Crohn's disease pharmascape cv

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Crohn's disease pharmascape cv

  1. 1. Crohn‘s diseaseC h ‘ diPharmascape pAll 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
  2. 2. Marketed biologics for Crohn‘s disease Remicade®, infliximab Humira®, adalimumab Tysabri®, natalizumab Cimzia®, certolizumab C ®2 Life Cycle Management Competitive intelligence analysis
  3. 3. Remicade®• Chimeric IgG1κ monoclonal antibody targeting TNF-α• Induction via intravenous infusion of 5mg/kg at week-0 & -2, followed by maintenance regimen of 5mg/kg every 6-weeks for responders at week-2• 1st registration trials based on 12- to 26-week endpoints, followed by label extensions in Crohn‘s disease acheieved with maintenance therapy in 2 large Phase III trials demonstrating efficacy & steroid sparing effects at 1-year in both severe active & fistulating CD as required by REMs• Results from 5mg/kg 2-week induction regimen followed by 5mg/kg every 8-weeks – ~60% responder rate to 1st administration (n=573) – 51% higher remission rate (CDAI <150 pts) at week-30 (39% Remicade@ vs 19% placebo) – median time to loss of response (↓ in CDAI score to ≥70 pts and ≥ 25% from baseline) was 27 weeks longer than placebo (46 weeks Remicade@ vs 19 weeks placebo) – 56% hi h proportion retained remission th higher ti t i d i i through week-54 (25% R i d @ vs 11% placebo) h k 54 Remicade@ l b )• Headache, abdominal pain, URTI & infusion site reactions most common reported AE• Black box warnings: malignancies specifically hepatosplenic T-cell lymphoma in CD patients, serious infections inclusive of Hepatitis B reactivation, hepatoxicity inclusive of death and liver transplant, cytopenias, hypersensitivity inclusive of anaphylaxis, demyelinating disorders, Lupus-like syndrome & myocardial infarction reported in rare cases• 6-13% of CD patients test positive for infliximab NABs which are associated with a higher incidence of injection site reactions• Intermittent therapy is not encouraged due to perceived higher immunogenicity risk• Crohn‘s disease was the 1st licensed indication• Annual cost €21,573/$21,1663 Life Cycle Management Competitive intelligence analysis
  4. 4. Remicade® – CD development plan 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 RA PsA UCPhase IIISevere active CDPhase IIIFistulizing active CD ACCENT I Severe active CD ACCENT II Fistulizing active CD SONIC Azothioprine/Infliximab combination Maintenance Fistulas Launch extension extension 4 Life Cycle Management Competitive intelligence analysis
  5. 5. Humira®• Humanized IgG1 monoclonal antibody targeting TNF α TNF-α• Induction via subcutaneous bolus dose of 80mg at week 0 followed by 40 or 80mg at week 2, followed by maintenance regimen of 40mg every other week with a pre-filled syringe or autoinjection pen in Crohn‘s Disease• Fast acting agent with limited long term responders g g g p• Results at week-26 maintained through week-56 with 80/40mg induction followed by 40mg EoW – 44% higher remission rate (CDAI <150 pts) at week-56 (79% Humira®, 50% placebo) – ~30% of patients achieve corticosteroid-free remission for ≥90 days – 127 days mean time to remission – complete fistula closure achieved in ~30% of patients• Injection site reaction/irritation most common reported AE• 2 cases of pulmonary tuberculosis and 1 case of MS reported in CHARM trial• Black bo warnings: malignancies specifically lymphoma, serious infections inclusive of ac box a gs a g a c es spec ca y y p o a, se ous ect o s c us e o bacterial sepsis, TB reactivation, invasive fungal infections reported in rare cases• ≥ 150,000 patients in safety database across all indications as of 2007• 0.4-3.6% of patients test positive for adalimumab NABs• Fourth indication following RA, Psoriatic arthritis & Ankylosing spondylitis g , y g p y• Annual cost €14,700/$20,3395 Life Cycle Management Competitive intelligence analysis
  6. 6. Humira® – CD development plan2000 2001 2002 2003 2004 200 2005 2006 200 2007 2008 2009 2010 2011 2012 RA PsA AS Pso JIA CLASSIC-I CLASSIC-II CHARM GAIN CHOICE Infliximab failures CARE QoL outcomes EXTEND Mucosal healing PYRAMID Long term safety US 6 Life Cycle Management Launch Competitive intelligence analysis
  7. 7. Tysabri®• Monthly 300mg i.v. infusion of humanized monoclonal antibody against α-4 integrin, reducing T cell traffic through the endothelium into tissue g• ENACT-1 trial failed to show significant induction effects at week-10, however ENCORE demonstrated significant results at week-8 30% higher proportion of clinical response (↓CDAI score by 100 pts) at week-4 (39% Tysabri® 300mg, 27% placebo) 33% higher proportion of clinical response (↓CDAI score by 70 pts) sustained from week-8 to week-12 (48% Tysabri® 300mg, 32% placebo) 300mg 38% higher proportion of clinical remission (CDAI score < 150) sustained from week-8 to week-12 (26% Tysabri® 300mg, 16% placebo)• ENACT-2 demonstrated significant benefit upon long-term treatment 54% higher rate of clinical response (↓CDAI score by 70 pts) sustained from week-10 to week-36 (61% Tysabri® 300mg, 28% placebo) 41% higher rate of clinical remission (CDAI score <150) sustained from week-10 to week-36 ( % ysab ® 300 g, 6% p acebo) (44% Tysabri® 300mg, 26% placebo)• Injection site reaction/irritation most common reported AE• Rare malignancies & opportunistic infections cited with long-term exposure• Black box warnings: PML, hypersensitivity specifically anaphylaxis, immunosuppression and hepatotoxicity reported in rare cases• As of 2010 one PML case reported in Crohn‘s Disease patients; in MS patients a total of 68 PML cases reported, inclusive of 14 deaths• ~10% of patients test positive for natalizumab NABs• Licensed exclusively in the US for Crohn‘s disease• Annual cost estimated at $ $37,000 (based on MS figures)7 Life Cycle Management Competitive intelligence analysis
  8. 8. Tysabri® – CD development plan1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 MS Launch PML Re-launchCD202 CD306 On top of Remicade® ENACT-1 ENACT 2 ENACT-2 ENACT-2 ext ENCORE CD305 Paediactric CD352 Paediactric CD INFORM Pharmacovigilance long-term safety US Launch 8 Life Cycle Management Competitive intelligence analysis
  9. 9. Cimzia®• Polyethylene glycolated Fab‘ fragment of humanized anti-TNF-α monoclonal antibody delivered by monthly 400mg subcutaneous injection• Phase IIb trial failed to demonstrate a benefit at week-12 in the ITT with 400mg against placebo; post- hoc analysis suggests a correlation between CRP levels >10mg/L and efficacy• PRECISE 1 & PRECISE 2 trials stratify by CRP levels yet fail to establish a correlation between CRP levels and efficacy, however reach statistical significance at week-6 and week-26 30% higher proportion of patients with baseline serum CRP levels of at least 10mg/L achieving a reduction of ≥ 100 points in the CDAI score at week-6 (37% Cimzia® 400mg, 26% placebo) 45% higher proportion of patients with baseline serum CRP levels of at least 10mg/L achieving a reduction of ≥ 100 points in the CDAI score at week-26 (62% Cimzia® 400mg, 34% placebo)• Statistical responses begin at week-2• No explanation accounts for the differences between the increased proportion of patients achieving a reduction in CDAI scores of ≥ 100 points or remission (CDAI total score <150) in PRECISE 2 (64%/43%) as opposed to PRECISE 1 (35%/22%)• Maintenance of remission was only achieved in PRECISE 2• Black box warnings: malignancies specifically lymphoma, serious infections inclusive of bacterial sepsis, TB reactivation, invasive fungal infections reported in rare cases• ~8% of patients test positive for certolizumab NABs• Licensed for use in Crohn‘s disease exclusively in the US; rejected by EMEA in 2007• Annual costs $18,4089 Life Cycle Management Competitive intelligence analysis
  10. 10. Cimzia® – CD development plan1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 CDP870 RA MUSIC PRECISE 1 Mucosal healing PRECISE 2 PRECISE 3 Long-term OL for P1/P2 PRECISE 4 Long-term OL for P1/P2 withdrawals due to CD exacerbation COSPAR1 Corticosteroid sparing - TERMINATED C87042 Remicade® failures C87085 Induction study SECURE Pharmacovigilance long-term safety US US 10 Life Cycle Management NDA Launch Competitive intelligence analysis
  11. 11. Comparative induction capacity at week-4 Clinical Response (↓CDAI ≥70) Active Placebo Difference Remicade®, (5mg) 81% 17% 65% Remicade®, (5, 10, 20mg) 65% 17% 48% Humira®, (80/40mg induction) 58% 36% 22% Humira®, (40mg maintenance) 52% 34% 18% Tysabri®, (300mg, ↑ CRP ENCORE) 51% 37% 15% Cimzia®, (↑ CRP sub-group analysis) 50% 31% 19% Cimzia®, (400mg, all patients) 44% 31% 10% p values p-values 0.011 - 0.00111 Life Cycle Management Competitive intelligence analysis
  12. 12. Comparative induction capacity at week-4 Clinical Remission (CDAI ≤150) Active Placebo Difference Remicade®, (5mg) 48% 4% 44% Remicade®, (5, 10, 20mg) 36% 4% 28% Humira®, (80/40mg induction) 33% 12% 24% Humira®, (40mg maintenance) 21% 7% 14% Tysabri®, (300mg, ↑ CRP ENCORE) 24% 16% 8% Cimzia®, (↑ CRP sub-group analysis) 20% 10% 10% Cimzia®, (400mg, all patients) 19% 11% 8% p values p-values 0.018 - 0.00112 Life Cycle Management Competitive intelligence analysis
  13. 13. Crohn‘s disease competitors in development Vedolizumab, MLN0002 CEP-37248 Traficet-EN, CCX282-B AIN457 Stelara* CCX025 Laquinimod CP 690.550 CEP-37247, ART-621 ELND004 Briakinumab, ABT-874** * Rumor: Phase II results positive and support Phase III ** Rumor: Clinical development stopped in CD due to negative Phase II results13 Life Cycle Management Competitive intelligence analysis
  14. 14. Crohn‘s disease: clinical development environment CCR9 antagonist α-4-integrin antagonist CCX025 CEP-37247 ELND004 Traficet-EN JAK3 antagonist Vedolizumab CP 690.550 Phase I Phase II Phase III Launched Laquinimod AIN457 Stelara Anti-proliferant/replicative Briakinumab Anti-IL-17 CEP-37248 oral parenteral Anti-IL-12/IL-2314 Life Cycle Management Competitive intelligence analysis
  15. 15. Conclusions• Remicade® dramatically changed the Crohn‘s disease treatment paradigm; diffcult differentiation between Remicade®, Humira®, Tysabri®, and Cimzia® outside of route of administration & rare safety signals as witnessed by comparable prescription rates• Response rates are only 30-60% in treatment naϊve patients; discontinuation in the case of inadequate initial response is recommended in posology label text• Although efficacy did not wane during the conduct of the published clinical trials, the presence of NAB titers is associated with a significant loss in efficacy upon extended administration, eg >1yr Confidential• Loss of efficacy & low differentiation drives high switch market between TNF-α agents• All registration trials assessed efficacy by ∆CDAI scores, however the index is intrinsically prone to subjective variability• Placebo effect appears to be more pronounced over time (up to 47% in Cimzia® trials; average of 19% across 21 randomized CD trials)• Alternative efficacy measures available Crohn‘s Disease Endoscopic Index of Severity (CDEIS)• Stellara® & briakinumab both demonstrated fast acting potential in other clinical trials, eg psoriasis• Biosimilars to Remicade® & Tysabri® may be available at the time of launch• Effective competitive oral therapy on the horizon 15 Life Cycle Management Competitive intelligence analysis
  16. 16. Back ups
  17. 17. Crohn‘s Disease Activity Index (CDAI) Remission of Crohns disease is defined as a CDAI <150 Clinical laboratory variable Cli i l or l b t i bl Weighting factor W i hti f t Moderate di M d disease i d fi d by a value of 220-450 is defined b l f 220 4 0 Number of liquid or soft stools each day for seven Severre disease is defined as >450 x2 days Clinical response is typically defined as a reduction >70 Abdominal pain (g p (graded from 0-3 on severity) y) x5 each day for seven days General well being, subjectively assessed from 0 x7 (well) to 4 (terrible) each day for seven days Presence of complications* x 20 *One point each is added for each set of complications: •the presence of joint pain (arthralgia) or frank arthritis Taking Lomitil or opiates for diarrhea x 30 •inflammation of the iris or uveitis •presence of erythema nodosum, pyoderma gangrenosum or Presence of an abdominal mass (0 as none, 2 as aphthous ulcers x 10 questionable, questionable 5 as definite) •Anal fissures, fistulae or abscesses Anal fissures •Other fistulae •Fever during the previous week Absolute deviation of Hematocrit from 47% in x6 men and 42% in women Percentage deviation from standard weight x117 Lifecycle management Competitive intelligence analysis
  18. 18. Loss of response to Remicade®18 Lifecycle management Competitive intelligence analysis
  19. 19. Loss of response to Remicade®19 Lifecycle management Competitive intelligence analysis
  20. 20. Loss of response to Remicade®20 Lifecycle management Competitive intelligence analysis
  21. 21. Loss of response to Humira®21 Lifecycle management Competitive intelligence analysis
  22. 22. Remicade®22 Lifecycle management Competitive intelligence analysis
  23. 23. Remicade® – US label; indication23 Lifecycle management Competitive intelligence analysis
  24. 24. Remicade® – US label; warnings24 Lifecycle management Competitive intelligence analysis
  25. 25. Remicade® – EU label; indication25 Lifecycle management Competitive intelligence analysis
  26. 26. Remicade® – EU label; warnings ®26 Lifecycle management Competitive intelligence analysis
  27. 27. Remicade® – EU label; warnings ®27 Lifecycle management Competitive intelligence analysis
  28. 28. Remicade® – EU label; warnings28 Lifecycle management Competitive intelligence analysis
  29. 29. Remicade® – Clinical trials overview• Phase III Induction trial in severe active CD – 4 week treatment in treatment failures – 5mg/kg, 10mg/kg, 20mg/kg or placebo on top of unsatisfactory background therapy – CDAI endpoints – 108 patients• Phase III Induction trial in fistulizing active CD (NCT00207662) – 26 week treatment – 5mg/kg, 10mg/kg or placebo – CDAI endpoints – 94 patients• ACCENT I Phase III Maintenance trial in severe active CD (NCT00207662) – 54 week treatment – 5mg/kg induction followed by 5mg/kg week-2 & 6 followed by 5mg/kg or 10mg/kg every 8-weeks, or placebo – CDAI endpoints p – 573 patients – 11 months recruitment – 6 countries, 55 sites (North America, Europe, IL)• ACCENT II Phase III Maintenance trial in fistulizing active CD (NCT00207766) – 54 week treatment – 5mg/kg induction followed by 5mg/kg week-2 & 6 followed by 5mg/kg or 10mg/kg every 8-weeks, or placebo – CDAI endpoints – 306 patients – 10 months recruitment – 6 countries, 45 sites (BE, CA, CZ, PL, NL, US)• SONIC Phase III Combination trial with azathiaprine (NCT00094458) – 1 yr trial; 34 week Treatment Period I, 20 week Treatment Period II – 5mg/kg induction followed by 5mg/kg week-2 & 6 followed by 5mg/kg or 10mg/kg every 8-weeks, 2.5mg/kg OD azathioprine or both – CDAI endpoints, mucosal healing, steroid free, clinical response & remission – 508 patients – 3 years 9 months recruitment29 Lifecycle management Competitive intelligence analysis
  30. 30. Remicade® – Phase III active CD; design 1998 FDA label 12-week alternative dosing regimens of Remicade® vs placebo on top of conventional therapies in patients who failed to achieve adequate response (n=108) Phase I Phase II Phase III Week 0 2 4 8 12 20 28 36 48Remicade® 5mg/kg 10mg/kg 20mg/kgPlacebo 10mg/kg* g g CDAI assessment * Infliximab treatment failures at the 1° endpoint received a 2nd infusion of 10mg/kg @ week-4 30 Lifecycle management Competitive intelligence analysis
  31. 31. Remicade® – Phase III active CD; results1998 FDA label31 Lifecycle management Competitive intelligence analysis
  32. 32. Remicade® – Phase III fistulizing CD; design 1998 FDA label22-week alternative dosing regimens of Remicade® vs placebo on top of conventionaltherapies in patients with inadequate response and fistulas ≥ 3-months(n=94) Week 0 2 6 10 14 18 22 Remicade® 5mg/kg x x x 10mg/kg x x x Placebo x x x Fistula assessment X = administration 32 Lifecycle management Competitive intelligence analysis
  33. 33. Remicade® – Phase III fistulating CD; results1998 FDA label33 Lifecycle management Competitive intelligence analysis
  34. 34. Remicade® – Phase III ACCENT I; design 2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial 54-week alternative dosing regimens of Remicade® vs placebo in responders to first 2-week induction therapy (n=573) Open label Double blind Week -2 0 2 6 10 14 22 30 38 46 54Remicade® 5mg/kg 10mg/kgPlaceboRescue Tx 5/10/15mg/kg CDAI assessment IBDQ Response assessed as CDAI score reduction at week-2 from baseline of either: ↓70 points 34 Lifecycle management 25% total score reduction Competitive intelligence analysis
  35. 35. Remicade® – Phase III ACCENT I; intent to treat2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial ;35 Lifecycle management Competitive intelligence analysis
  36. 36. Remicade® – Phase III ACCENT I; patient characteristics2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial ;36 Lifecycle management Competitive intelligence analysis
  37. 37. Remicade® – Phase III ACCENT I; endpoints & results2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial ;• Primary endpoints  proportion of patients which responded at @ week-2 and in remission (CDAI<150 points) @ week 30 week-30  time to loss of response up to week-54 in responders• Secondary endpoints  ∆ median IBDQ total score from baseline  ∆ median CDAI total score from baseline  ∆ median CRP levels from baseline Trial was powered assuming a 60% responder rate to induction to detect a significant difference between dose groups in terms of remission rate at week-30 (95%) and time to loss of response up to week-54 (90%) met x not met ~trend37 Lifecycle management Competitive intelligence analysis
  38. 38. Remicade® – Phase III ACCENT I; endpoints & results2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial ;38 Lifecycle management Competitive intelligence analysis
  39. 39. Remicade® – Phase III ACCENT I; endpoints & results2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial ;39 Lifecycle management Competitive intelligence analysis
  40. 40. Remicade® – Phase III ACCENT I; safety & tolerability2002 Maintenance infliximab for Crohn‘s disease; the ACCENT I randomised trial40 Lifecycle management Competitive intelligence analysis
  41. 41. Remicade® – Phase III ACCENT II; design 2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease 54-week maintenance Remicade® 5mg/kg vs placebo in responders to first 6-week induction therapy with fistulas ≥ 3-months (n=306) Open label Double blind Week -2 0 2 2 6 10 14 22 30 38 46 54Remicade® 10mg/kg XRemicade® 5mg/kg X XPlacebo FistulaX = re-randomisation assessmentX = up-titration possibility CDAI IBDQ Response assessed as 50% reduction from baseline in total number of fistulas at consecutive visits ≥ 4 weeks apart at week-14 visit 41 Lifecycle management Competitive intelligence analysis
  42. 42. Remicade® – Phase III ACCENT II; intent to treat2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease42 Lifecycle management Competitive intelligence analysis
  43. 43. Remicade® – Phase III ACCENT II; patient characteristics2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease43 Lifecycle management Competitive intelligence analysis
  44. 44. Remicade® – Phase III ACCENT II; endpoints & results2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease• Primary endpoints  36 weeks longer time to loss of response up to week-54 in responders (40 weeks on Remicade®, 14 weeks on placebo)• Secondary endpoints  50% higher proportion of responders maintained clinical response @ week-54 g (46% on Remicade®, 23% on placebo)  47% higher number of patients with full response at week-54 (36% on Remicade®, 19% on placebo)  84% higher response rate in patients with CDAI scores ≥220 at baseline (36% on Remicade® 6% on placebo) Remicade®,  median decrease of 26 and 25 points in baseline CDAI scores at week-30 and -54 (↓42 & ↓40 on Remicade®, ↓16 & ↓15 on placebo)  median increase of 10 and 5 in baseline IBDQ scores at week-30 and -54 (↑14 & ↑10 on Remicade®, ↑4 & ↑5 on placebo)• Crossover treatment results • Following loss initial response in the placebo maintenance regime, re-administration of 5mg/kg re-established clinical response in 61% of patients • Following loss initial response in the 5mg/kg maintenance regime, up-titration to 10mg/kg re-established clinical response in 61% of patients g g p % p met x not met ~trend44 Lifecycle management Competitive intelligence analysis
  45. 45. Remicade® – Phase III ACCENT II; endpoints & results2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease45 Lifecycle management Competitive intelligence analysis
  46. 46. Remicade® – Phase III ACCENT II; safety & tolerability2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease46 Lifecycle management Competitive intelligence analysis
  47. 47. Remicade® – Phase III ACCENT II; safety & tolerability2004 Infliximab Maintenance Therapy for Fistulizing Crohn‘s disease47 Lifecycle management Competitive intelligence analysis
  48. 48. Humira®48 Lifecycle management Competitive intelligence analysis
  49. 49. Humira® – US label; indication49 Lifecycle management Competitive intelligence analysis
  50. 50. Humira® – US label; warnings50 Lifecycle management Competitive intelligence analysis
  51. 51. Humira® – EU label; indication
  52. 52. Humira® – EU label; indication
  53. 53. Humira® – EU label; warnings
  54. 54. Humira® – EU label; warnings
  55. 55. Humira® – EU label; warnings
  56. 56. Humira® – EU label; warnings
  57. 57. Humira® – EU label; warnings
  58. 58. Humira® – Clinical trials overview• CLASSIC-I Phase IIb Induction – 4 week treatment – 160/80mg, 80/40mg, 40/20mg or placebo (1:1:1:1) – CDAI endpoints – 299 patients – 16 months recruitment – 6 countries, 55 sites (BE, CA, CZ, PL, NL, US)• CLASSIC-II Phase IIb Maintenance – 56 week treatment – 40mg EoW 40mg weekly or placebo EoW, – CDAI endpoints – 276 patients – 12 months recruitment – 6 countries, 53 sites (BE, CA, CZ, PL, NL, US)• CHARM Phase III (NCT00077779) – 56 week treatment – 80/40mg on week 0/2 followed by 40mg EoW, 40mg weekly or placebo – CDAI endpoints d i t – 778 patients – 14 months recruitment – 8 countries, 92 sites (AU, CA, LT, PL, RO, TR, US, ZA)• GAIN Phase III (NCT00105300) – 4-week treatment – 160mg/80mg or placebo – CDAI endpoints p – 325 patients – 12 months recruitment – 4 countries, 52 sites (BE, CA, FR, US)• EXTEND Phase III (NCT00348283) – 1 yr treatment; 12-week Treatment Period I, Week-13 to Week-52 Treatment Period II – 160mg/80mg/40mg or placebo in Treatment Period I, OL Treatment Period II – Mucosal healing 1° endpoint – 135 patients – 2 years recruitment – 8 countries, 21 sites (AT, BE, CA, DE, FR, IT, NL, US)58 Lifecycle management Competitive intelligence analysis
  59. 59. Humira® – Clinical trials overview• CHOICE Phase IIIb (NCT00338650) – 4 week treatment – 40mg weekly OL – Safety & QoL endpoints – 1000 patients – 1 countries, 97 sites (US)• CARE Phase IIIb (NCT00409617) – 20 week treatment – 40mg EoW, 40mg weekly or placebo – Clinical remission CDAI endpoints remission, – 945 patients – 12 months recruitment – 18 countries, 219 sites (AT, BE, CH, CZ, DE, DK, ES, FI, FR, GR, IR, IT, NO, PT, SE, SK, UK, US)• PYRAMID Phase IV (NCT00524537) – Long term safety registry study – 5000 patients – 24 countries, 416 sites (AT, AU, BE, CA, CZ, DE, DK, ES, FR, GR, HU, IS, IR, IT, NL, NO, NZ, PT, SE, SK, SL, UK, US, ZA)59 Lifecycle management Competitive intelligence analysis
  60. 60. Humira® – Phase IIb CLASSIC-I; design 2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody ( y (Adalimumab) in CD: the CLASSIC-I Trial ) 4-week alternative dosing regimens of Humira® vs placebo Anti-TNF-α treament naϊve patients (n=299) Week Week Week Week Week -2 0 1 2 4Humira® 160/80 mg 80/40 mg 40/20 mgPlacebo CDAI assessment IBDQ administration 60 Lifecycle management Competitive intelligence analysis
  61. 61. Humira® – Phase IIb CLASSIC-I; intent to treat2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody ( y (Adalimumab) in CD: the CLASSIC-I Trial )61 Lifecycle management Competitive intelligence analysis
  62. 62. Humira® – Phase IIb CLASSIC-I; patient characteristics2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody ( y (Adalimumab) in CD: the CLASSIC-I Trial )62 Lifecycle management Competitive intelligence analysis
  63. 63. Humira® – Phase IIb CLASSIC-I; endpoints & results2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody ( y (Adalimumab) in CD: the CLASSIC-I Trial )• Primary endpoints  Induction of remission as measured by CDAI score <150 @ week 4 (36% Humira® 160/80mg, 24% Humira® 80/40mg, 12% placebo) 160/80mg 80/40mg• Secondary endpoints  proportion of patients meeting 70-point reduction @ week 4 (59% Humira® 160/80mg, 59% Humira® 80/40mg, 37% placebo)  proportion of patients meeting 100-point reduction @ week 4 p p p g p (50% Humira® 160/80mg*, 40% Humira® 80/40mg, 25% placebo *statistical significance acheived only with 160/80mg dose group  ∆ IBDQ total score from baseline (158 Humira® 160/80mg & 80/40mg, 146 placebo) Trial was powered (80%) to detect differences between the 80/40mg and 160/80mg dose groups met x not met ~trend63 Lifecycle management Competitive intelligence analysis
  64. 64. Humira® – Phase IIb CLASSIC-I; endpoints & results2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody ( y (Adalimumab) in CD: the CLASSIC-I Trial )64 Lifecycle management Competitive intelligence analysis
  65. 65. Humira® – Phase IIb CLASSIC-I; endpoints & results2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody ( y (Adalimumab) in CD: the CLASSIC-I Trial )65 Lifecycle management Competitive intelligence analysis
  66. 66. Humira® – Phase IIb CLASSIC-I; endpoints & results2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody ( y (Adalimumab) in CD: the CLASSIC-I Trial )
  67. 67. Humira® – Phase IIb CLASSIC-I; safety & tolerability2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody ( y (Adalimumab) in CD: the CLASSIC-I Trial )67 Lifecycle management Competitive intelligence analysis
  68. 68. Humira® – Phase IIb CLASSIC-I; safety & tolerability2006 Human Anti-Tumor Necrosis Factor Monoclonal Antibody ( y (Adalimumab) in CD: the CLASSIC-I Trial )68 Lifecycle management Competitive intelligence analysis
  69. 69. Humira® – Phase IIb CLASSIC-II; design 2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial 56-week alternative dosing regimens of Humira® vs placebo in patients which acheived remission in CLASSIC-I (n=276) Week 0 2 4 8 12 16 20 24 32 40 48 56Humira® 40mg EoW 40mg weeklyPlaceboRescue therapy 40mg weekly CDAI assessment IBDQ 69 Lifecycle management Competitive intelligence analysis
  70. 70. Humira® – Phase IIb CLASSIC-II; intent to treat2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial Majority of CLASSIC-I patients did not maintain remission and were therefore ineligible for randomization70 Lifecycle management Competitive intelligence analysis
  71. 71. Humira® – Phase IIb CLASSIC-II; patient characteristics2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial71 Lifecycle management Competitive intelligence analysis
  72. 72. Humira® – Phase IIb C SS C endpoints & results ® CLASSIC-II; 2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial• Primary endpoints  44% higher proportion of patients in remission (CDAI score <150) @ week-56 g p p p ( ) (79% Humira® 40mg EoW, 83% Humira® 40mg weekly, 44% placebo)• Secondary endpoints  40% higher proportion of patients in remission @ week-24 (84% Humira® 40mg EoW, 94% Humira® 40mg weekly, 50% placebo)  12%/9% higher proportion of patients meeting 70 point reduction @ weeks 24 & -56 70-point weeks-24 56 (94%/79% Humira® 40mg EoW, 95%/89% Humira® 40mg weekly, 83%/72% placebo)  27%/29% higher proportion of patients meeting 100-point reduction @ weeks-24 & -56 (84%/79% Humira® 40mg EoW, 94%/89% Humira® 40mg weekly, 61%/56% placebo)  16/9 point higher IBDQ total score from baseline @ weeks-24 & -56 (178/176 H i ® 40mg E W 186/192 H i ® 40mg weekly, 162/167 placebo) Humira® 40 EoW, Humira® 40 kl l b )  proportion of patients which discontinued steroids without loss of remission @ weeks-24 & -56• Open label arm • 46% (93/204) of patients acheived remission • 72% (1477204) of patients acheived 70-point reduction • 65% (132/204) of patients acheived 100-point reduction • reduction of mean CDAI score of 158.4 points • 58% (21/36) of patients discontinued steroidal treatment from baseline ( ) p As an extension of the CLASSIC-I trial, CLASSIC-II was not powered All analyses are exploratory, reductions are simply numeric and sample sizes from the RCT are small 72 Lifecycle management Competitive intelligence analysis
  73. 73. Humira® – Phase IIb CLASSIC-II; endpoints & results2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial73 Lifecycle management Competitive intelligence analysis
  74. 74. Humira® – Phase IIb CLASSIC-II; endpoints & results2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial74 Lifecycle management Competitive intelligence analysis
  75. 75. Humira® – Phase IIb CLASSIC-II; safety & tolerability2006 Adalimumab for maintenance treatment of CD: results of the CLASSIC-II Trial75 Lifecycle management Competitive intelligence analysis
  76. 76. Humira® – Phase III CHARM; design 2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial 56-week alternative dosing regimens of Humira® vs placebo following induction with 80mg at week 0 and 40 mg at week 2 (n=778) Open label Double blind Week -2 0 2 4 6 8 12 16 20 26 32 40 48 56 60Humira® 40mg EoW 40mg weeklyPlaceboRescue therapy py 40mg EoW CDAI IBDQ 76 Lifecycle management Competitive intelligence analysis
  77. 77. Humira® – Phase III CHARM; intent to treat2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial ~ 30-40% do not respond at week-4 ~ 50% of responders discontinue ~ 75% of non-responders discontinue77 Lifecycle management Competitive intelligence analysis
  78. 78. Humira® – Phase III CHARM; patient characteristics2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial78 Lifecycle management Competitive intelligence analysis
  79. 79. Humira® – Phase III CHARM; endpoints & results 2007 Ad li Adalimumab f M i t b for Maintenance of Cli i l Response and Remission in Patients with CD: The CHARM T i l f Clinical R d R i i i P ti t ith CD Th Trial• Primary endpoints  58% higher proportion of patients in remission (CDAI score <150) @ week-26 (40% Humira® 40mg EoW, 47% Humira® 40mg weekly, 17% placebo)  67% higher proportion of patients in remission (CDAI score <150) @ week 56 week-56 (36% Humira® 40mg EoW, 41% Humira® 40mg weekly, 12% placebo)• Secondary endpoints  41% higher proportion of patients in remission @ week-26 (81% Humira® 40mg EoW, 81% Humira® 40mg weekly, 48% placebo)  48%/58% higher proportion of patients meeting 70-point reduction @ weeks-26/-56 (54/43% Humira® 40mg EoW, 56/49% Humira® 40mg weekly, 28/18% placebo)  49%/61% higher proportion of patients meeting 100-point reduction @ weeks-26/-56 (89/71% Humira® 40mg EoW, 82/75% Humira® 40mg weekly, 45/28% placebo)  ∆ IBDQ total score from baseline @ weeks-26/-56 weeks 26/ 56  proportion of patients which discontinued steroids without loss of remission @ weeks-26/-56  proportion of patients with fistula remission o effects of previous/concomitant use of immunosuppressant or TNF-α antagonist Tx o 251 days ↑ median time to remission in responders (378 d days H i ® 40mg E W 127 d Humira® 40 EoW, days placebo) l b ) met x not met ~trend 79 Lifecycle management Competitive intelligence analysis
  80. 80. Humira® – Phase III CHARM; endpoints & results2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial80 Lifecycle management Competitive intelligence analysis
  81. 81. Humira® – Phase III CHARM; endpoints & results2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial81 Lifecycle management Competitive intelligence analysis
  82. 82. Humira® – Phase III CHARM; endpoints & results2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial82 Lifecycle management Competitive intelligence analysis
  83. 83. Humira® – Phase III CHARM; endpoints & results2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial83 Lifecycle management Competitive intelligence analysis
  84. 84. Humira® – Phase III CHARM; safety & tolerability2007 Adalimumab for Maintenance of Clinical Response and Remission in Patients with CD: The CHARM Trial84 Lifecycle management Competitive intelligence analysis
  85. 85. Humira® – Phase III CHARM; intent to treat post-hoc analysis2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate to Severe CD: Results From the CHARM Trial Moderate-to-Severe85 Lifecycle management Competitive intelligence analysis
  86. 86. Humira® – Phase III CHARM; patient characteristics post-hoc analysis2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate to Severe CD: Results From the CHARM Trial Moderate-to-Severe86 Lifecycle management Competitive intelligence analysis
  87. 87. Humira® – Phase III CHARM; endpoints & result post-hoc analysis2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate-to-Severe CD: Results From the CHARM Trial• Primary endpoints  25% higher proportion of patients in remission (CDAI score <150) @ week-56 (51% Humira® 40mg EoW, 49% Humira® 40mg weekly, 38% placebo)• Secondary endpoints  proportion of patients in remission @ week-24 (51% Humira® 40mg EoW, 49% Humira® 40mg weekly, 38% placebo)  proportion of patients meeting 70-point reduction @ weeks-24/-56  proportion of patients meeting 100-point reduction @ weeks -24/-56  ∆ IBDQ total score from baseline @ weeks -24/-56  proportion of patients which discontinued steroids without loss of remission @ weeks -24/-56• Open label arm • 46% (93/204) of patients acheived remission • 72% (1477204) of patients acheived 70-point reduction • 65% (132/204) of patients acheived 100-point reduction • reduction of mean CDAI score of 158.4 points p • 58% (21/36) of patients discontinued steroidal treatment from baseline87 Lifecycle management Competitive intelligence analysis
  88. 88. Humira® – Phase III CHARM; endpoints & results post-hoc analysis2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate to Severe CD: Results From the CHARM Trial Moderate-to-Severe88 Lifecycle management Competitive intelligence analysis
  89. 89. Humira® – Phase III CHARM; endpoints & results post-hoc analysis2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate to Severe CD: Results From the CHARM Trial Moderate-to-Severe89 Lifecycle management Competitive intelligence analysis
  90. 90. Humira® – Phase III CHARM; safety & tolerability post-hoc analysis2008 Comparison of Two Adalimumab Treatment Schedule Strategies for Moderate to Severe CD: Results From the CHARM Trial Moderate-to-Severe90 Lifecycle management Competitive intelligence analysis
  91. 91. Humira® – Phase III GAIN; design 2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab 4-week Humira® vs placebo in Remicade® treatment failures following induction with 160mg at week-0 and 80 mg at week-2 (n=387) Week Week Week Week Week -2 0 1 2 4Humira® 160mg/80mgPlacebo CDAI assessment IBDQ 91 Lifecycle management Competitive intelligence analysis
  92. 92. Humira® – Phase III GAIN; intent to treat2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab92 Lifecycle management Competitive intelligence analysis
  93. 93. Humira® – Phase III GAIN; patient characteristics2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab93 Lifecycle management Competitive intelligence analysis
  94. 94. Humira® – Phase III GAIN; endpoints & results2007 Ad li Adalimumab I d ti Th b Induction Therapy f CD P i for Previously T l Treated with I fli i b t d ith Infliximab• Primary endpoints  66% higher proportion of patients in remission (CDAI score <150) @ week-4 (21% Humira® 160/80mg, 7% placebo)• S Secondary endpoints d d i t  proportion of patients in remission  40%/36%/35% higher proportion of patients meeting 70-point ↓ @ week-1/-2/-4 (35%/52%/52% Humira® 160/80mg, 21%/33%/34% placebo)  40%/44%/34% higher proportion of patients meeting 100-point ↓ @ week-1/-2/-4 100 point week 1/ 2/ 4 (20%/37%/38% Humira® 160/80mg, 12%/18%/25% placebo)  ∆ CDAI total score from baseline  11 point ↑ mean IBDQ score from baseline @ week-4 (150 Humira® 160/80mg, 139 placebo)  50% increase in IBQD score from baseline @ week 4 week-4 (30 Humira® 160/80mg, 15 placebo)  ↓ CRP levels from baseline @ week-4 (5.0 mg/L Humira® 160/80mg, 7.0 mg/L placebo) x ↓ number of draining fistulas x Fistula remission met x not met ~trend94 Lifecycle management Competitive intelligence analysis
  95. 95. Humira® – Phase III GAIN; endpoints & results2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab95 Lifecycle management Competitive intelligence analysis
  96. 96. Humira® – Phase III GAIN; endpoints & results2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab96 Lifecycle management Competitive intelligence analysis
  97. 97. Humira® – Phase III GAIN; safety & tolerability2007 Adalimumab Induction Therapy for CD Previously Treated with Infliximab97 Lifecycle management Competitive intelligence analysis
  98. 98. Tysabri®98 Lifecycle management Competitive intelligence analysis
  99. 99. Tysabri® – US label; indication99 Lifecycle management Competitive intelligence analysis
  100. 100. Tysabri® – US label; warnings100 Lifecycle management Competitive intelligence analysis
  101. 101. Tysabri® – Clinical trials overview• CD202 Phase IIb (N0192080633) – 8 week treatment – 3mg/kg, 2 x 3mg/kg, 2 x 6mg/kg or placebo (1:1:1:1) – CDAI endpoints – 248 patients – 11 months recruitment – 8 countries, 35 sites (BE, CZ, DE, DK, IL, NL, SE, UK)• CD306 Phase II (NCT00055536) – 12 week treatment – 300mg & Remicade®, or placebo & Remicade® (2:1) – CDAI endpoints – 79 patients – 11 months recruitment – 1 countries, 17 sites (US)• ENACT 1 ENACT-1 Phase III (NCT00032799) – CDAI (220 -450) – 12 week treatment – 300mg monthly, or placebo (4:1) – CDAI endpoints – 905 patients – 18 months recruitment – 15 countries, 133 sites (AU, CA, CZ, BE, DE, DK, ES, FR, IL, NL, NZ, RSA, SE, UK, US)• ENACT-2 Phase III (NCT00032786) – CDAI (0-220) – Up to 56 week treatment – 300mg monthly, or placebo (1:1) – CDAI endpoints – 339 patients – Extension of ENACT-1; no recruitment – 15 countries, 133 sites (AU, CA, CZ, BE, DE, DK, ES, FR, IL, NL, NZ, RSA, SE, UK, US)101 Lifecycle management Competitive intelligence analysis
  102. 102. Tysabri® – Clinical trials overview• ENCORE Phase III (NCT00078611) ( ) – 12 week treatment – 300mg monthly, or placebo (1:1) – CDAI endpoints – 509 patients – 12 months recruitment – 8 countries, 114 sites (AU, BE, CA, CZ, DE, HU, NZ, US)• CD INFORM Phase IV (NCT00707512) – Pharmacovigilance long term PML monitoring program – 2000 patients – 1 country, (US)• CD305 Phase II induction paediatric (NCT00055367) – 8 week treatment – 3mg/kg – PCDAI endpoints – 38 patients – 9 months recruitment – 3 countries, 18 sites (AU, UK, US)• CD352 Phase II maintenance paediatric (NCT00055367) – 2 year treatment – 3mg/kg – PCDAI endpoints – 24 patients – Extension of CD305; no recruitment – 3 countries, 18 sites (AU, UK, US)102 Lifecycle management Competitive intelligence analysis
  103. 103. Tysabri® – Phase IIb CD202; design 2003 Natalizumab for Active Crohn‘s Disease 12-week alternative dosing regimens of Tysabri® vs placebo CD patients (CDAI 220-450) (n=248) Week 0 2 4 6 8 12Tysabri® 3mg/kg + placebo 2 x 3mg/kg 2 x 6mg/kgPlacebo CDAI assessment CRP levels IBDQ 103 Lifecycle management Competitive intelligence analysis
  104. 104. Tysabri® – Phase IIb CD202; patient characteristics2003 Natalizumab for Active Crohn‘s Disease104 Lifecycle management Competitive intelligence analysis
  105. 105. Tysabri® – Phase IIb CD202; endpoints & results 2003 Natalizumab for Active Crohn‘s Disease• Primary endpoints x higher rate of remission (CDAI score <150) @ week-6 (16% Tysabri® 2 x 6mg/kg, 29% Tysabri® 2 x 3mg/kg, 20% Tysabri® 1 x 3mg/kg , 17% placebo)• Secondary endpoints  higher proportion of patients acheiving clinical response at week-4/-6/-8/-12* (155 Tysabri® 2 x 6mg/kg, 163 Tysabri® 2 x 3mg/kg, 155 Tysabri® 1 x 3mg/kg, 145 placebo)  higher IBDQ scores at week-6 (155 Tysabri® 2 x 6mg/kg, 163 Tysabri® 2 x 3mg/kg, 155 Tysabri® 1 x 3mg/kg, 145 placebo) l b ) ~ higher IBDQ scores at week-12* (155 Tysabri® 2 x 6mg/kg, 161 Tysabri® 2 x 3mg/kg, 149 Tysabri® 1 x 3mg/kg, 145 placebo)  lower CRP levels* *exclusively in dose groups with multiple infusions 3 or 6mg/kg met x not met ~trend105 Lifecycle management Competitive intelligence analysis
  106. 106. Tysabri® – Phase IIb CD202; endpoints & results2003 Natalizumab for Active Crohn‘s Disease106 Lifecycle management Competitive intelligence analysis
  107. 107. Tysabri® – Phase IIb CD202; safety & tolerability2003 Natalizumab for Active Crohn‘s Disease107 Lifecycle management Competitive intelligence analysis
  108. 108. Tysabri® – ENACT-1/2; design 2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease py 10-week induction with Tysabri® vs placebo CD patients (CDAI 220-450), followed by re-randomisation for patients sustaining response between week-10 and week-12 (CDAI ≤220) k 10 d k 12 220) (n=905/339) ENACT-1 ENACT-2 Week 0 4 8 10 12 16 20 24 28 32 36 40 44 48 54Tysabri® 300 mgPlacebo CDAI assessment 108 Lifecycle management Competitive intelligence analysis
  109. 109. Tysabri® – ENACT-1/2; intent to treat2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease109 Lifecycle management Competitive intelligence analysis
  110. 110. Tysabri® – ENACT-1/2; patient characteristics2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease110 Lifecycle management Competitive intelligence analysis
  111. 111. Tysabri® – ENACT-1/2; endpoints & results 2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s DiseaseENACT-1ENACT 1• Primary endpoints at week-10 x higher proportion of patients achieving clinical response (↓CDAI score by 70 pts) (56% Tysabri® 300mg, 49% placebo)• Secondary endpoints at week-10 x higher rate of clinical remission (CDAI score <150) (37% Tysabri® 300mg, 30% placebo)ENACT-2• Primary endpoints at week-36  54% higher proportion of patients achieving clinical response (↓CDAI score by 70 pts) (61% Tysabri® 300mg, 28% placebo)• Secondary endpoints scores at week-36  41% higher rate of clinical remission (CDAI score <150) (44% Tysabri® 300mg, 26% placebo) met x not met ~trend111 Lifecycle management Competitive intelligence analysis
  112. 112. Tysabri® – ENACT-1/2; endpoints & results2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease112 Lifecycle management Competitive intelligence analysis
  113. 113. Tysabri® – ENACT-1/2; endpoints & results2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease113 Lifecycle management Competitive intelligence analysis
  114. 114. Tysabri® – ENACT-1/2; safety & tolerability2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease114 Lifecycle management Competitive intelligence analysis
  115. 115. Tysabri® – ENACT-1/2; safety & tolerability2005 Natalizumab Induction and Maintenance Therapy for Crohn‘s Disease115 Lifecycle management Competitive intelligence analysis
  116. 116. Tysabri® – ENCORE; design 2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial ; 12-week induction trial Tysabri® vs placebo CD patients (CDAI 220-450) (n=509) Screening Double-blind Follow-up Week -2 0 4 8 12 20Tysabri® 300 mgPlacebo CDAI assessment CRP levels IBDQ SF-36 116 Lifecycle management Competitive intelligence analysis
  117. 117. Tysabri® – ENCORE; intent to treat2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial117 Lifecycle management Competitive intelligence analysis
  118. 118. Tysabri® – ENCORE; patient characteristics2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial118 Lifecycle management Competitive intelligence analysis
  119. 119. Tysabri® – ENCORE; endpoints & results2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial• Primary endpoints  33% higher proportion of patients acheiving clinical response (↓CDAI score by 70 pts) sustained from week-8 to week-12 (48% Tysabri® 300mg, 32% placebo)• Secondary endpoints  38% higher proportion of patients acheiving clinical remission (CDAI score < 150) sustained from week-8 to week-12 (26% Tysabri® 300mg, 16% placebo)  27% higher proportion of patients acheiving clinical response (↓CDAI score by 70 pts) @ week-12 (60% Tysabri® 300mg, 44% placebo)  35% higher proportion of patients acheiving clinical remission (↓CDAI score by 150 pts) @ week-12 (38% Tysabri® 300mg 25% placebo) 300mg, met x not met ~trend119 Lifecycle management Competitive intelligence analysis
  120. 120. Tysabri® – ENCORE; endpoints & results 2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial• Tertiary endpoints  44% higher proportion achieving a 100-point decrease in baseline C % CDAI score at both week- 8 and -12 (39% Tysabri® 300mg, 22% placebo)  27% higher proportion achieving a clinical response (↓CDAI score by 70 pts) at both week-4 and -8 (51% Tysabri® 300mg, 37% placebo) 300mg  proportion achieving a clinical remission (CDAI score < 150) at both week-4 and -8  26 day reduction in time to clinical response, defined as a 70-point decrease in baseline CDAI score (31 days Tysabri® 300mg, 57 days placebo) ~ time to clinical remission defined as a CDAI score of 150 remission, (86 days Tysabri® 300mg, undeterminable for placebo)  proportion achieving a clinical response (↓CDAI score by 70 pts) at week-8  mean change from baseline CDAI score at week-4, -8, and -12 (83 pt mean decrease at week-4 Tysabri® 300mg)  mean change from baseline platelet count at week-4 -8 and -12 week-4, -8, (55% Tysabri® 300mg, 25% placebo restored to normal levels)  ↓ mean change from baseline CRP level at week-4, -8, and -12 (15 mg/L Tysabri® 300mg, 24.7mg/L placebo at week-12)  11.5 increase mean change in IBDQ from baseline at week-12 (26.7 pts Tysabri® 300mg, 15.2 pts placebo) - mean change in the SF-36 or its components from baseline at week-12 120 Lifecycle management met x not met ~trend – not reported Competitive intelligence analysis
  121. 121. Tysabri® – ENCORE; endpoints & results2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial121 Lifecycle management Competitive intelligence analysis
  122. 122. Tysabri® – ENCORE; endpoints & results2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial122 Lifecycle management Competitive intelligence analysis
  123. 123. Tysabri® – ENCORE; safety & tolerability2007 Natalizumab Treatment of Active Crohn‘s Disease; Results of the ENCORE Trial123 Lifecycle management Competitive intelligence analysis
  124. 124. Cimzia®124 Lifecycle management Competitive intelligence analysis
  125. 125. Cimzia® – US label; indication125 Lifecycle management Competitive intelligence analysis
  126. 126. Cimzia® – US label; warnings126 Lifecycle management Competitive intelligence analysis
  127. 127. Cimzia® – Clinical trials overview• Phase IIb – 12 week treatment – 100mg, 200mg, 400mg, or placebo (1:1:1:1) – CDAI endpoints – 291 patients – 10 months recruitment – 10 countries, 58 sites (BE, CA, DE, DK, IR, RS, RU, SE, UK, ZA)• PRECISE 1 (NCT000152490) – 26 week treatment – 400mg monthly or placebo (1:1) – CDAI endpoints – 662 patients – 12 months recruitment – 22 countries, 157 sites (AT, AU, BE, BG, BY, CA, CZ, DE, DK, ET, GE, HK, HU, IT, LV, NO, PL, RU, SI, SE, UA, US, ZA)• PRECISE 2 (NCT000152425) – CDAI (220 -450) – 26 week treatment – 400mg monthly, or placebo (1:1) – CDAI endpoints – 668 patients – 10 months recruitment – 15 countries, 147 sites (AU, DE, DK, ES, HU, IR, IL, LI, NO, NZ, PL, UA, US)• C87042 (NCT00308581) – Remicade® failures – 26 week treatment – 400mg every other month, 200mg every two weeks, or placebo (1:1:1) – CDAI endpoints – 539 patients – 18 months recruitment – 14 countries, 107 sites (AT, BE, CA, CH, DE, DK, ES, FR, IT, NL, NO, SE, UK, US)127 Lifecycle management Competitive intelligence analysis
  128. 128. Cimzia® – Clinical trials overview• C87085 (NCT00552058) – 6 week treatment – 400mg or placebo (1:1) – CDAI endpoints – 439 patients – 16 months recruitment – 20 countries, 116 sites (AT, AU, BE, BR, CA, CL, CZ, DE, ET, FI, HK, HU, IL, IT, LV, NZ, PL, RO, RU, UA, US)• MUSIC (NCT00297648) – Mucosal healing – 54 week treatment – 400mg monthly – CDEIS endpoints – 89 patients – 10 months recruitment – 3 countries, 20 sites (BE, DE, FR)• COSPAR1 (NCT00349752) – Corticosteroid sparing – 38 week treatment – 400mg monthly or placebo – 174 patients – Terminated due to low recruitment – 3 countries, 68 sites (CA, DE, US)• SECURE (NCT00844285) – Long term safety – 4000 patients• Japanese studies – NCT00291668 – NCT00329550 – NCT00329420128 Lifecycle management Competitive intelligence analysis
  129. 129. Cimzia® – Clinical trials overview• PRECISE 3 (NCT00160524) – 84 month treatment – 400mg – Long-term safety – 595 patients – 20 countries, 168 sites (AT, AU, BE, BG, BY, CA, CZ, DE, DK, ET, GE, HK, HU, IT, LV, NO, PL, RU, SI, SE, UA, US, ZA)• PRECISE 4 (NCT00160706) – 84 month treatment for PRECISE 1 or 2 withdrawals due to CD exacerbation – 400mg monthly – Long-term safety – 310 patients – 20 countries, 127 sites (AT, AU, BE, BG, BY, CA, CZ, DE, DK, ET, GE, HK, HU, IT, LV, NO, PL, RU, SI, SE, UA, US, ZA)• COSPAR1 (NCT00349752) – Corticosteroid sparing – 38 week treatment – 400mg monthly or placebo – 174 patients – Terminated due to low recruitment – 3 countries, 68 sites (CA, DE, US)• SECURE (NCT00844285) – Long term safety – 4000 patients• Japanese studies – NCT00291668 – NCT00329550 – NCT00329420129 Lifecycle management Competitive intelligence analysis
  130. 130. Cimzia® – Phase IIb; design 2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease , g ( ) 12-week alternative dosing regimens of Cimzia® vs placebo CD patients (CDAI 220-450) (n=291) Week -2 0 2 4 6 8 10 12Cimzia® 100mg 200mg 400mgPlacebo CDAI assessment CRP levels IBDQ 130 Lifecycle management Competitive intelligence analysis
  131. 131. Cimzia® – Phase IIb; intent to treat2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease131 Lifecycle management Competitive intelligence analysis
  132. 132. Cimzia® – Phase IIb; patient characteristics2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease132 Lifecycle management Competitive intelligence analysis
  133. 133. Cimzia® – Phase IIb; patient characteristics2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease , g ( )133 Lifecycle management Competitive intelligence analysis
  134. 134. Cimzia® – Phase IIb; endpoints & results 2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease• Primary endpoints x higher proportion of patients achieving clinical response (↓CDAI score ≥100 or remission) @ week-12 (44.4% Cimzia® 400mg, 36.1% Cimzia® 200mg, 36.5% Cimzia® 100mg , 35.6% placebo)• Secondary endpoints  higher proportion of patients acheiving clinical response at week-2/-4/-6/-8/-10 (33.3% Cimzia® 400mg, 30.6% Cimzia® 200mg, 29.7% Cimzia® 100mg , 15.1% placebo at week-2; 52.8% Cimzia® 400mg, 30.1% placebo at week-10) x higher remission rate (CDAI score ≤ 150) at week-12 week 12 (26.4% Cimzia® 400mg, 19.4% Cimzia® 200mg, 27% Cimzia® 100mg , 23.3% placebo)  lower mean CDAI scores  15.9 points higher mean IBDQ scores at week-12 p g (156.4 pts Cimzia® 400mg, 140.5 pts placebo)  lower CRP levels met x not met ~trend134 Lifecycle management Competitive intelligence analysis
  135. 135. Cimzia® – Phase IIb; endpoints & results2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease135 Lifecycle management Competitive intelligence analysis
  136. 136. Cimzia® – Phase IIb; endpoints & results2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease136 Lifecycle management Competitive intelligence analysis
  137. 137. Cimzia® – Phase IIb; safety & tolerability2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn s Disease Placebo Controlled Crohn‘s137 Lifecycle management Competitive intelligence analysis
  138. 138. Cimzia® – Phase IIb; safety & tolerability2005 A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for the Treatment of Crohn‘s Disease138 Lifecycle management Competitive intelligence analysis
  139. 139. Cimzia® – Precise 1; design 2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease g 26-week induction & maintenance study of Cimzia® 400mg vs placebo CD patients (CDAI 220-450) (n=662) Week -2 0 2 4 6 8 12 16 20 24 26Cimzia® 400mgPlacebo CDAI assessment CRP levels IBDQ 139 Lifecycle management Competitive intelligence analysis
  140. 140. Cimzia® – Precise 1; intent to treat2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease140 Lifecycle management Competitive intelligence analysis
  141. 141. Cimzia® – Precise 1; patient characteristics2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease141 Lifecycle management Competitive intelligence analysis
  142. 142. Cimzia® – Precise 1; endpoints & results2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease• Primary endpoints  30% higher proportion of patients with baseline serum CRP levels of at least 10mg/L acheiving a reduction of ≥ 100 points in the CDAI score at week-6 (37% Cimzia® 400mg 26% placebo) 400mg,  45% higher proportion of patients with baseline serum CRP levels of at least 10mg/L acheiving a reduction of ≥100 in CDAI score at both week-6 and week-26 (22% Cimzia® 400mg, 12% placebo)• Secondary endpoints  23% higher proportion of patients regardless of baseline serum CRP levels acheiving a reduction of ≥ 100 points in the CDAI score at week-6 and at both week-6 and week-26 (35% Cimzia® 400mg 27% placebo) 400mg, x Higher proportion of patients with baseline serum CRP levels of at least 10mg/L acheiving a remission at week-6 and at both week-6 and week-26 x Higher proportion of patients regardless of baseline serum CRP levels acheiving remission at at week-6 and at both week-6 and week-26 met x not met ~trend142 Lifecycle management Competitive intelligence analysis
  143. 143. Cimzia® – Precise 1; endpoints & results2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease143 Lifecycle management Competitive intelligence analysis
  144. 144. Cimzia® – Precise 1; endpoints & results2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease144 Lifecycle management Competitive intelligence analysis
  145. 145. Cimzia® – Precise 1; safety & tolerability2007 Certolizumab Pegol for the Treatment of Crohn‘s Disease145 Lifecycle management Competitive intelligence analysis
  146. 146. Cimzia® – Precise 2; design 2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease 26-week i d ti & maintenance study of Ci i ® 400mg vs placebo 26 k induction i t t d f Cimzia 400 l b CD patients (CDAI 220-450) (n=668) g Screening Open label p Double-blind Week -2 0 2 4 6 8 12 16 20 24 26Cimzia® 400mgPlacebo CDAI assessment CRP levels IBDQ 146 Lifecycle management Competitive intelligence analysis
  147. 147. Cimzia® – Precise 2; intent to treat2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease147 Lifecycle management Competitive intelligence analysis
  148. 148. Cimzia® – Precise 2; patient characteristics2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease148 Lifecycle management Competitive intelligence analysis
  149. 149. Cimzia® – Precise 2; endpoints & results 2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease• Efficacy at week-6 • 33% higher proportion of patients acheiving a reduction of ≥ 100 points in the CDAI score at week-6 (64% Cimzia® 400mg, 43% placebo)• Pi Primary endpoints d i t  45% higher proportion of patients with baseline serum CRP levels of at least 10mg/L acheiving a reduction of ≥ 100 points in the CDAI score at week-26 (62% Cimzia® 400mg, 34% placebo)• Secondary endpoints  43% higher proportion of patients regardless of baseline serum CRP levels acheiving a reduction of ≥ 100 points in the CDAI score at week-26 ( (63% Cimzia® 400mg, 36% placebo) g, p )  40% higher remission rate (total CDAI score < 150) in patients regardless of baseline serum CRP levels at week-26 (48% Cimzia® 400mg, 29% placebo)  28% higher IBDQ response rate at week-26 (60% Ci i ® 400 Cimzia® 400mg, 43% placebo) l b ) met x not met ~trend149 Lifecycle management Competitive intelligence analysis
  150. 150. Cimzia® – Precise 2; endpoints & results2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease150 Lifecycle management Competitive intelligence analysis
  151. 151. Cimzia® – Precise 2; safety & tolerability2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease151 Lifecycle management Competitive intelligence analysis
  152. 152. Cimzia® – Precise 2; safety & tolerability2007 Maintenance Therapy with Certolizumab Pegol for Crohn‘s Disease152 Lifecycle management Competitive intelligence analysis

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