritis– renal transplant– Graft vs host disease


CNTO 1959

F ll h i d ti IL 12/23 tib d• Fully humanized anti-IL-12/23 antibody• EIM June 2009

– Phase I placebo-controlled trial – 3 US sites – 71 healthy volunteers & psoriasis patients – evaluating the PK profile and antibody development with both i.v. g p y p

infusion and subcutaneous formulations– 11 month estimated duration


Back-ups



• US label– RA

• reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoidfunction in patients with moderately to severely active rheumatoid arthritis. ENBREL can be initiated in combination with MTX or used alone

– Polyarticular juvenile idiopathic arthritis• reducing signs and symptoms of moderately to severely active• reducing signs and symptoms of moderately to severely active

polyarticular juvenile idiopathic arthritis in patients ≥ 2 yrs– Psoriatic arthritis

• reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis and improving physical function in patientsdamage of active arthritis, and improving physical function in patients with psoriatic arthritis. ENBREL can be used in combination with MTX for those patients who do not respond adequately to MTX alone

34 Competitive intelligence analysis


• US label, continuedUS label, continued– Ankylosing spondylitis

• reducing signs and symptoms in patients with active ankylosing spondylitis

– Plaque psoriasis • treatment of patients ≥ 18 yrs with chronic moderate to severe plaque

psoriasis who are candidates for systemic therapy or phototherapy


• EU label


– RA• in combination with MTX for the treatment of moderate to severe active

rheumatoid arthritis in adults when the response to disease-modifiying antirheumatic drugs including MTX (unless contraindicated) has been g g ( )inadequate

• can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate

• treatment of severe, active and progressive rheumatoid arthritis in d lt t i l t t d ith MTXadults not previously treated with MTX

• alone or in combination with MTX, Enbrel reduces the rate of progression of joint damage as measured by X-ray and to improve physical function

Polyarticular juvenile idiopathic arthritis– Polyarticular juvenile idiopathic arthritis• treatment of active polyarticular juvenile idiopathic arthritis in children

and adolescents ≥ 4 yrs who have had an inadequate response to, or who have proved intolerant of, MTX. Enbrel has not been studied in children < 4yrs


children 4yrs

• EU label, continued


,– Psoriatic arthritis

• treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate. Enbrel has been shown to improve physical function in patients with psoriatic arthritis and to reduce the rate of progressionin patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease

– Plaque psoriasis• treatment of adults with moderate to severe plaque psoriasis who failed

t d t h h t i di ti t i t l t tto respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, MTX and PUVA

– Paediatric plaque psoriasis• treatment of chronic severe plaque psoriasis in children and

adolescents ≥ 8 years who are inadequately controlled by, or are y q y y,intolerant to, other systemic therapies or phototherapies

– Ankylosing spondylitis• treatment of adults with severe active ankylosing spondylitis who have

has an inadequate response to conventional therapy



• US label– Rheumatoid arthritis

• REMICADE, in combination with MTX, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderate to severely active h t id th itirheumatoid arthritis

– Crohn‘s disease• REMICADE is indicated for reducing signs and symptoms and inducing

and maintaining clinical remission in adult and pediatric patients with moderatel to se erel acti e Crohn‘s disease ho ha e had anmoderately to severely active Crohn‘s disease who have had an inadequate response to conventional therapy

• REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn‘s diseaseclosure in adult patients with fistulizing Crohn s disease

– Ankylosing spondylitis• REMICADE is indicated for reducing signs and symptoms in patients

with active ankylosing spondylitis



• US label, continued– Ulcerative colitis

• REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional q ptherapy

– Psoriatic arthritis• REMICADE is indicated for reducing signs and symptoms of active

arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritisphysical function in patients with psoriatic arthritis

– Plaque psoriasis• REMICADE is indicated for the treatment of adult patients with chronic

severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate REMICADE should only be administered tomedically less appropriate. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician



• EU label– Rheumatoid arthritis

Remicade, in combination with MTX, is indicated for:the reduction of signs and symptoms, as well as improving physical function in:

– patients with active disease when the response to disease-modifying anti-rheumatic drugs (DMARDs) including MTX has been inadequaterheumatic drugs (DMARDs), including MTX has been inadequate

– patients with severe, active and progressive disease not previously treated with MTX or other DMARDs

In these patient populations, a reduction in the rate of the progression of joint damage, as measured by X-ray, has been demonstrated

– Ulcerative colitisRemicade is indicated for:

– treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response to conventional therapy including corticosteroids and 6-MP or AZA, or who are intolerant to or have medicalcorticosteroids and 6 MP or AZA, or who are intolerant to or have medical contraindications for such therapies

– Ankylosing spondylitisRemicade is indicated for:

– treatment of severe, active ankylosing spondylitis, in adult patients who have responded inadeq atel to con entional therap


responded inadequately to conventional therapy


• EU label, continued– Adult Crohn‘s disease

Remicade is indicated for:– treatment of severe, active Crohn‘s disease, in patients who have not

responded despite a full and adequate course of therapy with a corticosteroid and/or immunosuppressant; or who are intolerant to or have medicaland/or immunosuppressant; or who are intolerant to or have medical contraindications for such therapies

– treatment of fistulising, active Crohn‘s disease, in patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy)

Paediatric Crohn‘s disease– Paediatric Crohn s diseaseRemicade is indicated for:

– treatment of severe, active Crohn‘s disease, in paediatric patients aged 6 to 17 years, who have not responded to conventional therapy including a corticosteroid and an immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for such therapy Remicade hasare intolerant to or have contraindications for such therapy. Remicade has been studied only in combination with conventional immunosuppressive therapy



• EU label, continued– Psoriasis

Remicade is indicated for:– treatment of moderate to severe plaque psoriasis in adults who failed to

respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine MTX and PUVAsystemic therapy including cyclosporine, MTX and PUVA

– Psoriatic arthritisRemicade is indicated for:

– treatment of active and progressive psoriatic arthritis in adults when the response to previous DMARD therapy has been inadequate

Remicade should be administered– in combination with MTX– or alone in patients who show intolerance to MTX or for whom MTX is

contraindicatedRemicade has been shown to improve physical function in patients with psoriaticRemicade has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease


H i ® ( d li b)Humira® (adalimumab) • US label

– Rheumatoid arthritis• reducing signs and symptoms, including major clinical response, inhibiting

th i f t t l d d i i h i l f ti ithe progression of structural damage, and improving physical function in adult patients with moderate to severely active disease

– Juvenile idiopathic arthritis• reducing signs and symptoms of moderately to severely active polyarticular

juvenile idiopathic arthritis in patients ≥ 4yrsjuvenile idiopathic arthritis in patients 4yrs– Psoriatic arthritis

• reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function

– Ankylosing spondylitis• reducing signs and symptoms in patients with active disease

– Crohn‘s disease• reducing signs and symptoms and inducing and maintaining clinical

remission in adult patients with moderately to severely active Crohn‘s disease who have had an inadequate response to conventional therapydisease who have had an inadequate response to conventional therapy. Reducing signs and symptoms and inducing clinical remission in these patients if they have lost response to or are intolerant to infliximab

– Plaque psoriasis• the treatment of adult patients with moderate to severe chronic plaque

i i h did t f t i th h t th d


psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate

H i ® ( d li b)Humira® (adalimumab) • EU label

– Rheumatoid arthritis• Humira in combination with MTX is indicated for:• Humira in combination with MTX is indicated for:

– the treatment of moderate to severe active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs including MTX has been inadequate

– the treatment of severe, active and progressive rheumatoid arthritis in d lt t i l t t d ith MTXadults not previously treated with MTX

• Humira can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate

• Humira has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in

bi ti ith MTXy y p p y g

combination with MTX– Polyarticular juvenile idiopathic arthritis

• Humira in combination with MTX is indicated for the treatment of active polyarticular juvenile idiopathic arthritis, in adolescents aged 13 to 17 years who have had an inadequate response to one or more disease-modifyingwho have had an inadequate response to one or more disease modifying ant-rheumatic drugs (DMARDs). Humira can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate

– Ankylosing spondylitistreatment of adults with severe active ankylosing spondylitis who have had


• treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy

Humira® (adalimumab) • EU label, continued

Crohn‘s disease– Crohn s disease• treatment of severe, active Crohn‘s disease, in patients who have not

responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. For induction ptreatment, Humira should be given in combination with corticosteroids. Humira can be given as monotherapy in case of intolerance to corticosteroids or when continued treatment with corticosteroids is inappropriate

Psoriasis– Psoriasis• treatment of moderate to severe chronic plaque psoriasis in adult patients

who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, MTX or PUVA

– Psoriatic arthritisPsoriatic arthritis• Humira is indicated for the treatment of active and progressive psoriatic

arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. Humira has been shown to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease


X ray in patients with polyarticular symmetrical subtypes of the disease and to improve physical function

Enbrel® – Clinical trials overview• Study-1, 20021632

– 25 mg vs placebo (1:1)°– 1° endpoints

• Proportion of patients achieving PASI 75 @ week 12– 2° endpoints

• Proportion of patients achieving PASI 50 & 90 @ week 24• Proportion of patients with PGA score of cleared or minimal @ week 24• QoL; DLQI

– 112 moderate-to-severe patients– 24 week trial

St d 2 20021639• Study-2, 20021639– 25 mg, 25 mg twice weekly, 50 mg twice weekly vs placebo (1:1:1:1)– 1° endpoints


• Proportion of patients achieving PASI 50 & 90 @ week 24• Proportion of patients with PGA score of cleared or minimal @ week 24• QoL; DLQI

– 652 moderate-to-severe patients– 24 week trial– 5 months recruitment– 47 sites– US only


Enbrel® – Study-1; study design2003 ARCH DERMATOL

Double blind core study

Etanercept 25 mg

Placebo

scr x 2 4 8 12 16 20 24 weeks

PASIPGA

DLQI


Enbrel® – Study-1; patient flow2003 ARCH DERMATOL


Enbrel® – Study-1; baseline characteristics2003 ARCH DERMATOL


Enbrel® – Study-1; study results2003 ARCH DERMATOL


• Efficacy endpoints


• Efficacy endpoints– 1° endpoints

30% of patients achieving PASI 75 @ week 12– 2° endpoints

77% patients achieving PASI 50 @ week 24 56% patients achieving PASI 75 @ week 24 21% patients achieving PASI 90 @ week 24 53% patients with PGA score of cleared or minimal @ week 24p @ improvement in DLQI from baseline

met x not met ~trend


Enbrel® – Study-1; safety & tolerability2003 ARCH DERMATOL

No treatment associated SAE was reportedNo treatment associated SAE was reported

Most common AEs – URT infections, headache & injection site reactions


Enbrel® – Study-2; study design2003 NEJM

Double blind core study Follow-up period

Etanercept 25 mg(once weekly)

Etanercept 25 mg

scr x 2 4 8 12 16 20 24 weeks

(twice weekly)

Etanercept 50 mg(twice weekly)

Placebo

PASIPGA

blood & urine analysisx x

DLQI

y


x = entanercept antibody assay

Enbrel® – Study-2; baseline characteristics2003 NEJM


Enbrel® – Study-2; study results2003 NEJM




14% of 25 mg weekly patients achieving PASI 75 @ week 12 34% of 25 mg twice weekly patients achieving PASI 75 @ week 12 34% of 25 mg twice weekly patients achieving PASI 75 @ week 12 34% of 50 mg twice weekly patients achieving PASI 75 @ week 12

– 2° endpoints 25% of 25 mg weekly patients achieving PASI 75 @ week 24 % f S @ 44% of 25 mg twice weekly patients achieving PASI 75 @ week 24 59% of 50 mg twice weekly patients achieving PASI 75 @ week 24 improvement in both PGA & DLQI scores at week 12 from baseline

59 Competitive intelligence analysismet x not met ~trend

Enbrel® – Study-2; safety & tolerability2003 NEJM


Remicade®


Remicade® – Clinical trials overview• SPIRIT (NCT00230529), Study III

– 2 doses vs placebo (2:2:1)– 1° endpoints

• Proportion of patients achieving ≥PASI 75 @ week 10p p g @– 2° endpoints

• Anitbodies to infliximab• QoL: DLQI

– 249 patients– 26 week trial

• EXPRESS I (NCT00106834), Study I– 1 dose vs placebo (4:1)

1° d i– 1° endpoints• Proportion of patients achieving PASI 75 @ week 10

– 2° endpoints• Proportion of patients achieving PASI 75 @ week 24• Proportion of patients with PGA score of cleared or minimal @ week 10, 24 & 50• Proportion of patients @ week 10, 24, & 50 acheiving:

– PASI 50– PASI 90 – % improvement in PASI from baselinep– % improvement in NAPSI

– 378 moderate-to-severe patients– 66 week trial– 7 months recruitment– 32 sites– 8 countries, (AT, BE, CA, CH, DE, DK, FR, UK, US)

• EXPRESS II (NCT00106847), Study II– 2 doses vs placebo (2:2:1)– 1° endpoints

• Proportion of patients achieving ≥PASI 75 @ week 10– 2° endpoints

• Efficacy of 4 maintenance regimens• QoL: DLQI, SF-36 & Economic Questionnaire

– 835 moderate-to-severe patients– 66 week trial

6 months recruitment


– 6 months recruitment– 63 sites– 4 countries, (AT, CA, FR, IT, US)

Remicade® –SPIRIT; study design2005 New Medicines Profile


Infliximab 3 mg/kg

Infliximab 5 mg/kg

scr x 2 6 10 26 weeks

g g

Placebo

PASIPGA

DLQI


Remicade® –SPIRIT; patient flow2004 Gottlieb J Am Acad Dermatol


Remicade® –SPIRIT; baseline characteristics2004 Gottlieb J Am Acad Dermatol


Remicade® –SPIRIT; study results2005 New Medicines Profile

Infliximab 3 mg/kg

Infliximab5 mg/kg

Placebo

PASI 75 @ week 10(p<0.001) 72% 88% 6%

DLQIMedian ∆ from baseline*

(p<0.001)-8 -10 0

* median baseline values 11,12,14 respectively


Remicade® –SPIRIT; study results2004 Gottlieb J Am Acad Dermatol


Remicade® –SPIRIT; safety & tolerability2004 Gottlieb J Am Acad Dermatol


Remicade® – EXPRESS I; study design2005 Lancet, Infliximab induction and maintenance therapy


Infliximab 5 mg/kg

Placebo

scr x 2 6 10 14 22 24 26 30 38 46 50 66 weeks

x

x

x

x

x

x

x

x

x

x

x

x

xxxxx

NAPSI

PASIPGA

[Infliximabserum]

Infliximab antibodies

Anti-nuclear & anti-double stranded DNA antibodies

71 Competitive intelligence analysis x 5 mg/kg adminsitration

Remicade® – EXPRESS I; patient flow2005 Lancet, Infliximab induction and maintenance therapy


Remicade® – EXPRESS I; baseline characteristics2005 Lancet, Infliximab induction and maintenance therapy


Effi d i t

Remicade® – EXPRESS I; study results2005 Lancet, Infliximab induction and maintenance therapy


80% of patients achieving PASI 75 @ week 10– 2° endpoints2 endpoints

82% patients achieving PASI 75 @ week 24 83%, 74%, 53% patients with PGA score of cleared or minimal @ week 10, 24 & 50 Proportion of patients @ week 10, 24, & 50 acheiving:

91% 90% 69% PASI 50 91%, 90%, 69% PASI 50 57%, 58%, 45% PASI 90 86%, 84%, 64% improvement in PASI from baseline 26%, 56%, 56% improvement in NAPSI



met x not met trend

Remicade® – EXPRESS I; pre-infusion concentrations2005 Lancet, Infliximab induction and maintenance therapy


Remicade® – EXPRESS I; safety & tolerability2005 Lancet, Infliximab induction and maintenance therapy


Remicade® – EXPRESS I; antibody development2005 Lancet, Infliximab induction and maintenance therapy


Remicade® – EXPRESS II; study design2005 FDA website, Clinical Study Report


Infliximab 3 mg/kg

scr x 2 6 10 14 16 18 22 30 38 46 50 66 weeks

period

x x x xx x x x

Infliximab 5 mg/kg x x x x x x xx x x x

x x x

Placebo

PASIPGA

x x x

Infliximab antibodies

Anti nuclear & anti double stranded DNA antibodies

80 Competitive intelligence analysis xx

3 or 5 mg/kg group adminsitrationplacebo re-rand. group adminsitration

Anti-nuclear & anti-double stranded DNA antibodies

Infliximab 3 mg/kg

Infliximab5 mg/kg

Placebo

Remicade® – EXPRESS II; study results2005 FDA website, Clinical Study Report

3 mg/kg 5 mg/kg

≥ PASI 75 @ week 10(p<0 001) 71% 76% 2%(p<0.001) 71% 76% 2%

PASI 90 @ week 10(p<0.001) 37% 45% 0 5%(p 0 00 ) 37% 45% 0.5%

PGA score of excellent or cleared @ week 10 70% 76% 1%@ 70% 76% 1%

DLQIMedian ∆ from baseline* -9 -9 0


Median ∆ from baseline (p<0.001)

9 9 0

* median baseline value 12

S @

Remicade® – EXPRESS II; study results2005 FDA website, Clinical Study Report

≥PASI 75 @ week 50(p<0.001)

Continuous Infliximab 44%Infliximab 3 mg/kg

44%

IntermittantInfliximab 24%3 mg/kg

24%

Continuous Infliximab 55%5 mg/kg

55%

Intermittant Infliximab 38%


5 mg/kg38%

Therapy associated adverse event profile

Remicade® – EXPRESS II; safety & tolerability2005 FDA website, Clinical Study Report

• Therapy associated adverse event profile– Serious infections

• tuberculosis (2)• undisclosed (9)

– Cardiovascular eventsCardiovascular events• congestive heart failure (1)

– Malignancies• basal cell carcinomas (9)• squamous cell carcinomas (1)• adenocarcinoma (1)• adenocarcinoma (1)• breast cancer (1)

– Lupus erythematosus (4)– Increased liver enzymes @ week 50

• 4.9% patients had markedly abnormal ALT valuesp y• 3.1% patients had markedly abnormal AST values

– Increased antibodies @ week 50• 55% of anti-Infliximab antibody-positive patients presented with titers ≤ 1:40;

however 5 mg/kg was associated with lower titers than 3 mg/kg• 65% patients were newly positive for ANA antibodies


65% patients were newly positive for ANA antibodies• 26.8% patients were newly positive for anti-dsDNA antibodies

Humira® (adalimumab)


Humira® – Clinical trials overview• Phase II, Study Ps-II (NCT00645814)

– 40 mg weekly or eow vs placebo (1:1:1)– 1° endpoints

• Proportion of patients achieving ≥PASI 75 @ weeks 12 & 24Proportion of patients achieving PASI 75 @ weeks 12 & 24• Proportion of patients with an improved PGA score at weeks 12 & 24

– 2° endpoints• Proportion of patients achieving PASI 50 @ weeks 12 & 60• Proportion of patients achieving PASI 90 @ weeks 12 & 60• Proportion of patients with an improved PGA score @ weeks 12 & 60

– 147 patients– 60 week trial– 2 months recruitment– 18 sites– 2 countries, (CA, US)

• Phase III, Study Ps-I (NCT00237887)– 40 mg eow vs placebo (2:1 Period A & 1:1 Period C)– 1° endpoints

• Proportion of patients achieving PASI 75 @ week 16• Proportion of patients losing adequate response after week 33 & on or before week 52

– 1212 patients– 52 week trial– 81 sites– 2 countries, (CA, US)

• Phase III, CHAMPION (NCT00235820)– 40 mg eow vs methotrexate vs placebo (2:2:1)– 1° endpoints


• Proportion of patients achieving PASI 50 @ week 16• Proportion of patients achieving PASI 90 @ week 16• Proportion of patients achieving PASI 100 @ week 16• Proportion of patients with an improved PGA score @ week 16

– 271 patients– 16 week trial


– 28 sites– CA, Europe

Humira® – Study Ps-II; study design2006 Gordon, J Am Acad Dermatology

S

2 4 8 16 20 22 28 32 36 44 52


PASIPGA

H i ® St d P II ti t flHumira® – Study Ps-II; patient flow2006 Gordon, J Am Acad Dermatology


Humira® – Study Ps-II; baseline characteristics2006 Gordon, J Am Acad Dermatology


Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology


53% of eow patients achieving ≥PASI 75 @ weeks 12 & 24 80% of weekly patients achieving ≥PASI 75 @ weeks 12 & 24 80% of weekly patients achieving ≥PASI 75 @ weeks 12 & 24

– 2° endpoints Proportion of eow patients @ week 12, & 60 acheiving:

76%, 64% PASI 50 % % S 24%, 33% PASI 90 49%, 44% improvement from baseline to PGA clear or almost clear

Proportion of weekly patients @ week 12, & 60 acheiving: 88%, 66% PASI 50 48%, 48% PASI 90 76%, 52% improvement from baseline to PGA clear or almost clear

met x not met trend



Humira® – Study Ps-II; safety & tolerability2006 Gordon, J Am Acad Dermatology


• Therapy associated adverse event profile

Humira® – Study Ps-II; safety & tolerability2006 Gordon, J Am Acad Dermatology

– Serious infections (1)– Cardiovascular events

• palpitations• coronary artery disease

– Malignancies (5)li l (2)• malignant melanoma (2)

• squamous cell carcinoma (1)• breast carcinoma (1)• gastric adenocarcinoma (1)

– Cerebrovascular accidents (2)• undisclosed; 1 death• undisclosed; 1 death

– Tuberculosis• recent-onset latent TB (1)

– Others• migraines• bronchitisbronchitis• osteoarthritis• kidney stones

– 2 patients discontinued due to liver enzyme increases between 3 - 3.5 ≥ ULN


No cases of lymphoma, demyelinating syndrome, or lupuslike syndrome were reported

Humira® – Study Ps-I; study design2008 Menter, J Am Acad Dermatology

PASIPGA

4 8 12 24 36 40 44 48


PGA

Humira® – Study Ps-I; patient flow2008 Menter, J Am Acad Dermatology

PlaceboAdalimumab 40 mg

71% progress7% progress

Adalimumab 40 mg

85% progress 85% progress85% progress 85% progress

6% ≤ PASI 50 @ week 54

97 Competitive intelligence analysis39% ≤ PASI 50

@ week 54

Humira® – Study Ps-I; baseline characteristics2008 Menter, J Am Acad Dermatology


Humira® – Study Ps-I; study results2008 Menter, J Am Acad Dermatology



39% @ wk 54

28% @ wk 52

39% @ wk 54

6% @ wk 545% @ wk 52


Humira® – Study Ps-I; safety & tolerability2008 Menter, J Am Acad Dermatology


Therapy associated adverse event profile


• Therapy associated adverse event profile– Serious infections (12)

• tuberculosis (1)• oral candidiasis (1)• undisclosed (10)( )

– Cardiovascular events• congestive heart failure (1)

– Malignancies (10)• basal cell carcinoma (3)• squamous cell carcinoma (3)• squamous cell carcinoma (3)• atypical endophytic epidermoid proliferation (1)• breast cancer (1)• undisclosed (2)

– Increased liver enzymes @ week 52• 2.8% patients had ≥ 2.5 ULN ALT values

– Increased antibodies @ week 52• 8.8% of patients tested positive for anti-adalimumab antibodies

No cases of lymphoma demyelinating syndrome lupuslike syndrome or rebound were reported


No cases of lymphoma, demyelinating syndrome, lupuslike syndrome, or rebound were reported

Humira® – CHAMPION; study design2007 Saurat, British Journal of Dermatology

PASI/PGA week 0 1 2 4 8 12 16


Humira® – CHAMPION; baseline characteristics2007 Saurat, British Journal of Dermatology


• Efficacy endpoints1° d i t

Humira® – CHAMPION; study results2007 Saurat, British Journal of Dermatology

– 1° endpoints 80% of 40 mg eow patients achieving PASI 75 @ week 16 36% of MTX patients achieving PASI 75 @ week 16 19% of placebo patients achieving PASI 75 @ week 16

– 2° endpoints Proportion of 40 mg eow patients @ week 16 acheiving: Proportion of 40 mg eow patients @ week 16 acheiving:

88% PASI 50 51% PASI 90 17% PASI 100

Proportion of MTX patients @ week 16 acheiving: 62% PASI 50 14% PASI 90 7% PASI 100

Proportion of placebo patients @ week 16 acheiving: 9% PASI 50 11% PASI 90 2% PASI 100 2% PASI 100

Proportion of patients @ week 16 acheiving a clear or minimal PGA score: 73% 40 mg eow 30% MTX 11% placebo



met x not met ~trendNB: unusually high placebo rate attributed to (1) european population (2) folate suppliment (3) MTX naïve inclusion criteria

• Therapy associated adverse event profile


• Therapy associated adverse event profile– nonserious infections (51)– nasopharyngitis (30)– headache (14)– pancreatitis (1)– enlargement of ovarian cyst (1)

– 2% of patients showed liver enzyme increases

No serious adverse events nor any cases of TB, lymphoma, demyelinatingsyndrome, or lupuslike syndrome or associated deaths were reported


Ustekinumab


Ustekinumab – Clinical trials overview

• PHOENIX I (NCT00267969)– 2 doses vs placebo (1:1:1)– 1° endpoints


Proportion of patients with PGA score of cleared or minimal @ week 12• Proportion of patients with PGA score of cleared or minimal @ week 12• ∆ dermatology QoL @ week 12• Time to loss of PASI 75 response following randomized withdrawal

– 766 moderate-to-severe patients– 76 week trial– 9 months recruitment– 48 sites– 3 countries (US, CA, BE)3 countries (US, CA, BE)

• PHOENIX II (NCT00307437)– 2 doses vs placebo (1:1:1)– 1° endpoints


• Proportion of patients with PGA score of cleared or minimal @ week 12p p @• ∆ dermatology QoL @ week 12• # of visits with PASI 75 response between weeks 40 and 52 in the intensified groups compared to maintained dosing

– 1230 moderate-to-severe patients– 6 months recruitment– 70 sites– 7 countries, (AT, CA, CH, DE, FR, UK, US)


Ustekinumab – PHOENIX I; study design2008 Lancet, Efficacy and safety of ustekinumab


Ustekinumab – PHOENIX I; patient flow2008 Lancet, Efficacy and safety of ustekinumab


Ustekinumab – PHOENIX I; baseline characteristics2008 Lancet, Efficacy and safety of ustekinumab


Ustekinumab – PHOENIX I; endpoints & results2008 Lancet, Efficacy and safety of ustekinumab

• Efficacy endpoints– 1° endpoints67% f ti t hi i PASI 75 @ k 12 ith 4567% of patients achieving PASI 75 @ week 12 with 45 mg66% of patients achieving PASI 75 @ week 12 with 90 mg76% of patients achieving PASI 75 @ week 24 with 45 mg85% of patients achieving PASI 75 @ week 24 with 90 mg85% of patients achieving PASI 75 @ week 24 with 90 mg

– 2° endpointsSustained improved PGA score of cleared or minimal @ week 12Sustained improved ∆ dermatology QoL @ week 12Median time to loss of PASI 75 response following randomized withdrawal

was 15 weeks

117 Competitive intelligence analysismet x not met ~trend

Ustekinumab – PHOENIX I; results2008 Lancet, Efficacy and safety of ustekinumab


Ustekinumab – PHOENIX I; safety & tolerability2008 Lancet, Efficacy and safety of ustekinumab

• Therapy associated adverse event profileTherapy associated adverse event profile– Serious infections

• viral syndrome (1)• foot ulcer of diabetic patient (1)• osteomyelitis (1)

gastroenteritis (1)• gastroenteritis (1)• appendicitis (1)

– Cardiovascular events• myocardial infarction (2)• stroke (1)

– Malignancies• prostate cancer (1)• thyroid cancer (1)• colon cancer (1)• breast cancer (1)breast cancer (1)• lentigo maligna (1)• transitional cell carcinoma (1)


Ustekinumab – PHOENIX I; safety & tolerability2008 Lancet, Efficacy and safety of ustekinumab


Ustekinumab – PHOENIX II; study design2008 Lancet, Efficacy and safety of ustekinumab


Ustekinumab – PHOENIX II; patient flow2008 Lancet, Efficacy and safety of ustekinumab


Ustekinumab – PHOENIX II; baseline characteristics2008 Lancet, Efficacy and safety of ustekinumab


Ustekinumab – PHOENIX II; endpoints & results2008 Lancet, Efficacy and safety of ustekinumab

• Efficacy endpoints• Efficacy endpoints– 1° endpoints67% of patients achieving PASI 75 @ week 12 with 45 mg76% of patients achieving PASI 75 @ week 12 with 90 mg

2° endpoints– 2° endpointsSustained improved PGA score of cleared or minimal @ week 12Sustained improved ∆ dermatology QoL @ week 1290 mg every 8 weeks was the only group to show an advantage with

intensified dosingintensified dosing

• Further analysis• 75% of patients acheiving PASI 75 @ week 20 with 45 mg• 84% of patients acheiving PASI 75 @ week 20 with 90 mg• only 5-7% of all patients with less than PASI 50 @ week 28

t t t t d



Ustekinumab – PHOENIX II; results2008 Lancet, Efficacy and safety of ustekinumab


Ustekinumab – PHOENIX II; safety & tolerability2008 Lancet, Efficacy and safety of ustekinumab

• Therapy associated adverse event profileTherapy associated adverse event profile– Serious infections (4)– Cardiovascular events (5, including 1 death)

• angina• non-ischaemic sudden cardiac death with underlying dilatednon ischaemic sudden cardiac death with underlying dilated

cardiomyopathy (90 mg)• transient palpitations• ventricular extrasystoles• hypertension

– Malignancies (8)• Cutaneous (6)• basal cell carcinoma• squamous cell carcinoma

No dose proportional observations in the rates of adverse reactions


Ustekinumab – PHOENIX II; safety & tolerability2008 Lancet, Efficacy and safety of ustekinumab


Briakinumab


Briakinumab – Clinical trials overview

• Phase IIb NCT00292396Phase IIb NCT00292396 – 5 doses vs placebo (1:1:1:1:1:1)– 1° endpoints

• Proportion of patients achieving PASI 75 @ week 12– 180 patients– 48 week trial

• Phase III NCT00570986– 2 doses vs placebo (1:1:1)– 1° endpoints

• Proportion of patients achieving PASI 75 @ week 12• Proportion of patients with PGA score of cleared or minimal @ week 12p p @• Proportion of patients maintaining PGA score of cleared or minimal @ week 52

– 2° endpoints• ∆ DLQI score between baseline & week 12• ∆ NAPSI score between baseline & week 12• Proportion of patients achieving PASI 90 & 100 @ week 12

– 1465 moderate-to-severe patientsp– 52 week trial– 122 sites– 2 countries, (CA, US)


Briakinumab – Clinical trials overview• Phase III NCT00691964

1 dose vs Enbrel® vs placebo (1:1:1)– 1 dose vs Enbrel® vs placebo (1:1:1)– 1° endpoints

• Proportion of patients achieving PASI 75 @ week 12• Proportion of patients with PGA score of cleared or minimal @ week 12

– 2° endpoints• Proportion of patients achieving PASI 100 @ week 12

– 347 patients– 12 week trial– 33 sites– US only

• Phase III NCT00710580– 1 dose vs Enbrel® vs placebo (1:1:1)– 1° endpoints


– 2° endpoints• Proportion of patients achieving PASI 100 @ week 12

– 350 patients– 12 week trial– 41 sites– US only

• Phase III NCT00679731– 1 dose vs MTX (1:1)– 1° endpoints


P i f i hi i PASI @ k 2• Proportion of patients achieving PASI 75 @ week 52• Proportion of patients with PGA score of cleared or minimal @ week 52

– 2° endpoints• Proportion of patients achieving PASI 100 @ week 24• ∆ DLQI from baseline @ week 24• Proportion of patients achieving PASI 100 @ week 52• ∆ DLQI from baseline @ week 52

– 317 patients– 52 week trial– 44 sites


– 14 countries (AT, BE, CA, CH, DE, DK, ES, FI, FR, GR, IT, NL, SE, UK)

Competitors in development

• Rejected for lack of efficacy or an unsuitable safety & tolerability profile


Golimumab

• Never assessed in plaque psoriasis• Marketed as Simponi® for Rheumatoid Arthritis, Psoriatic Arthritis &

Ankolysing Spondylitis in the US & CAAnkolysing Spondylitis in the US & CA• Clinical trials in Ulcerative Colitis ongoing• previously abandoned Uveitis, Crohn‘s Disease, chronic asthma


• PEGylated Fc-free anti-TNFα antagonist delivered by subcutaneous

Cimzia® (Certolizumab pegol) PEGylated Fc free anti TNFα antagonist delivered by subcutaneous injection; t½ ~ 2 weeks

• PoC– 200 or 400 mg vs placebo every 2 weeks for 12 weeks– 176 patients (1:1:1)– 75% and 83% acheived PASI 75 respectively at week 12, p<0.001– placebo like tolerability

• Registered in the US & CA for Crohn‘s Disease and Rheumatoid Arthritis• EMEA rejected the MAA for Crohn‘s Disease citing low & potentially waning

efficacy and safety concerns of long-term immunosuppression; t i ti i f ti d liopportunistic infections and malignancy

• Phase III program in psoriasis terminated; UCB product pipeline lists Crohn‘s Disease and Rheumatoid Arthritis in the EU only

i l b d d A k l i S d liti P i ti A th iti


• previously abandoned Ankylosing Spondylitis, Psoriatic Arthritis

• US label

Cimzia® (Certolizumab pegol)

– Crohn‘s disease• CIMZIA is a tumor necrosis factor (TNF) blocker indicated for:

– Reducing signs and symptoms of Crohn‘s disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventionaldisease who have had an inadequate response to conventional therapy

– Rheumatoid arthritisin combination with methotrexate (MTX), for the treatment of moderate to

severe active rheumatoid arthritis (RA) in adult patients when the response to disease modifying antirheumatic drugs (DMARDs)response to disease-modifying antirheumatic drugs (DMARDs), including MTX, has been inadequate. In these patients, Cimzia(R) can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate. Cimzia(R) has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combinationby X ray and to improve physical function, when given in combination with MTX.


Apremilast • Oral twice daily phosphodiesterase IV inhibitor promising to halt the

inflammatory cytokine cascade• POC

– 260 patients, 20 mg BID vs placebo– 24.4% reach PASI 75 at week 12 (p=0.023)– 57% reach PASI 50 at week 12 (p<0.001)– Placebo-like tolerability profile

SAE• no SAEs• most common AEs nausea, nasopharyngitis, headache and diarrhea

• Phase IIb348 patients 10 20 30 mg BID vs placebo– 348 patients,10, 20, 30 mg BID vs placebo

– exploring the % of patients reaching PASI 75 at week 16– 10 sites, US only

6 month treatment period; study duration Sep08 Sep09


– 6 month treatment period; study duration Sep08 – Sep09

Apremilast • additional indications

– Psoriatic Arthritis; phase II– Bechet‘s Syndrome; phase II

• IIS• IIS– Discoid cutaneous lupus erythematosus – Uveitis

Chronic prostatitis & chronic pelvic syndrome– Chronic prostatitis & chronic pelvic syndrome– Chronic cutaneous sarcoidosis– Vulvodynia

P i d l i– Prurigo nodularis• previously abandoned asthma


Voclosporin

T i d l C l i i i hibit i i ffi th• Twice a day oral Calcineurin inhibitor; promises superior efficacy than cyclosporin-A with less toxicity

• Phase III psoriasis program completed in CA & EU Oct06; no registration• Additional indications

– renal transplant– Uveitis


Bimosiamose

S b t i j ti f ll dh i l l (CAM) i hibit hi h• Subcutaneous injection of cell adhesion molecule (CAM) inhibitor which prevents the signaling leukocyte tethering to the vascular endothelial cells

• PoC ongoing• No listing of the compound in Pfizer‘s pipeline


SCH 527123

Once daily oral CXCR2/IL 8β G protein coupled receptor inhibitor• Once daily oral CXCR2/IL-8β G-protein coupled receptor inhibitor• Psoriasis development halted with Phase II; results available in Oct07,

however Product Pipeline Apr 09 mentions only COPD


INCB-18424

Selective JAK 2 inhibitor• Selective JAK-2 inhibitor• JAK-1/2 inhibitors have shown perinatal and embryonic lethality• Topical cream for psoriasis

– 2 x PoCs; 28 day, 28 patient, twice daily application• improved lesion score; thickness, erythema and scaling• supported increased body surface area (BSA) 2-7%• well tolerated

• Systemic exposure assessed in Rheumatoid Arthritis, Myelofibrosis, Polycythaemia vera, & Thrombocythaemia


Psoriasis pharmascape cv

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