11/7/2011. Disclosures

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1 11/7/11 Efficacy & Safety of, a Fully Human Selective Anti-IL-1β Antibody, In Active Systemic Juvenile Idiopathic Arthritis Results From Two Phase III Studies Disclosures This study was sponsored by Novartis H. Brunner: Consultant & Coordinating Center contract to Cincinnati Children s Hospital HI Brunner, N Ruperto, G Horneff, P Quartier, T Constantin, Y Berkun, M Erguven, T Kallinich, R Brik, NM Wulffraat, MA Ferrandiz, L Rutkowska-sak, H Ozdogan, L Mccann, K Lheritier, R Preiss, L Tseng, A Martini, DJ Lovell. For The Paediatric Rheumatology International Trials Organisation (PRINTO) & The Pediatric Rheumatology Collaborative Study Group (PRCSG) References A phase II study to evaluate dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Nicolino Ruperto, Pierre Quartier, Nico Wulffraat, Patricia Woo, Angelo Ravelli, Richard Mouy, Brigitte Bader-Meunier, Sebastiaan J Vastert, et al for the Paediatric Rheumatology International Clinical Trials Organisation (PRINTO); Arthritis & Rheumatism, 11; DOI: 1.1/art Summary of Product Characteristics. Novartis Europharm Ltd. May 1. Ilaris (canakinumab) Prescribing Information. Novartis Pharmaceuticals Corp. 3 Acknowledgments PRCSG Site Investigators Canada United States PRINTO Site Investigators Argentina Austria Belgium Brazil France Germany Greece Israel Italy Netherlands Norway Peru Poland Sweden Spain Switzerland Turkey United Kingdom R. Schneider, E. Haddad, K. Houghton G. Higgins, D.l Kingsbury, J. Lopez-Benitez, K. Marzan, P. Morris, K. Schikler, A.Grom, D. Lovell, H Brunner R. Cuttica W.Emminger C. Wouters, L. Goffin, R. Joos, B.Lauwerys F.Sztajnbok,, S. Knupp, M. Hilario, S. Radominski M. Desjonqueres, M. Fischbach, I. Kone-Paut, P. Quartier T. Kallinich, R. Berner, M. Frosch, A. Thon, R. Trauzeddel, E. Weibarth-Riedel, G. Horneff, T Kallinich T Constantin M. Trachana Y, Uziel, J. Barash, L. Harel, Y Berkun, R Brik R. Cimaz, S. Viola, M. Alessio, F. Corona, V. Gerloni, Nicola Ruperto, A Martini NM Wulffraat B.Flato MA. Ferrandiz L. Rutkowska-Sak B. Magnusson M. Luz Gamir, I. Calvo, J. Anton, J. Carlos Robledillos M. Hofer S. Ozen, O. Kasapcopur, M.D., E. Unsa, M Erguven, H Ozdogan K. Nistala, A. Chieng, H. Foster, A. Ramanan, N. Wilkinson, L Mccann 4 selectively inhibits IL-1β-mediated inflammation A fully human selective anti-il-1β monoclonal antibody binds with high affinity selectively to IL-1β, preventing: 1-3 Interaction between IL-1β and IL-1 receptor,3 IL-1-induced gene activation Production of inflammatory mediators Phase III Program Design (SJIA Plus Fever) 4 mg/kg/month sc (n=41) (n= 43) Day 1 Day 3 Day 15 Day 9 Study 1 Patients allowed to discontinue in case of unsatisfactory therapeutic effect Study (n=5) 4 mg/kg/mo sc (n=177) 4 mg/kg/mo sc (n=5) Prednisone 1 mg/kg/day Prednisone..5 mg/kg/day Months mg/kg/mo sc (n=119) 1 Church LD, McDermott MF. Expert Rev Clin Immunol. 1;6: Ilaris (canakinumab) Summary of Product Characteristics. Novartis Europharm Ltd. May 1. 3 Ilaris (canakinumab) Prescribing Information. Novartis Pharmaceuticals Corp. June 9. 5 Part I Open label Part II Double-blind, flare withdrawal Until 37 flares have occurred Long-term extension (ongoing) 6 1

2 % of patients 11/7/11 Phase III Program: Key Eligibility Criteria Inclusion Criteria SJIA (ILAR criteria) Age 19 years Presence of active SJIA joints with active arthritis CRP > 3 mg/l (normal range <1 mg/l) Spiking, intermittent fever (>38 C) for at least 1 days Prednisone 1. mg/kg/day for at least 3 days prior to entry Stable dose of methotrexate for 8 weeks Stable dose of <1 NSAID for at least weeks Exclusion Criteria Diagnosis of active macrophage activation syndrome (MAS) within 6 months of enrollment (Ravelli 5) Active infections (e.g. TB), malignancies Concurrent use of other biologics 7 Study 1: Endpoints Primary endpoint Proportion of patients achieving the adapted ACR Pediatric 3 Response at Day 15 (plus absence of fever) Secondary endpoints Proportion of patients achieving the adapted ACR Pediatric (3)/5/7/9/1 Response at Day 15 and Day 9 Safety and tolerability 8 Study 1: Baseline Characteristics Study 1: Patient Disposition Baseline, n (%) or Median (range) (n=43) (n=41) Female, n (%) 7 (6.8) 3 (56.1) Age [years] 8 ( 18) 9 (4 19) Disease duration [years].35 (. 1.1) 1.99 ( ) VAS of physician s global assessment of disease activity 67 (5 1) 66 (1 99) Number of joints with active arthritis 1 ( 58) 7 ( 55) CHAQ [ 3] 1.63 ( 3) 1.5 (.13 3) CRP [mg/l] * 155 (1 8) 15 (.68 1,313) Prednisone equivalent [mg/kg/day] *Standardized to ULN of 1 mg/l.34 (. 1.) [8% steroid free].1 (.9 1.) [3% steroid free] 9 (n=43) Completed (n=37) 86.% Randomized (N=84) Discontinued (n=6) 14.% (n=41) Completed (n=4) 9.8% Discontinued (n=37) 9.% The sole reason for early discontinuation in both groups was unsatisfactory therapeutic effect 1 Study 1: Adapted ACR Pediatric Response Study 1: Change of JIA Core Set Variables 1 8 Primary endpoint 83.7* Day 15 1 Day * * ACR3 ACR5 ACR1 5 Median number of joints with active disease Median score of the physician global assessment of SJIA Activity (VAS) * 3.6* Primary endpoint Baseline Day 15 Day Baseline Day 3 Day 15 Day 9 n *P <.1; P =.1 canakinumab versus placebo 11 n= n= and placebo data should be interpreted within the context of their different observation periods (9 vs. 8 days). Error bars represent interquartile ranges 1

3 KM-Estimates: % of patients without flare Percentage of steroid- treated patients in Part I 11/7/11 Study 1: Change of JIA Core Set Variables Study 1: Safety Data Median CHAQ Baseline Day 15 Day Median CRP (mg/l) n= n= Baseline Day 3 Day 15 Day 9 and placebo data should be interpreted within the context of their different observation periods (9 vs. 8 days). Error bars represent interquartile ranges [n=43], n (%) [n=41], n (%) No. of patients with adverse events (AEs) 4 (55.8) 16 (39.) Infections and infestations 13 (3.) 5 (1.) Gastrointestinal disorders 7 (16.3) (4.9) Skin and subcutaneous tissue disorders 6 (14.) 1 (.4) Nervous system disorders 4 (9.3) 1 (.4) Respiratory, thoracic & mediastinal disorders 3 (7.) 1 (.4) Most common AEs with canakinumab: diarrhea, nasopharyngitis, and upper respiratory tract infection (n=3, 7% for each AE). No discontinuations due to a AE in either group. No injection-site reactions reported with canakinumab. serious AEs in each group: : 1 each; varicella, MAS : 1 each; gastroenteritis, MAS 14 Study : Primary Objectives Part I: To assess if canakinumab allows tapering of steroids in at least 5% of patients entering the study on steroids. Part II: To demonstrate that the time to flare is longer in patients on canakinumab than those receiving placebo. Prednisone 1 mg/kg/day Months 4 mg/kg/mo sc (n=177) Part I Open label Single arm Prednisone..5 mg/kg/day 7 8 (n=5) 4 mg/kg/mo sc (n=5) Part II Randomized, double-blind, placebo controlled flare withdrawal Until 37 flares have occurred 4 mg/kg/mo sc (n=119) Long-term extension 15 Study : Part I - Primary Efficacy Outcome 18 of 177 SJIA patients who entered Part I were on steroids 1% 9% 8% 7% 6% 5% 4% 3% % 1% % 1.% All patients who entered Part I on steroids (N=18) 3.8% Discontinued steroids (n=4) 44.5% (57/18) of these patients decreased or stopped steroids by month 7 (p <.1) 11.7% Decreased steroids (n=15) 55.5% Stable steroids (n=74) Study : Part II - Primary Efficacy Outcomes Study : Safety Data (Part I) (n=5) p <.43 (n=5) Study Day Based on K-M analysis,nearly 3 times as many patients on placebo as compared to those on canakinumab experienced a flare: 7% vs. 75%; p <.43 Median time to flare in the placebo group was 36 days (95% CI: ; p <.43) 17 [N=177], n (%) No. of patients with adverse events (AEs) 138 (78.) Infections & infestations 97 (54.8) Gastrointestinal disorders 5 (9.4) Respiratory, thoracic & mediastinal disorders 37 (.9) Skin & subcutaneous tissue disorders 33 (18.6) Musculoskeletal & connective tissue disorders 9 (16.4) Most common AEs were nasopharyngitis (15%), headache (13%), and cough (11%). 5 patients discontinued due to an AE. 14 patients reported a serious AE; most were due to infections, MAS, or flare-associated events. One patient died due to MAS. 18 3

4 11/7/11 Study : Safety Data (Part II) [N=5], n (%) * [N=5], n (%) No. of patients with adverse events (AEs) 4 (8.) 35 (7.) Infections & infestations 7 (54.) 19 (38.) Musculoskeletal & connective tissue disorders 17 (34.) 1 (.) Gastrointestinal disorders 15 (3.) 15 (3.) Respiratory, thoracic & mediastinal disorders 13 (6.) 1 (4.) Skin & subcutaneous tissue disorders 11 (.) 13 (6.) *After canakinumab [half-life of 6 days] Most common AEs in the canakinumab group were arthralgia (4%), cough (16%), nasopharyngitis (14%), and fever (14%). 6 patients (all in the placebo group) discontinued due to an AE. 6 patients in each group reported a serious AE; most were due to infections, MAS, or flare-associated events. One patient died due to MAS (5 months on placebo). 19 Conclusions A single dose of canakinumab has superior efficacy to placebo in SJIA patients with fever, providing rapid onset of action and a robust response in the majority of patients. Monthly dosing of canakinumab (4mg/kg/mo) significantly reduces the risk of flare and allows for successful steroid tapering/discontinuation. In the Phase III program, canakinumab shows an acceptable safety and tolerability profile. Infections predominantly of the upper respiratory tract, some serious, were the most frequent AEs reported. MAS was observed with equal frequency in the canakinumab and placebo groups in Study 1 and was also observed in Study. Ongoing longer-term studies will further evaluate the role of canakinumab for the treatment of SJIA. Primary Study Objective: Demonstrate Superiority Of Over Back up slides Primary objective To demonstrate that the proportion of patients who met the adapted ACR Ped3 criteria at Day 15, was higher with canakinumab than with placebo Main secondary objectives Demonstrate efficacy of canakinumab compared with placebo, with respect to: Adapted ACR Ped3 criteria at Day 9 Adapted ACR Ped5, 7, 9 and 1 criteria at Days 15 and 9 % of patients with 38 C body temp at Day 3 Overall pain over the last week assessed on a 1 mm VAS at Days 15 and 9 Change in disability over time as measured by CHAQ Evaluate safety and tolerability of canakinumab 1 G35: Day 15 Modified ACR Ped Responses in Patients who Previously Failed Anakinra [n=43], n (%) [n=41], n (%) Previous anakinra use 6 (14.) 3 (7.3) ACR Ped responders at Day 15 ACR Ped3 () () ACR Ped5 (4.7) () ACR Ped7 1 (.3) () ACR Ped1 (4.7) () 3 Baseline demographics and characteristics: groups were comparable and represented moderate disease Gender, n (%) n=43 n=41 Male 16 (37) 18 (44) Female 7 (63) 3 (56) Mean years of age [± SD]; n (%) 8.3 [± 5.1] 9.7 [± 4.3] <4 9 (1) () 4 <6 8 (19) 7 (17) 6 <1 14 (33) (54) 1 < 1 (8) 1 (9) Mean years from SJIA diagnosis to study entry [± SD] 3.1 (n=9) [±.9] 3.6 (n=7) [± 3.6] Mean CRP, mg/l (nl range 1 mg/l) [± SD] 6 [± 16.7] 195 [± 17.4] Mean number of active joints [± SD] 15.7 [± 15.3] 1.4 [± 1.] < 6 active joints (n,%) 34 (79.1) 36 (87.8) > 6 active joints (n,%) 9 (.9) 5 (1.) Median prednisone equivalent dose (mg/kg/d).34 (n=31).1 (n=8) Steroid free (n,%) 1 (7.9) 13 (31.7) < oral prednisone.4 mg/kg/day equivalent (n,%) 1 (48.8) (48.8) >.4 mg/kg/day oral prednisone equivalent (n,%) 1 (3.3) 8 (19.5) 4 4

5 Pain intensity VAS score (mm) Mean number of joints involved 11/7/11 Provided A Significant & Rapid Improvement In Patient Pain Intensity Statistics performed on least squares (LS) means Mean patient pain intensity (VAS 1) over time 66.7 Baseline Day 15 Day * * * P < n= n= data should be interpreted with caution because of high discontinuation rate of non-responders 5 Improved Number Of Active Joints & Joints With Limited ROM Number of active joints and limited ROM over time Active arthritis Limited ROM Baseline Day 15 Day 9 Baseline Day 15 Day 9 n = 43 associated 41 with: 38 n = % and 7% reduction in active joints at Days 15 and 9, respectively 63% and 68% reduction in no. joints with limited ROM at Days 15 and 9, respectively Statistical analysis not performed 6 Safety Data Safety Data [N=43], n (%) No discontinuations due to a AE in either group Two serious AEs reported in each group: : Varicella; MAS : Gastroenteritis; MAS No injection-site reactions reported with canakinumab [N=41], n (%) Total patient-years exposure (years) Patients with at least 1 adverse event (AE) 4 (55.8) 16 (39.) Patients with at least 1 serious AE (SAE) (4.7) (4.9) Patients with at least 1 infection/infestation 13 (3.) 5 (1.) and placebo data should be interpreted within the context of their different observation periods 7 [n=43], n (%) No discontinuations due to AEs in any group Two serious AEs reported in each group: : Varicella; MAS : Gastroenteritis; MAS No injection-site reactions reported with canakinumab [n=41], n (%) Patients with an adverse event (AE) 4 (55.8) 16 (39.) (.5% of patients in either group) Infections and infestations 13 (3.) 5 (1.) Gastrointestinal disorders 7 (16.3) (4.9) Skin and subcutaneous tissue disorders 6 (14.) 1 (.4) Nervous system disorders 4 (9.3) 1 (.4) Respiratory, thoracic and mediastinal disorders 3 (7.) 1 (.4) General disorders and administration site conditions (4.7) 1 (.4) Musculoskeletal and connective tissue disorders (4.7) (4.9) Investigations 1 (.3) (4.9) 8 Key Newly Occurring Notable Laboratory Abnormalities 31: SAE by primary system organ class (Part II) Leukocytosis ( 1.x ULN) Low hemoglobin (<8.5 g/dl [<16 years] or <1 g/dl [ 16 years]) [N=43], n (%) [N=41], n (%) (4.8) 4 (9.8) 3 (7.1) 3 (7.3) Platelet count (<LLN) (4.8) 1 (.6) Clinically relevant transaminitis 1 (>3x ULN) Clinically relevant neutropenia (ANC <1 cells/mm 3 ) 1 One case of MAS, 1 non-responder (4.7)* (.) (.) (.) 9 Equal number of patients with SAEs in treatment groups and similar pattern of SAE SOCs canakinumab N=5 n (%) N=5 N (%) Patients with SAE(s) 6 (1.) 6 (1.) Infections and infestations (4.) (4.) Respiratory tract infection 1 (.) (.) Investigations (4.) (.) Blood and lymphatic system disorders 1 (.) (.) Injury, poisoning and procedural complications 1 (.) (4.) Musculoskeletal and connective tissue disorders 1 (.) (4.) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 1 (.) 1 (.) Respiratory, thoracic and mediastinal disorders 1 (.) 1 (.) Cardiac disorders (.) 1 (.) Gastrointestinal disorders (.) 1 (.) Renal and urinary disorders (.) 1 (.) Skin and subcutaneous tissue disorders (.) 1 (.) 3 5

6 11/7/11 31: Macrophage Activation Syndrome 5 MAS adverse events were reported during the trial 4 during open-label (canakinumab) Part I considered life threatening 1 occurred during part Ic 15 yo female developed MAS from acute EBV infection weeks after 1 st CS dose reduction in part Ic. Recovered from MAS and discontinued from trial because of it. 1 occurred at end of part Ib 13 yo male developed severe MAS with fatal pulmonary HTN and sepsis weeks after recovered from SAE adnovirus gastroenteritis. Patient died from pulmonary HTN cases not considered life threatening 4 yo female with SAE Left lower lobe pneumonia on Day 15. Developed loculated pleural abscess requiring chest tube drainage. Labs consistent with developing MAS. Full recovery 17 yo female with UTI on Day 7 which was successfully treated with antibioctics. She developed signs/symptoms consistent with developing MAS 1 week later. Fully recovery 1 in a placebo patient in Part II Considered life threatening 14 yo female with h/o nephrolithiasis developed UTI at Month 3 of Part II which did not get treated for 3 weeks. She presented with urosepsis and developing MAS. She died days after leaving trial. 31 Conclusions single injection: Demonstrated a clinically meaningful improvement in all efficacy parameters: Primary endpoint: ACR3 at Day 15 (83% canakinumab vs 9.8% placebo; P <.1) Main secondary endpoints: ACR 5/7/9/1 at Days 15 and 9 (all P.1) Pain intensity (P <.1) CHAQ disability score (P =.) No. of active joints and joints with limited ROM CRP: improvement seen as early as Day 3 High response rate in patients with history of anakinra non-response Demonstrated acceptable safety and tolerability in this short-term study No difference between groups in number of serious AEs reported No study discontinuation due to AEs No injection-site reactions in canakinumab group 3 Phase II Study 13 of enrolled subjects (59%) experienced a substantial clinical benefit at Day 15 (ACR Pedi 5) 4 of enrolled subjects (18%) achieved inactive disease at Day 15 Therapeutic effect was sustained over time Steroids tapered in 7% of responders Acceptable safety/tolerability profile Recommended dose 4 mg/kg/month subcutaneously 33 6