American Academy of Neurology 65th Annual Meeting San Diego, CaliforniaThe Safety and Efficacy of Daclizumab HYP inRelapsing-Remitting Multiple Sclerosis in theSELECTION Extension Study: Primary ResultsDr Gavin Giovannoni, MBBCh, PhD, FRCP, FRCPathMarch 19, 2013 Gavin Giovannoni1, Ralf Gold2, Krzysztof Selmaj3, Eva Havrdova4, Xavier Montalban5, Ernst-Wilhelm Radue6, Dusan Stefoski7, Manjit McNeill8, Jitesh Rana8, Jacob Elkins8, and Gilmore O’Neill8 1Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK; 2St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany; 3Medical University of Lodz, Lodz, Poland; 4Charles University in Prague, Prague, Czech Republic; 5Hospital Vall dHebron University, Barcelona, Spain; 6University Hospital Basel, Basel, Switzerland. 7Rush University Medical Center, Chicago, IL. USA; 8Biogen Idec, Cambridge, MA, USA
Disclosures This study was supported by Biogen Idec and AbbVie Eva Havrdova: Has received speakers’ honoraria Biotherapeutics. and research grant support from Bayer Schering Gavin Giovannoni: Has received research grant Healthcare, Biogen Idec, Genzyme, Merck Serono, support from Bayer Schering Healthcare, Biogen Novartis, and Teva. Dr Havrdova has received Idec, GW Pharma, Merck Serono, Merz, Novartis, compensation for Advisory Board activities from Teva and sanofi-aventis. Dr Giovannoni has received Biogen Idec, Genzyme, Merck Serono, Novartis and personal compensation for participating on Advisory TEVA. Boards in relation to clinical trial design, trial steering Xavier Montalban: Has received speaking honoraria committees and data and safety monitoring and travel expenses for speaking and scientific committees from: Bayer Schering Healthcare, Biogen meetings, has been a steering committee member of Idec, Eisai, Elan, Five Prime Therapeutics, Genzyme, clinical trials or participated in advisory boards of Genentech, GSK, Ironwood Pharma, Merck Serono, clinical trials in the past years with Bayer Schering Novartis, Pfizer, Roche, sanofi-aventis, Synthon BV, Pharma, Biogen Idec, EMD Merck Serono, Teva, UCB Pharma and Vertex Pharmaceuticals. Genentech, Genzyme, Novartis, sanofi-aventis, Teva Ralf Gold: Has received speakers’ honoraria and Pharmaceuticals, Almirall and BTG. research grant support from Bayer Schering Ernst-Wilhelm Radue: Has received research Healthcare, Biogen Idec, Merck Serono, Merz, support (mainly for MS projects) and lecture fees Novartis, Teva and sanofi-aventis. Dr Gold has from: Actelion, Basilea, Bayer Schering, Biogen Idec, received compensation for Advisory Board activities Merck Serono, Novartis and others. Lecture fees from Biogen Idec, Merck Serono, Novartis and TEVA have been mainly used for research funding at the Krzysztof Selmaj: Has received speaker’s honoraria Medical Image Analysis Center (former MS MRI from Novartis, Merck Serono, Gedeon Richter, ONO Evaluation Center), University Hospital Basel Pharma, and Biogen Idec. Dr Selmaj has received Dusan Stefoski: Has received research funding and personal compensation for participation in Advisory support, and speaker bureau honoraria from: Biogen Boards and steering committees from Biogen Idec, Idec, EMD Serono, Teva, Pfizer, Elan, and Novartis. Roche, Genzyme, ONO Pharma, Merck Serono, and Manjit McNeill, Jitesh Rana, Jacob Elkins, and Novartis. Gilmore O’Neill: Full-time employees of Biogen Idec.2
Hypothesized Immunomodulatory Effect of Daclizumab Treatment 1. Bielekova B, et al. Proc Natl Acad Sci USA 2006;103: 5941–5946. 2. Martin J, et al. J Immunol 2010;185:1311–1320.3
Study Design of SELECT and SELECTION Double-blind Treatment SELECT: n=621 SELECTION: n=517 Year 1 Year 2 DAC HYP 300mg Placebo * First year of DAC HYP treatment DAC HYP 150mg 24wk wash out DAC HYP 300mg Washout/ Reinitiation DAC HYP 300mg SC every 4 Weeks * DAC HYP 300mg Continuous 2 y DAC HYP 300mg 24wk wash out DAC HYP 150mg Washout/ Reinitiation DAC HYP 150mg SC every 4 weeks * DAC HYP 150mg Continuous 2 y DAC HYP 150mgBaseline Year 1 End of washout Year 2 * Randomization4 All DAC HYP treatments were subcutaneous (SC) injections every 4 weeks. DAC HYP, daclizumab high-yield process
Three Key Objectives in SELECTION Year 1 Year 2 DAC HYP 300mg Placebo DAC HYP 150mg 24wk wash out DAC HYP 300mg DAC HYP 300mg SC every 4 Weeks DAC HYP 300mg 24 wk wash out DAC HYP 150mg DAC HYP 150mg SC every 4 weeks DAC HYP 150mg1. Safety / Efficacy of DAC HYP in subjects initiating treatment - How does MS activity in year 2 after starting DAC HYP compare to year 1 on placebo?2. Safety / Efficacy of DAC HYP in subjects treated continuously for 2-years - Are effects maintained in year 2 of treatment compared to year 1?3. Impact of washout period - Rebound disease activity? - Safety/efficacy after treatment re-initiation?5
Efficacy of DAC HYP in Subjects Initiating Treatment SELECT SELECTION Weeks 0-52 Weeks 0-52 DAC HYP 300mg SC every 4 weeks Placebo DAC HYP 150mg SC every 4 weeks Wash Out DAC HYP 300mg DAC HYP 300mg SC every 4 Weeks DAC HYP 300mg Wash Out DAC HYP 150mg DAC HYP 150mg SC every 4 weeks DAC HYP 150mg7
Reduced Annualized Relapse Rate after 1-year of DAC HYP ARR=0.434 (0.347,0. 544) ARR Reduction = 59% P<0.001 ARR=0.179 (0.123, 0.261) Year 1 Year 2 Placebo DAC HYP n=163 n=1638 ARR, annualized relapse rate
Reduced Confirmed Disability Progression after 1-year of DAC HYP confirmed disability progression Reduction = 54% P = 0.033 Percent of patients with 18 subjects 8 subjects with progression with progression Year 1 Year 2 Placebo DAC HYP n=163 n=163Sustained progression is defined as at least a 1.0 point increase on the EDSS from a SELECT baseline EDSS >= 1.0 sustained for 3 months or at least a 1.5 point increase on the EDSS from 9a SELECT baseline EDSS of 0 sustained for 3 months. A cutoff of 74 days was used to determine sustained progression for 3 months.
Reduction in Number of New MRI Lesions after 1-year of DAC HYP New/enlarging T2 lesions New Gd+ T1 lesions 8.0 (9.5) Reduction in new or = 74% newly enlarging T2 Lesions Reduction in = 86% Gd+ Lesions 2.1 (3.7) 1.4 (2.4) 0.2 (0.8) Year 1 Year 2 Year 1 Year 2 Placebo DAC HYP Placebo DAC HYP n=162 n=156 n=163 n=16310 Gd+, gadolinium enhancing T1 lesions
Efficacy of DAC HYP in Subjects Treated Continuously for 2 years SELECT SELECTION Weeks 0-52 Weeks 0-52 DAC HYP 300mg SC every 4 weeks DAC HYP 300mg SC every 4 weeks DAC HYP 150mg SC every 4 weeks DAC HYP 150mg SC every 4 weeks11
Reduction in ARR was Sustained during Year 2 of DAC HYP Treatment 0.434 (0.347, 0.544)Annualized Relapse Rate Year 1 of DAC HYP Year 2 of DAC HYP 66% reduction vs. 62% reduction vs. SELECT placebo SELECT placebo 0.148 (0.096, 0.229) Year 1 Year 1 Year 2 Placebo DAC HYP DAC HYP 12 n=163 n=129 n=129
Confirmed Disability Progression over 2 Years of DAC HYP Treatment Proportion of patients with confirmed disability progression 0.3 Placebo DAC HYP continuous DAC HYP after placebo 0.2 Placebo patients start DAC HYP 16% DAC HYP 13% 12% 50% risk reduction 0.1 (95% CI, 12-71%; P=0.015) DAC HYP Placebo 6% DAC HYP 0.0 0 3 6 9 12 15 18 21 24 Time on study (months)Sustained progression is defined as at least a 1.0 point increase on the EDSS from a SELECT baseline EDSS >= 1.0 sustained for 3 months or at least a 1.5 point increase on the EDSS from 13a SELECT baseline EDSS of 0 sustained for 3 months. A cutoff of 74 days was used to determine sustained progression for 3 months.
Reduction in New/Newly Enlarging T2 Lesions During Year 2 of DAC HYP treatment 8.2 (9.3)Number new T2 lesions (mean) Fewer new T2 lesions in Year 2 vs. Year 1 of DAC HYP (P=0.032) Year 1 Year 1 76% reduction vs. 79% reduction vs. SELECT placebo SELECT placebo Year 2 Year 2 83% reduction vs. 88% reduction vs. SELECT placebo SELECT placebo 2.0 (4.0) 1.7 (3.6) 1.4(5.3) 1.0 (3.1) Year 1 Year 1 Year 2 Year 1 Year 2 n=195 n=64 n=65 n=64 n=63 Placebo DAC HYP 150 mg DAC HYP 300 mg 14
Impact of Washout / Re-initiation of DAC HYP SELECT SELECTION Weeks 0-52 Weeks 0-52 DAC HYP 300mg SC every 4 weeks Washout DAC HYP 300mg DAC HYP 150mg SC every 4 weeks Washout DAC HYP 150mg15
After 24-Week Washout from DAC HYP,Gd+ Lesions were Below Pre-treatment Baseline 2 1.9 Baseline Wk 24 1.8 End of 24 week washout Wk 52 1.6 End of 24-wk washoutNumber New Gd+ Lesions (mean) 1.4 32-wks after restart 1.2 1.2 1.2 End of 24 week washout 1 0.9 0.8 0.6 0.5 0.4 0.4 0.2 0.2 0.2 0.2 0.2 0 DAC HYP 150 mg DAC HYP 300 mg Year 1 Year 2 Year 1 Year 2 16
CD56bright NK Cell Counts During Washout and Continuous DAC HYP treatment 100 CD56 bright NK cell count (cells/mm 3) 2-Year Continuous Treatment With 24-Week Washout Median (25 th-75th percentiles) 80 60 40 20 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 Time (Weeks)21 NK, natural killer
Summary (1)Evidence for high efficacy in subjects initiating DAC HYP 59% reduction in ARR after treatment start vs. year 1 placebo phase (P<0.001) 54% reduction in EDSS progression after treatment start vs. year 1 placebo phase (P=0.033)Evidence for sustained efficacy in subjects continuing on DAC HYP for 2 years In subjects randomized to DAC HYP for 2 years • ARR (0.15 in year 1; 0.17 in year 2) • New T2 lesions at 52 weeks (1.9 in year 1 reduced to 1.2 in year 2, P=0.03)No evidence for disease rebound during DAC washout22
Summary (2)Pharmacodynamic changes plateau by second year of treatment and are reversible over 24-week washoutSafety profile was similar in year 2 compared to year 1 SELECTION vs. SELECT • Serious infections: 2% vs. 2% • Serious cutaneous events: 1.1% vs. 1.0% • New LFT abnormalities >5x ULN: 1.5% vs. 4% • No LFT elevations > 5x ULN or serious cutaneous events in year 2 of DAC HYP 150mg continuous treatment group23
AcknowledgementsSELECTION Study Investigators• Czech Republic: Prof. Zdeněk Ambler, Prof. Ivan Rektor, Dr. Radomir Talab, Prof. Petr Kanovsky, Dr. Pavel Stourac, Dr. Denisa Zimova, Dr. Marta Vachova• Germany: Prof. Dr. Bernd C. Kieseier, Dr. Björn Tackenberg, Prof. Dr. Heinz Wiendl, Prof. Dr. Reinhard Hohlfeld, PD Dr. Klemens Angstwurm, Prof. Dr. Judith Haas, Prof. Dr. Uwe Zettl, Prof. Dr. Florian Stögbauer, Dr. Ralf Linker, Prof. Dr. Andrew Chan, Prof. Dr. Patrick Oschmann• Hungary: Dr. Attila Csányi, Dr. Péter Diószeghy, Dr. János Nikl, Dr. Gyula Pánczel, Dr. Béla Clemens, Dr. Etelka Jófejű, Dr. Attila Valikovics, Dr. István Kondákor, Dr. Dániel Bereczki, Dr. Zsuzsanna Lohner, Prof. Lászlo Csiba, Dr. András Folyovich, Dr . Péter Harcos, Dr. Gabriella Kovács, Dr. Mária Sátori• India: Dr. Rajaram Agarwal, Dr. Pahari Ghosh, Dr. Sangeeta Ravat, Dr. Subhash Mukherjee, Dr. Rustom Wadia, Prof. Kolichana Venkateswarlu, Dr. Meenakshisundaram Umaiorubahan, Prof. Medasari Padma, Dr. Thomas, Dr. A K Meena, Dr. Suresh Kumar• Poland: Dr. Wieslaw Drozdowski, Dr. Waldemar Fryze, Dr. Jan Kochanowicz, Prof. Anna Kaminska, Dr. Krzysztof Selmaj, Dr. Andrzej Szczudlik, Dr. Andrzej Wajgt, Dr. Anna Czlonkowska, Dr. Zbigniew Stelmasiak, Dr. Gabriela Klodowska-Duda, Dr. Janusz Zbrojkiewicz• Romania: Dr. Ovidiu Bajenaru, Dr. Dafin Fior Muresanu, Dr. Mihaela Simu• Russia: Dr. Olga Vorobyeva, Dr. Leonid Zaslavsky, Dr. Sergey Shvarkov, Dr. Miroslav Odinak, Dr. Anna Belova, Dr. Irina Sokolova, Dr. Farit Khabirov, Dr. Natalia Nikolaevna Maslova, Dr. Irina Poverennova, Dr. Nikolay Spirin, Dr. Nadezhda Malkova, Dr. Semen Prokopenko, Dr. Alexey Rozhdestvensky, Dr. Alexei Boiko, Dr. Rim Magzhanov• Turkey: Prof. Sabahattin Saip, Prof. Omer Faruk Turan, Ass. Prof. Serhat Ozkan, Prof. Ayse Sagduyu Kocaman• Ukraine: Dr. Natalia Buchakchyyska, Dr. Natalia Lytvynenko, Dr. Borys Palamar, Dr. Tatyana Nehrych, Dr. Natalia Voloshina, Dr. Larisa Sokolova, Prof. Olexandr Kozyolkin, Dr. Olena Moroz, Prof. Valeriy Pashkovskyy, Dr. Elena Statinova, Dr. Tetjana Kobys, Dr. Igor Pasyura• United Kingdom: Dr. Clive Hawkins, Dr. Basil Sharrack, Dr. Cris Constantinescu, Dr. John Zajicek, Dr. David Bates, Dr. Eli SilberData Safety Monitoring Board: Dr. Volker Limmroth (Chair), Dr. Richard Furie, Dr. Daniel McQuillen, Dr. Raymond Chung, Dr. Richard KayRelapse Adjudication Committee: Dr. Chris Polman, Dr. Ted Phillips, Dr. Paul O’Connor, Dr. Ari Green, Dr. Oliver Lyon-Caen This study was supported by Biogen Idec and AbbVie Biotherapeutics. Ed Parr of UBC Scientific24 Solutions provided editorial support to the authors in the development of this presentation, which was funded by Biogen Idec and AbbVie Biotherapeutics.