psoriasis pharmascape cv
TRANSCRIPT
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
3 Life Cycle ManagementCompetitive intelligence analysis
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)
4 Life Cycle ManagementCompetitive intelligence analysis
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
Dosing regimens for adults US & EU
Rheumatoid Arthritis*
Psoriatic Arthritis
Ankylosing Spondylitis
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)
Life Cycle ManagementCompetitive intelligence analysis
Dosing regimens for adults US & EU
Rheumatoid ArthritisPsoriatic Arthritis
Ankylosing Spondylitis
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)
Life Cycle ManagementCompetitive intelligence analysis
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
9 Life Cycle ManagementCompetitive intelligence analysis
• 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
Life Cycle ManagementCompetitive intelligence analysis
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
11 Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
• 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
Life Cycle ManagementCompetitive intelligence analysis
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
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PsoriasisEXPRESS I NCT00106834 EXPRESS II NCT00106847 2 Phase III trials
Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
• 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
16 Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
Compounds in clinical development for psoriasis
Briakinumab, ABT874
ART621
BMS-582949
CP-690.550
R348
CNTO 1959
24 Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
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
Life Cycle ManagementCompetitive intelligence analysis
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
27 Life Cycle ManagementCompetitive intelligence analysis
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
28 Life Cycle ManagementCompetitive intelligence analysis
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
29 Life Cycle ManagementCompetitive intelligence analysis
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
30 Life Cycle ManagementCompetitive intelligence analysis
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
31 Life Cycle ManagementCompetitive intelligence analysis
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
32 Life Cycle ManagementCompetitive intelligence analysis
Back-ups
33 Life Cycle ManagementCompetitive intelligence analysis
Enbrel® (etanercept)
• 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
Enbrel® (etanercept)
• 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
35 Competitive intelligence analysis
• EU label
Enbrel® (etanercept)
– 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
36 Competitive intelligence analysis
children 4yrs
• EU label, continued
Enbrel® (etanercept)
,– 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
37 Competitive intelligence analysis
Remicade® (infliximab)
• 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
38 Competitive intelligence analysis
Remicade® (infliximab)
• 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
39 Competitive intelligence analysis
Remicade® (infliximab)
• 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
40 Competitive intelligence analysis
responded inadequately to conventional therapy
Remicade® (infliximab)
• 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
41 Competitive intelligence analysis
Remicade® (infliximab)
• 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
42 Competitive intelligence analysis
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
43 Competitive intelligence analysis
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
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• 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
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X ray in patients with polyarticular symmetrical subtypes of the disease and to improve physical function
Enbrel® (etanercept)
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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 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
– 652 moderate-to-severe patients– 24 week trial– 5 months recruitment– 47 sites– US only
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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
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Enbrel® – Study-1; patient flow2003 ARCH DERMATOL
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Enbrel® – Study-1; baseline characteristics2003 ARCH DERMATOL
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Enbrel® – Study-1; study results2003 ARCH DERMATOL
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Enbrel® – Study-1; study results2003 ARCH DERMATOL
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• Efficacy endpoints
Enbrel® – Study-1; study results2003 ARCH DERMATOL
• 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
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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
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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
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x = entanercept antibody assay
Enbrel® – Study-2; baseline characteristics2003 NEJM
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Enbrel® – Study-2; study results2003 NEJM
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Enbrel® – Study-2; study results2003 NEJM
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Enbrel® – Study-2; study results2003 NEJM
• Efficacy endpoints– 1° endpoints
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
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Remicade®
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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
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– 6 months recruitment– 63 sites– 4 countries, (AT, CA, FR, IT, US)
Remicade® –SPIRIT; study design2005 New Medicines Profile
Double blind core study Follow-up period
Infliximab 3 mg/kg
Infliximab 5 mg/kg
scr x 2 6 10 26 weeks
g g
Placebo
PASIPGA
DLQI
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Remicade® –SPIRIT; patient flow2004 Gottlieb J Am Acad Dermatol
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Remicade® –SPIRIT; baseline characteristics2004 Gottlieb J Am Acad Dermatol
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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
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Remicade® –SPIRIT; study results2004 Gottlieb J Am Acad Dermatol
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Remicade® –SPIRIT; study results2004 Gottlieb J Am Acad Dermatol
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Remicade® –SPIRIT; study results2004 Gottlieb J Am Acad Dermatol
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Remicade® –SPIRIT; safety & tolerability2004 Gottlieb J Am Acad Dermatol
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Remicade® – EXPRESS I; study design2005 Lancet, Infliximab induction and maintenance therapy
Double blind core study Follow-up period
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
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Remicade® – EXPRESS I; patient flow2005 Lancet, Infliximab induction and maintenance therapy
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Remicade® – EXPRESS I; baseline characteristics2005 Lancet, Infliximab induction and maintenance therapy
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Effi d i t
Remicade® – EXPRESS I; study results2005 Lancet, Infliximab induction and maintenance therapy
• Efficacy endpoints– 1° endpoints
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
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met x not met trend
Remicade® – EXPRESS I; study results2005 Lancet, Infliximab induction and maintenance therapy
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Remicade® – EXPRESS I; study results2005 Lancet, Infliximab induction and maintenance therapy
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Remicade® – EXPRESS I; pre-infusion concentrations2005 Lancet, Infliximab induction and maintenance therapy
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Remicade® – EXPRESS I; safety & tolerability2005 Lancet, Infliximab induction and maintenance therapy
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Remicade® – EXPRESS I; antibody development2005 Lancet, Infliximab induction and maintenance therapy
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Remicade® – EXPRESS II; study design2005 FDA website, Clinical Study Report
Double blind core study Follow-up period
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
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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
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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%
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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
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65% patients were newly positive for ANA antibodies• 26.8% patients were newly positive for anti-dsDNA antibodies
Humira® (adalimumab)
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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 75 @ week 16– 2° 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
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– 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
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PASIPGA
H i ® St d P II ti t flHumira® – Study Ps-II; patient flow2006 Gordon, J Am Acad Dermatology
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Humira® – Study Ps-II; baseline characteristics2006 Gordon, J Am Acad Dermatology
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Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology
• Efficacy endpoints– 1° endpoints
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
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met x not met ~trend
Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology
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Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology
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Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology
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Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology
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Humira® – Study Ps-II; safety & tolerability2006 Gordon, J Am Acad Dermatology
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• 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
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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
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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
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@ week 54
Humira® – Study Ps-I; baseline characteristics2008 Menter, J Am Acad Dermatology
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Humira® – Study Ps-I; study results2008 Menter, J Am Acad Dermatology
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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
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Humira® – Study Ps-I; study results2008 Menter, J Am Acad Dermatology
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Humira® – Study Ps-I; safety & tolerability2008 Menter, J Am Acad Dermatology
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Humira® – Study Ps-I; safety & tolerability2008 Menter, J Am Acad Dermatology
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Therapy associated adverse event profile
Humira® – Study Ps-I; safety & tolerability2008 Menter, J Am Acad Dermatology
• 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
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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
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Humira® – CHAMPION; baseline characteristics2007 Saurat, British Journal of Dermatology
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• 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 ~trend
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met x not met ~trendNB: unusually high placebo rate attributed to (1) european population (2) folate suppliment (3) MTX naïve inclusion criteria
Humira® – CHAMPION; study results2007 Saurat, British Journal of Dermatology
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Humira® – CHAMPION; study results2007 Saurat, British Journal of Dermatology
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Humira® – CHAMPION; study results2007 Saurat, British Journal of Dermatology
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• Therapy associated adverse event profile
Humira® – CHAMPION; study results2007 Saurat, British Journal of Dermatology
• 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
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Ustekinumab
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Ustekinumab – Clinical trials overview
• PHOENIX I (NCT00267969)– 2 doses vs placebo (1:1:1)– 1° endpoints
• Proportion of patients achieving PASI 75 @ week 12– 2° 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 achieving PASI 75 @ week 12– 2° 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)
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Ustekinumab – PHOENIX I; study design2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX I; patient flow2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX I; baseline characteristics2008 Lancet, Efficacy and safety of ustekinumab
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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
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Ustekinumab – PHOENIX I; results2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX I; results2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX I; results2008 Lancet, Efficacy and safety of ustekinumab
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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)
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Ustekinumab – PHOENIX I; safety & tolerability2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX II; study design2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX II; patient flow2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX II; baseline characteristics2008 Lancet, Efficacy and safety of ustekinumab
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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
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met x not met ~trend
Ustekinumab – PHOENIX II; results2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX II; results2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX II; results2008 Lancet, Efficacy and safety of ustekinumab
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Ustekinumab – PHOENIX II; results2008 Lancet, Efficacy and safety of ustekinumab
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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
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Ustekinumab – PHOENIX II; safety & tolerability2008 Lancet, Efficacy and safety of ustekinumab
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Briakinumab
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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)
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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
• 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
– 350 patients– 12 week trial– 41 sites– US only
• Phase III NCT00679731– 1 dose vs MTX (1:1)– 1° endpoints
• Proportion of patients achieving PASI 75 @ week 12• Proportion of patients with PGA score of cleared or minimal @ week 12
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
135 Competitive intelligence analysis
– 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
136 Competitive intelligence analysis
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
137 Competitive intelligence analysis
• 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
138 Competitive intelligence analysis
• 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.
139 Competitive intelligence analysis
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
140 Competitive intelligence analysis
– 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
141 Competitive intelligence analysis
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
142 Competitive intelligence analysis
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
143 Competitive intelligence analysis
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
144 Competitive intelligence analysis
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
145 Competitive intelligence analysis