Psoriasis pharmascape cv

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Psoriasis pharmascape cv

  1. 1. PharmascapePsoriasis therapy: today & tomorrowAll information herein is publically availableThis document is meant only to illustrate Oliver Vit’s professional competencesand does not reflect Actelion Pharmaceuticals Ltd s corporate views Ltd’s
  2. 2. Psoriasis; approved biologics Etanercept, Enbrel® Adalimumab, Humira ® Infliximab, Remicade ® Ustekinumab, Stelara ®2 Life Cycle Management Competitive intelligence analysis
  3. 3. Psoriasis therapies; EU market protection estimates 1st Indication Use in Parent Market Parent psoriasis Market patent authorisation patent patent SPC exclusivity 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 Stelara S EP 1309692 07-Aug-01 0 01 16-Jan-09 16 09 07-Aug-21 0 21 15-Jan-24 1 24 16-Jan-19 16 19 Briakinumab EP 1175446* 24-Mar-00 (Apr-11) 24-Mar-20 (24-Mar-25) (Apr-21) * may not be granted3 Life Cycle Management Competitive intelligence analysis
  4. 4. Psoriasis therapies; US market protection estimates 1st Use in Indication Use in Parent Use in psoriasis Market Parent psoriasis PT patent psoriasis patent authorisation patent patent extension 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 Stelara St l US 6902734 01-Aug-01 01 A 01 (Oct-09) (O t 09) 24-Jul-22 24 J l 22 (Oct-23) (O t 23) Briakinumab US 6914128 24-Mar-00 (Apr-11) 24-Mar-20 (Aug-23)4 Life Cycle Management Competitive intelligence analysis
  5. 5. Licensed indications Rheumatoid Crohn‘s Juvenile Psoriatic Ulcerative Ankylosing Psoriasis Arthritis A th iti disease Arthritis Arthritis Colitis Spondylitis S d liti   Enbrel®  (≥2 yrs US; yrs,   (≥8 yrs, EU) (etanercept) ≥4 yrs, EU)  Remicade®  ( yrs (≥6 y     (infliximab) EU& US)  Humira®   (≥4 yrs, US;   (adalimumab) ≥13 yrs, EU) Stelara®  (EU & CA only) onl )(ustekinumab) 5 Life Cycle Management Competitive intelligence analysis
  6. 6. Dosing regimens for adults US & EU Rheumatoid Psoriatic Ankylosing Plaque Arthritis* Arthritis Spondylitis Psoriasis 25 mg twice weekly Enbrel® or 25 mg twice weekly 50 mg weekly (etanercept) or or subcutaneous 50 mg weekly 50 mg twice weekly for 12 weeks injections followed by 50 mg weekly y g y (max 24 weeks in EU) Annual cost €13,400 €19,326* per patient $20,190 $24,848** (ex-factory price)Annual global sales $3.6 bio (2008) * Average of FR & DE prices & based on 1 yr continuous use ** Wholesale Acquisition Cost (WAC) 6 Life Cycle Management Competitive intelligence analysis
  7. 7. Dosing regimens for adults US & EU Rheumatoid Psoriatic Ankylosing Crohn‘s Ulcerative Plaque Arthritis* Arthritis Spondylitis Disease Colitis Psoriasis 3 mg/kg induction 3 mg/kg weeks 2 & 6 g g Remicade® 5 mg/kg induction 3 mg/kg every 8 (infliximab) weeks 5 mg/kg weeks 2 & 6 Incomplete 5 mg/kg every 8 weeks intravenous infusion responders up to 7.5mg/kg 7 5mg/kgAnnual cost per patient €17,400 €21,573* (ex-factory price) $19,510 $21,166** Annual global sales $3.7 bio (2008) * Average of FR & DE prices & based on 1 yr continuous use ** Wholesale Acquisition Cost (WAC)7 Life Cycle Management Competitive intelligence analysis
  8. 8. Dosing regimens for adults US & EU Psoriatic Ankylosing Crohn‘s Plaque Rheumatoid Arthritis Arthritis Spondylitis Disease Psoriasis Humira® 80 mg induction g (adalimumab) ( ) 80 mg induction i d ti 40 mg every other week 40 mg at week 3 40 mg every subcutaneous (12 week maximum exposure for Pso.Ar. & A.S.) 40 mg every other week other week injections Annual cost €14,200 €3,300 €14,700 €15,898* per patient $18,886 $18,886 $20,339 $18,886** (ex-factory price)Annual global sales $4.5 bio (2008) * Average of FR & DE p g prices & based on 1 y continuous use yr ** Wholesale Acquisition Cost (WAC)8 Life Cycle Management Competitive intelligence analysis
  9. 9. Prescribing paradigm• Enbrel® i li E b l® is licensed f chronic th d for h i therapy i th US & ≤ 24 weeks i th EU in the k in the• 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 – visible efficacy – long term side effects; both perceived & real –d t doctor-patient relationship ti t l ti hi• Awareness of malignancies & serious opportunistic infections is on the rise9 Life Cycle Management Competitive intelligence analysis
  10. 10. Enbrel® (etanercept)• Dimeric fusion protein which binds TNFα and lowers the concentration of free TNFα 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 subcutaneous injections is on the rise• 34% of 25 mg twice weekly patients reached PASI 75 @ week 12 with continued improvement to 44% @ week 24 in Study-2• SAEs: malignancies (breast and lung carcinomas, lymphomas, non-melanoma skin cancers), 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 term observational pregnancy registry in place• No head-to-head comparative trials• Abandoned indications: idiopathic pulmonary fibrosis asthma uveitis cachexia fibrosis, asthma, uveitis, cachexia, myelodysplastic syndrome, congestive heart failure, Wegener‘s granulomatosis10 Life Cycle Management Competitive intelligence analysis
  11. 11. Enbrel® – Development overview 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 RA PsA AS Pso MA MA MA MARheumatoid ArthritisStudy I / II / III3 Phase III registration trials Psoriatic Arthritis NCT00317499 single Phase III registration Ankylosing spondylitis single Phase III registration Psoriasis Study I / II 2 Phase III registration trials 11 Life Cycle Management Competitive intelligence analysis
  12. 12. Enbrel® – Psoriasis development 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010Study-120021632 Study-2 20021639 NCT00121615 OL ext NCT00111449 50 mg twice weekly NCT00333034 50 mg once weekly NCT00110981 UVB combination Tx MAA MA Launch 12 Life Cycle Management Competitive intelligence analysis
  13. 13. Remicade® (infliximab)• 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• 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) & 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, 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 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 indication• Abandoned indications: congestive heart failure asthma, COPD, sarcoidosis, failure, asthma COPD sarcoidosis multiple myeloma13 Life Cycle Management Competitive intelligence analysis
  14. 14. Remicade® – Development overview 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Crohn‘s RA AS PsA UC Pso MA MA MA MA MA MACrohn‘s diseaseACCENT Isingle Phase III registration i l Ph i t tiRheumatoid ArthritisATTRACTsingle Phase III registration Ankylosing spondylitis NCT00207701 single Phase III registration Psoriatic Arthritis NCT00051623 single Phase III registration Ulcerative Colitis UCI NCT00096655 & UC II NCT00036439 2 Phase III trials Psoriasis EXPRESS I NCT00106834 14 Life Cycle Management EXPRESS II NCT00106847 Competitive intelligence analysis 2 Phase III trials
  15. 15. Remicade® – Psoriasis development1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 SPIRIT Phase IIb EXPRESS I EXPRESS II NCT00687401 Standard Tx & biologic Tx failures NCT00251641 MTX head-to-head NCT00358670 OL ext NCT00527072 Etanercept Tx failures NCT00833053 dose optimization p NCT00686595 Etanercept switch Long term observation, registry & cross-indication surveillance MAA MA Launch 15 Life Cycle Management Competitive intelligence analysis
  16. 16. Humira® (adalimumab)• Fully humanized TNFα inhibitor• 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, & rash j• 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 asthma16 Life Cycle Management Competitive intelligence analysis
  17. 17. Humira® – Development overview2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 RA PsA AS CD Pso JIA UC MA MA MA MA MA MA MA Rheumatoid Arthritis Studies I / II / III / IV / V 5 Phase III registration trials Psoriatic Arthritis Study PsA-I, NCT00646386 NCT00646178 2 Phase III registration trials Ankylosing spondylitis NCT00085644 single Phase III registration trial Crohn‘s Disease CD-II, NCT00105300 CD-III, NCT00077779 2 Phase III registration trials Psoriasis Ps-I, NCT00237887 single Phase III registration trial Juvenile Idiopathic Arthritis NCT00237887 single Phase III registration trial Ulcerative Colitis 17 Life Cycle Management NCT00408629 & NCT00385736 Competitive intelligence analysis 2 Phase III registration trials
  18. 18. Humira® – Psoriasis development2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 NCT00646191 NCT00645905 NCT00645892 OL extention Study Ps-II Study Ps-I Ps I NCT00566722 OL in suboptimal response patients CHAMPION MTX & placebo controlled NCT00195676 Phase III catch-all OL extention NCT00735787 Hands & Feet ESPRIT, NCT00799877 10 year post marketing safety study MAA MA Launch 18 Life Cycle Management Competitive intelligence analysis
  19. 19. Ustekinumab• Fully humanized anti IL-12/23 antibody delivered by subcutaneous injection via anti-IL 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 mg y 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• Ustekinumab specific antibodies noted i 5% of patients U ki b ifi ib di d in % f i19 Life Cycle Management Competitive intelligence analysis
  20. 20. Ustekinumab – Development overview 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017NCT00267956Psoriatic arthritis x NCT00771667 Crohn‘s disease (pivotal IIb/III) Crohn‘s disease (confirmatory III) PHOENIX I Psoriasis P i i PHOENIX II Psoriasis MAA MA Launch MAA MA Launch 20 Life Cycle Management Competitive intelligence analysis
  21. 21. Ustekinumab – Psoriasis development2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 NCT00320216 x PHOENIX I PHOENIX II PHOENIX 5yr OL NCT00454584 Enbrel® controlled x NCT00723528 JP NCT00747344 KR TW MAA MA Launch 21 Life Cycle Management Competitive intelligence analysis
  22. 22. Efficacy & median time to relapse Half life Elimination PASI 75 Median time to relapse (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 (ustekinumab) 1 http://www.wyeth.com/news/archive?nav=display&navTo=/wyeth_html/home/news/pressreleases/2004/1145887154280.html22 Life Cycle Management 2 SPIRIT trial, http://www.mims.co.uk/news/891873/Remicade-approved-use-psoriasis/ 3 Study Ps-I, Extrapolated from graph Competitive intelligence analysis 4 Phoenix I, trial Etrapolated from graph
  23. 23. Psoriasis therapy: competitive environment IL-12/IL-23 inhibitor TNFα inhibitor CNTO 1959 ART621 Briakinumab Phase I Phase II Phase III Launched BMS-582949 CP-690.550 R348 JAK inhibitor p38 kinase inhibitor23 Life Cycle Management Competitive intelligence analysis
  24. 24. Compounds in clinical development for psoriasis Briakinumab, ABT874 ART621 BMS-582949 CP-690.550 R348 CNTO 195924 Life Cycle Management Competitive intelligence analysis
  25. 25. Briakinumab• Fully humanized anti-IL-12/23 antibody anti IL 12/23• 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 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 disease – previously abandoned MS & RA programs25 Life Cycle Management Competitive intelligence analysis
  26. 26. Briakinumab – Psoriasis development2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 NCT00292396 NCT00570986 NCT00691964 Enbrel® head-to-head placebo controlled NCT00710580 Enbrel® head-to-head placebo controlled NCT00679731 MTX controlled NCT00626002 OL catch-all ext. NCT00870948 Bioavailability for CMC process MAA MA Launch 26 Life Cycle Management Competitive intelligence analysis
  27. 27. ART621• Subcutaneous anti-TNFα monoclonal antibody; i S b t ti TNF l l tib d incorporates d t domain i antibodies (dAb) which being smaller improves manufacturing yield, lowers immunogenicity and improves tissue penetration• PoC – factorial-design, randomised, double-blind, placebo-controlled, dose optimisation, pharmacokinetics, safety, efficacy study – multiple dose administration of ART621. lti l d d i i t ti f ART621 – 1 site in NZ – results from Mar09; well tolerated and exhibiting a safety profile consistent with anti-TNF activity i t t ith ti TNF ti it• IND filed in Rheumatoid Arthritis27 Life Cycle Management Competitive intelligence analysis
  28. 28. BMS-582949• Oral O l once daily p38 mitogen-activated protein (MAP) kinase inhibitor d il 38 it ti t d t i ki i hibit 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, talmapimod p – Vertex, VX-74528 Life Cycle Management Competitive intelligence analysis
  29. 29. 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 function B cell• Preclinical models show efficacy – arthritis – asthma – transplant• Additional indications: Crohn‘s disease, Rheumatoid Arthritis, psoriasis, renal t l transplant l t• NK cell levels reduced with no reduction in CD4+ or CD8+ levels Results from 58 patient PoC29 Life Cycle Management Competitive intelligence analysis
  30. 30. CP-690550• Phase II trials – Dose dependent increase in HDL & LDL levels – Increased ALT & AST levels > 3 x ULN – 3 sudden cardiac deaths • 1 in 12 week study • 2 in long term follow-up 6-12 months – 9 serious infections in 9 patients • Bacterial • Viral • Fungal30 Life Cycle Management Competitive intelligence analysis
  31. 31. R348• Oral d l JAK-3 Syk inhibitor O l dual JAK 3 & S k i hibit• EIM Jan08; combi SAD/MAD• Preclinical models show efficacy – arthritic symptoms, bone destruction & swelling – psoriasis – transplant p• Planned clinical programs – psoriasis – Rheumatiod Arthritis – renal transplant – Graft vs host disease31 Life Cycle Management Competitive intelligence analysis
  32. 32. CNTO 1959• Fully humanized anti-IL-12/23 antibody F ll h i d ti IL 12/23 tib d• EIM June 2009 – Phase I placebo-controlled trial – 3 US sites – 71 healthy volunteers & psoriasis patients – evaluating the PK p g profile and antibody development with both i.v. y p infusion and subcutaneous formulations – 11 month estimated duration32 Life Cycle Management Competitive intelligence analysis
  33. 33. Back-ups33 Life Cycle Management Competitive intelligence analysis
  34. 34. 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 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 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 patients arthritis, with psoriatic arthritis. ENBREL can be used in combination with MTX for those patients who do not respond adequately to MTX alone34 Competitive intelligence analysis
  35. 35. Enbrel® (etanercept)• US 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 phototherapy35 Competitive intelligence analysis
  36. 36. Enbrel® (etanercept)• 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 ( g g (unless contraindicated) has been ) 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 adults not previously t t d with MTX d lt t i l treated ith • 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 • 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 < 4yrs36 Competitive intelligence analysis
  37. 37. Enbrel® (etanercept)• 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 progression arthritis, 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 to t respond t or who h d to, h have a contraindication t or are i t l t i di ti to, intolerant t t 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 therapy37 Competitive intelligence analysis
  38. 38. 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 rheumatoid arthritis h t id th iti – Crohn‘s disease • REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately se erel acti e moderatel to severely active Crohn‘s disease who ha e had an ho have 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 disease Crohn s – Ankylosing spondylitis • REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis38 Competitive intelligence analysis
  39. 39. 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 p therapy – 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 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 to appropriate. patients who will be closely monitored and have regular follow-up visits with a physician39 Competitive intelligence analysis
  40. 40. 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 inadequate (DMARDs) – 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 colitis Remicade 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 medical 6 MP contraindications for such therapies – Ankylosing spondylitis Remicade is indicated for: – treatment of severe, active ankylosing spondylitis, in adult patients who have responded inadeq atel to con entional therap inadequately conventional therapy40 Competitive intelligence analysis
  41. 41. 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 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 Crohn s Remicade 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 has therapy. been studied only in combination with conventional immunosuppressive therapy41 Competitive intelligence analysis
  42. 42. 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 PUVA cyclosporine – Psoriatic arthritis Remicade 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 contraindicated Remicade 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 disease42 Competitive intelligence analysis
  43. 43. Humira® (adalimumab)H i ® ( d li b)• US label – Rheumatoid arthritis • reducing signs and symptoms, including major clinical response, inhibiting the th progression of structural damage, and i i f t t ld d improving physical f i h i l function i ti 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 ≥ 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 therapy 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 psoriasis who are candidates f systemic th i i h did t for t i therapy or phototherapy, and h t th d when other systemic therapies are medically less appropriate43 Competitive intelligence analysis
  44. 44. Humira® (adalimumab)H i ® ( d li b)• EU label – Rheumatoid arthritis • 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 adults not previously t t d with MTX d lt t i l treated ith • 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 p y y y p physical function, when g given in combination with MTX bi ti ith – 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-modifying 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 spondylitis • treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy44 Competitive intelligence analysis
  45. 45. Humira® (adalimumab)• EU label, continued – Crohn‘s disease Crohn s • 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 p treatment, 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 • 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 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 X-ray in patients with polyarticular symmetrical subtypes of the disease and to improve physical function45 Competitive intelligence analysis
  46. 46. Enbrel® (etanercept)46 Competitive intelligence analysis
  47. 47. 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• Study-2, St d 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 only47 Competitive intelligence analysis
  48. 48. Enbrel® – Study-1; study design 2003 ARCH DERMATOL Double blind core study scr x 2 4 8 12 16 20 24 weeksEtanercept 25 mgPlacebo PASI PGA DLQI 48 Competitive intelligence analysis
  49. 49. Enbrel® – Study-1; patient flow2003 ARCH DERMATOL49 Competitive intelligence analysis
  50. 50. Enbrel® – Study-1; baseline characteristics2003 ARCH DERMATOL50 Competitive intelligence analysis
  51. 51. Enbrel® – Study-1; study results2003 ARCH DERMATOL51 Competitive intelligence analysis
  52. 52. Enbrel® – Study-1; study results2003 ARCH DERMATOL52 Competitive intelligence analysis
  53. 53. 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 24 p  improvement in DLQI from baseline met x not met ~trend53 Competitive intelligence analysis
  54. 54. Enbrel® – Study-1; safety & tolerability2003 ARCH DERMATOL No treatment associated SAE was reported Most common AEs – URT infections, headache & injection site reactions54 Competitive intelligence analysis
  55. 55. Enbrel® – Study-2; study design 2003 NEJM Double blind core study Follow-up period scr x 2 4 8 12 16 20 24 weeksEtanercept 25 mg(once weekly)Etanercept 25 mg(twice weekly)Etanercept 50 mg(twice weekly)Placebo PASI PGA x blood & urine analysis y x DLQI x = entanercept antibody assay 55 Competitive intelligence analysis
  56. 56. Enbrel® – Study-2; baseline characteristics2003 NEJM56 Competitive intelligence analysis
  57. 57. Enbrel® – Study-2; study results2003 NEJM57 Competitive intelligence analysis
  58. 58. Enbrel® – Study-2; study results2003 NEJM58 Competitive intelligence analysis
  59. 59. 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 50 mg twice weekly patients achieving PASI 75 @ week 12 – 2° endpoints  25% of 25 mg weekly patients achieving PASI 75 @ week 24  44% of 25 mg twice weekly patients achieving PASI 75 @ week 24 % f S  59% of 50 mg twice weekly patients achieving PASI 75 @ week 24  improvement in both PGA & DLQI scores at week 12 from baseline met x not met ~trend59 Competitive intelligence analysis
  60. 60. Enbrel® – Study-2; safety & tolerability2003 NEJM60 Competitive intelligence analysis
  61. 61. Remicade®61 Competitive intelligence analysis
  62. 62. Remicade® – Clinical trials overview• SPIRIT (NCT00230529), Study III – 2 doses vs placebo (2:2:1) – 1° endpoints • Proportion of p p patients achieving ≥PASI 75 @ week 10 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° endpoints d i • 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 baseline p – % 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 – 63 sites – 4 countries, (AT, CA, FR, IT, US)62 Competitive intelligence analysis
  63. 63. Remicade® –SPIRIT; study design 2005 New Medicines Profile Double blind core study Follow-up period scr x 2 6 10 26 weeksInfliximab 3 mg/kgInfliximab 5 mg/kg g gPlacebo PASI PGA DLQI 63 Competitive intelligence analysis
  64. 64. Remicade® –SPIRIT; patient flow2004 Gottlieb J Am Acad Dermatol64 Competitive intelligence analysis
  65. 65. Remicade® –SPIRIT; baseline characteristics2004 Gottlieb J Am Acad Dermatol65 Competitive intelligence analysis
  66. 66. Remicade® –SPIRIT; study results2005 New Medicines Profile Infliximab Infliximab Placebo 3 mg/kg 5 mg/kg PASI 75 @ week 10 (p<0.001) 72% 88% 6% DLQI Median ∆ from baseline* -8 -10 0 (p<0.001) * median baseline values 11,12,14 respectively66 Competitive intelligence analysis
  67. 67. Remicade® –SPIRIT; study results2004 Gottlieb J Am Acad Dermatol67 Competitive intelligence analysis
  68. 68. Remicade® –SPIRIT; study results2004 Gottlieb J Am Acad Dermatol68 Competitive intelligence analysis
  69. 69. Remicade® –SPIRIT; study results2004 Gottlieb J Am Acad Dermatol69 Competitive intelligence analysis
  70. 70. Remicade® –SPIRIT; safety & tolerability2004 Gottlieb J Am Acad Dermatol70 Competitive intelligence analysis
  71. 71. Remicade® – EXPRESS I; study design 2005 Lancet, Infliximab induction and maintenance therapy Double blind core study Follow-up period scr x 2 6 10 14 22 24 26 30 38 46 50 66 weeksInfliximab 5 mg/kg x x x x x x x x x x xPlacebo x x x x x x PASI PGA NAPSI [Infliximab serum] Infliximab antibodies Anti-nuclear & anti-double stranded DNA antibodies 71 Competitive intelligence analysis x 5 mg/kg adminsitration
  72. 72. Remicade® – EXPRESS I; patient flow2005 Lancet, Infliximab induction and maintenance therapy72 Competitive intelligence analysis
  73. 73. Remicade® – EXPRESS I; baseline characteristics2005 Lancet, Infliximab induction and maintenance therapy73 Competitive intelligence analysis
  74. 74. Remicade® – EXPRESS I; study results2005 Lancet, Infliximab induction and maintenance therapy• Efficacy endpoints Effi d i t – 1° endpoints  80% of patients achieving PASI 75 @ week 10 – 2° endpoints 2  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%,  57%, 58%, 45% PASI 90  86%, 84%, 64% improvement in PASI from baseline  26%, 56%, 56% improvement in NAPSI met x not met ~trend met trend74 Competitive intelligence analysis
  75. 75. Remicade® – EXPRESS I; study results2005 Lancet, Infliximab induction and maintenance therapy75 Competitive intelligence analysis
  76. 76. Remicade® – EXPRESS I; study results2005 Lancet, Infliximab induction and maintenance therapy76 Competitive intelligence analysis
  77. 77. Remicade® – EXPRESS I; pre-infusion concentrations2005 Lancet, Infliximab induction and maintenance therapy77 Competitive intelligence analysis
  78. 78. Remicade® – EXPRESS I; safety & tolerability2005 Lancet, Infliximab induction and maintenance therapy78 Competitive intelligence analysis
  79. 79. Remicade® – EXPRESS I; antibody development2005 Lancet, Infliximab induction and maintenance therapy79 Competitive intelligence analysis
  80. 80. Remicade® – EXPRESS II; study design 2005 FDA website, Clinical Study Report Double blind core study Follow-up period scr x 2 6 10 14 16 18 22 30 38 46 50 66 weeks x x x xInfliximab 3 mg/kg x x x x x x x xInfliximab 5 mg/kg x x x x x x x x x xPlacebo x x x PASI PGA Infliximab antibodies Anti-nuclear anti double Anti nuclear & anti-double stranded DNA antibodies 80 Competitive intelligence analysis x 3 or 5 mg/kg group adminsitration x placebo re-rand. group adminsitration
  81. 81. Remicade® – EXPRESS II; study results2005 FDA website, Clinical Study Report Infliximab Infliximab Placebo 3 mg/kg 5 mg/kg ≥ PASI 75 @ week 10 (p<0.001) (p<0 001) 71% 76% 2% PASI 90 @ week 10 (p 0 00 ) (p<0.001) 37% 45% 0.5% 0 5% PGA score of excellent or cleared @ week 10 70% 76% 1% DLQI Median ∆ from baseline baseline* -9 9 -9 9 0 (p<0.001)81 Competitive intelligence analysis * median baseline value 12
  82. 82. Remicade® – EXPRESS II; study results2005 FDA website, Clinical Study Report ≥PASI 75 @ week 50 S (p<0.001) Continuous Infliximab 44% 3 mg/kg Intermittant Infliximab 24% 3 mg/kg Continuous Infliximab 55% 5 mg/kg Intermittant Infliximab 38% 5 mg/kg82 Competitive intelligence analysis
  83. 83. Remicade® – EXPRESS II; safety & tolerability2005 FDA website, Clinical Study Report• Therapy associated adverse event profile – Serious infections • tuberculosis (2) • undisclosed (9) – Cardiovascular events • congestive heart failure (1) – Malignancies • basal cell carcinomas (9) • squamous cell carcinomas (1) • adenocarcinoma (1) • breast cancer (1) – Lupus erythematosus (4) – Increased liver enzymes @ week 50 • 4.9% patients had markedly abnormal ALT values p 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 • 26.8% patients were newly positive for anti-dsDNA antibodies83 Competitive intelligence analysis
  84. 84. Humira® (adalimumab)84 Competitive intelligence analysis
  85. 85. 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 & 24 PASI • 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 – 28 sites – CA, Europe85 Competitive intelligence analysis
  86. 86. Humira® – Study Ps-II; study design2006 Gordon, J Am Acad Dermatology 2 4 8 16 20 22 28 32 36 44 52 PASI S PGA86 Competitive intelligence analysis
  87. 87. Humira® – St d Ps-II; patient flowH i ® Study P II ti t fl2006 Gordon, J Am Acad Dermatology87 Competitive intelligence analysis
  88. 88. Humira® – Study Ps-II; baseline characteristics2006 Gordon, J Am Acad Dermatology88 Competitive intelligence analysis
  89. 89. 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 – 2° endpoints ̶ Proportion of eow patients @ week 12, & 60 acheiving:  76%, 64% PASI 50  24%, 33% PASI 90 % % S  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 trend89 Competitive intelligence analysis
  90. 90. Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology90 Competitive intelligence analysis
  91. 91. Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology91 Competitive intelligence analysis
  92. 92. Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology92 Competitive intelligence analysis
  93. 93. Humira® – Study Ps-II; study results2006 Gordon, J Am Acad Dermatology93 Competitive intelligence analysis
  94. 94. Humira® – Study Ps-II; safety & tolerability2006 Gordon, J Am Acad Dermatology94 Competitive intelligence analysis
  95. 95. Humira® – Study Ps-II; safety & tolerability2006 Gordon, J Am Acad Dermatology• Therapy associated adverse event profile – Serious infections (1) – Cardiovascular events • palpitations • coronary artery disease – Malignancies (5) • malignant melanoma (2) li l • squamous cell carcinoma (1) • breast carcinoma (1) • gastric adenocarcinoma (1) – Cerebrovascular accidents (2) • undisclosed; 1 death – Tuberculosis • recent-onset latent TB (1) – Others • migraines • bronchitis • osteoarthritis • kidney stones – 2 patients discontinued due to liver enzyme increases between 3 - 3.5 ≥ ULNNo cases of lymphoma, demyelinating syndrome, or lupuslike syndrome were reported95 Competitive intelligence analysis
  96. 96. Humira® – Study Ps-I; study design2008 Menter, J Am Acad Dermatology 4 8 12 24 36 40 44 48 PASI PGA96 Competitive intelligence analysis
  97. 97. Humira® – Study Ps-I; patient flow2008 Menter, J Am Acad Dermatology Placebo Adalimumab 40 mg 7% progress 71% progress 85% progress 85% progress 6% ≤ PASI 50 @ week 54 39% ≤ PASI 5097 Competitive intelligence analysis @ week 54
  98. 98. Humira® – Study Ps-I; baseline characteristics2008 Menter, J Am Acad Dermatology98 Competitive intelligence analysis
  99. 99. Humira® – Study Ps-I; study results2008 Menter, J Am Acad Dermatology99 Competitive intelligence analysis
  100. 100. Humira® – Study Ps-I; study results2008 Menter, J Am Acad Dermatology 39% @ wk 54 28% @ wk 52 6% @ wk 54 5% @ wk 52100 Competitive intelligence analysis
  101. 101. Humira® – Study Ps-I; study results2008 Menter, J Am Acad Dermatology101 Competitive intelligence analysis
  102. 102. Humira® – Study Ps-I; safety & tolerability2008 Menter, J Am Acad Dermatology102 Competitive intelligence analysis
  103. 103. Humira® – Study Ps-I; safety & tolerability2008 Menter, J Am Acad Dermatology103 Competitive intelligence analysis
  104. 104. 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) • 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 antibodiesNo cases of lymphoma demyelinating syndrome lupuslike syndrome or rebound were reported lymphoma, syndrome, syndrome,104 Competitive intelligence analysis
  105. 105. Humira® – CHAMPION; study design2007 Saurat, British Journal of Dermatology PASI/PGA week 0 1 2 4 8 12 16105 Competitive intelligence analysis
  106. 106. Humira® – CHAMPION; baseline characteristics2007 Saurat, British Journal of Dermatology106 Competitive intelligence analysis
  107. 107. Humira® – CHAMPION; study results2007 Saurat, British Journal of Dermatology• Efficacy endpoints – 1° endpoints d i t  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:  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 ̶ 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 NB: unusually high placebo rate attributed to (1) european population (2) folate suppliment (3) MTX naïve inclusion criteria107 Competitive intelligence analysis
  108. 108. Humira® – CHAMPION; study results2007 Saurat, British Journal of Dermatology108 Competitive intelligence analysis
  109. 109. Humira® – CHAMPION; study results2007 Saurat, British Journal of Dermatology109 Competitive intelligence analysis
  110. 110. Humira® – CHAMPION; study results2007 Saurat, British Journal of Dermatology110 Competitive intelligence analysis
  111. 111. 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 increasesNo serious adverse events nor any cases of TB, lymphoma, demyelinatingsyndrome, or lupuslike syndrome or associated deaths were reported111 Competitive intelligence analysis
  112. 112. Ustekinumab112 Competitive intelligence analysis
  113. 113. 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 • ∆ 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)• PHOENIX II (NCT00307437) – 2 doses vs placebo (1:1:1) – 1° endpoints • Proportion of patients achieving PASI 75 @ week 12 – 2° endpoints • Proportion of p p patients with PGA score of cleared or minimal @ week 12 • ∆ 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)113 Competitive intelligence analysis
  114. 114. Ustekinumab – PHOENIX I; study design2008 Lancet, Efficacy and safety of ustekinumab114 Competitive intelligence analysis
  115. 115. Ustekinumab – PHOENIX I; patient flow2008 Lancet, Efficacy and safety of ustekinumab115 Competitive intelligence analysis
  116. 116. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX I; baseline characteristics116 Competitive intelligence analysis
  117. 117. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX I; endpoints & results• Efficacy endpoints – 1° endpoints 67% of patients achieving PASI 75 @ week 12 with 45 mg f ti t hi i k ith 66% of patients achieving PASI 75 @ week 12 with 90 mg 76% of patients achieving PASI 75 @ week 24 with 45 mg 85% of patients achieving PASI 75 @ week 24 with 90 mg 85% – 2° endpoints Sustained improved PGA score of cleared or minimal @ week 12 Sustained improved ∆ dermatology QoL @ week 12 Median time to loss of PASI 75 response following randomized withdrawal was 15 weeks met x not met ~trend117 Competitive intelligence analysis
  118. 118. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX I; results118 Competitive intelligence analysis
  119. 119. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX I; results119 Competitive intelligence analysis
  120. 120. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX I; results120 Competitive intelligence analysis
  121. 121. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX I; safety & tolerability• Therapy associated adverse event profile – Serious infections • viral syndrome (1) • foot ulcer of diabetic patient (1) • osteomyelitis (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) • lentigo maligna (1) • transitional cell carcinoma (1)121 Competitive intelligence analysis
  122. 122. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX I; safety & tolerability122 Competitive intelligence analysis
  123. 123. Ustekinumab – PHOENIX II; study design2008 Lancet, Efficacy and safety of ustekinumab123 Competitive intelligence analysis
  124. 124. Ustekinumab – PHOENIX II; patient flow2008 Lancet, Efficacy and safety of ustekinumab124 Competitive intelligence analysis
  125. 125. Ustekinumab – PHOENIX II; baseline characteristics2008 Lancet, Efficacy and safety of ustekinumab125 Competitive intelligence analysis
  126. 126. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX II; endpoints & results• Efficacy endpoints – 1° endpoints 67% of patients achieving PASI 75 @ week 12 with 45 mg 76% of patients achieving PASI 75 @ week 12 with 90 mg – 2° endpoints Sustained improved PGA score of cleared or minimal @ week 12 Sustained improved ∆ dermatology QoL @ week 12 90 mg every 8 weeks was the only group to show an advantage with intensified 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 x not met ~trend met t t t d126 Competitive intelligence analysis
  127. 127. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX II; results127 Competitive intelligence analysis
  128. 128. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX II; results128 Competitive intelligence analysis
  129. 129. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX II; results129 Competitive intelligence analysis
  130. 130. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX II; results130 Competitive intelligence analysis
  131. 131. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX II; safety & tolerability• Therapy associated adverse event profile – Serious infections (4) – Cardiovascular events (5, including 1 death) • angina • non-ischaemic sudden cardiac death with underlying dilated non ischaemic cardiomyopathy (90 mg) • transient palpitations • ventricular extrasystoles • hypertension – Malignancies (8) • Cutaneous (6) • basal cell carcinoma • squamous cell carcinomaNo dose proportional observations in the rates of adverse reactions131 Competitive intelligence analysis
  132. 132. Ustekinumab of ustekinumab2008 Lancet, Efficacy and safety – PHOENIX II; safety & tolerability132 Competitive intelligence analysis
  133. 133. Briakinumab133 Competitive intelligence analysis
  134. 134. Briakinumab – Clinical trials overview• Phase 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 p p patients with PGA score of cleared or minimal @ week 12 • 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 patients p – 52 week trial – 122 sites – 2 countries, (CA, US)134 Competitive intelligence analysis
  135. 135. Briakinumab – Clinical trials overview• Phase III NCT00691964 – 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 • Proportion of patients achieving PASI 75 @ week 52 P i f i hi i k 2 • 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)135 Competitive intelligence analysis
  136. 136. Competitors in development• Rejected for lack of efficacy or an unsuitable safety & tolerability profile136 Competitive intelligence analysis
  137. 137. Golimumab• Never assessed in plaque psoriasis• Marketed as Simponi® for Rheumatoid Arthritis, Psoriatic Arthritis & Ankolysing Spondylitis in the US & CA• Clinical trials in Ulcerative Colitis ongoing• previously abandoned Uveitis, Crohn‘s Disease, chronic asthma137 Competitive intelligence analysis
  138. 138. Cimzia® (Certolizumab pegol)• PEGylated Fc free anti-TNFα antagonist delivered by subcutaneous Fc-free anti TNFα 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; opportunistic infections and malignancy t i ti i f ti d li• Phase III program in psoriasis terminated; UCB product pipeline lists Crohn‘s Disease and Rheumatoid Arthritis in the EU only• previously abandoned A k l i S i l b d d Ankylosing Spondylitis, P i ti A th iti d liti Psoriatic Arthritis138 Competitive intelligence analysis
  139. 139. Cimzia® (Certolizumab pegol)• US label – 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 conventional therapy – Rheumatoid arthritis in 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) disease modifying (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 combination X ray with MTX.139 Competitive intelligence analysis

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