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Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
Daclizumab Selection Slides ECTRIMS 2012
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Daclizumab Selection Slides ECTRIMS 2012

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  • 1. Primary Results of the SELECTION Trial of Daclizumab HYP in Relapsing Multiple Sclerosis 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
  • 2. Disclosures• This study was supported by Biogen Idec and Abbott • Eva Havrdova: Has received speakers’ honoraria Biotherapeutics Corp. 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 • Randy Robinson: Full-time employee of Abbott Novartis. Biotherapeutics. • Manjit McNeill, Jitesh Rana, Jacob Elkins, and Gilmore O’Neill: Full-time employees of Biogen Idec. 2
  • 3. Hypothesized Immunomodulatory Effect of Daclizumab Treatment1. 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
  • 4. 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 150mg Baseline Year 1 End of washout Year 2 * RandomizationAll DAC HYP treatments were subcutaneous (SC) injections every 4 weeks.
  • 5. 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
  • 6. Accounting of subjects Placebo + Placebo + DAC HYP DAC HYP DAC HYP DAC HYP TOTAL DAC HYP DAC HYP 150 mg + 150 mg 300 mg + 300 mg 150 mg 300 mg Washout for 2 yrs Washout for 2 yrsNumber randomized 86 84 86 86 88 87 517in SELECTIONPercent of subjects 89% 95% 86% 88% 88% 84% 88%who completed studytreatmentPercent of subjects 92% 95% 89% 91% 92% 89% 91%who completed 1year treatment phase
  • 7. 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
  • 8. Reduced annualized relapse rate after initiation of DAC HYP 0.5 0.45 ARR=0.434 (0.347,0. 544) 0.4 ARR Reduction = 59% 0.35 P<0.001Annualized relapse rate 0.3 0.25 0.2 ARR=0.179 (0.123, 0.261) 0.15 0.1 0.05 0 Placebo (Year 1) DAC HYP (Year 2) n=163 n=163
  • 9. Reduced confirmed 3-month disability progression after initiation of DAC HYP 12% 10%Percent of patients with confirmed 10% disability progression 8% Reduction = 50% P = 0.033 6% 5% 4% 17 subjects 7 subjects 2% with progression with progression 0% Year 1 Year 2 Placebo DAC HYP n=163 n=163
  • 10. Reduced number of new MRI lesions after initiation of DAC HYP 9 New/enlarging T2 lesions New Gd+ T1 lesions 8.0 (9.5) 8Number of new MRI lesions (mean) 7 6 Reduction in new or 5 = 74% newly enlarging T2 Lesions 4 3 2.1 (3.7) 2 Reduction in 1.4 (2.4) = 86% Gd+ Lesions 1 0.2 (0.8) 0 Year 1 Year 2 Year 1 Year 2 Placebo DAC HYP Placebo DAC HYP n=162 n=156 n=163 n=163
  • 11. 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
  • 12. 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 pbo SELECT pbo 0.148 (0.096, 0.229) Year 1 Year 1 Year 2 Placebo DAC HYP DAC HYP 12 n=163 n=129 n=129
  • 13. Low rate (12%) of confirmed disability progression over 2 years of DAC HYP treatment 0.3 PlaceboProportion of patients with confirmed disability progression DAC HYP continuous 0.2 13% 50% risk reduction 0.1 (95% CI, 12-71%; P=0.015) 6% DAC HYP Placebo 0.0 0 3 6 9 12 15 18 21 24 Time on study (months)
  • 14. Low rate (12%) of confirmed disability progression over 2 years of DAC HYP treatment 0.3 PlaceboProportion of patients with confirmed disability progression DAC HYP continuous DAC HYP after placebo 0.2 Placebo patients start DAC HYP 16% DAC HYP 13% 12% 0.1 DAC HYP 6% Placebo 0.0 0 3 6 9 12 15 18 21 24 Time on study (months)
  • 15. Reduction in new/newly enlarging T2 lesions was stronger during year 2 of DAC HYP treatment 9 8.2 (9.3) Fewer new T2 lesions in Year 2 vs. Year 1 of DAC HYP (P=0.032) 8 7Number new T2 lesions (mean) 6 Year 1 Year 1 76% reduction 79% reduction 5 vs. SELECT pbo vs. SELECT pbo 4 Year 2 Year 2 83% reduction 88% reduction vs. SELECT pbo vs. SELECT pbo 3 2.0 (4.0) 2 1.7 (3.6) 1.4(5.3) 1.0 (3.1) 1 0 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
  • 16. 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 150mg16
  • 17. After 24-week washout from DAC HYP, GD+ lesions were below pre-treatment baseline 2 1.9 End of 24 week washout 1.8 1.6Number New Gd+ Lesions (mean) End of 24 week washout 1.4 1.2 1.2 Baseline 1.2 Wk 24 1 0.9 Wk 52 0.8 End of 24-wk washout 32-wks after restart 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
  • 18. Safety Results18
  • 19. Adverse event summary DAC HYP Starters DAC HYP Continuous DAC HYP Washout / Year 1 of DAC HYP Year 2 of DAC HYP Reinitiation DAC HYP DAC HYP DAC HYP DAC HYP DAC HYP DAC HYP 150 mg 300 mg 150 mg 300 mg 150 mg 300 mg (n=86) (n=84) (n=86) (n=87) (n=86) (n=88)Any adverse event 71% 68% 66% 71% 81% 69%Any seriousadverse event 15 (17) 11 (13) 15 (17) 11 (13) 18 (21) 15 (17)Any seriousadverse event 7 (8) 4 (5) 6 (7) 7 (8) 6 (7) 4 (5)excluding MSrelapseDeath, n 0 0 0 0 0 1** One patient died due to autoimmune hepatitis prior to implementation of hepatic monitoring rules 19
  • 20. Adverse events of interest DAC HYP Starters DAC HYP Continuous DAC HYP Washout / Year 1 of DAC HYP Year 2 of DAC HYP Reinitiation DAC HYP DAC HYP DAC HYP DAC HYP DAC HYP DAC HYP 150 mg 300 mg 150 mg 300 mg 150 mg 300 mg (n=86) (n=84) (n=86) (n=87) (n=86) (n=88)Serious Infections, n 3 1 2 2 3 2Serious CutaneousEvents, n 2 0 0 3 1 0ALT/AST > 5x ULN, n 1 1 0 2 1 3Other SeriousImmune-Mediated 0 0 0 2 0 1Adverse Events, nMalignancy, n 0 1 0 0 0 0 20
  • 21. PD Results21
  • 22. CD56bright NK cell counts plateaued during second year of DAC HYP treatment 100CD56bright NK cell count (cells/mm 3) N=114 Median (25-75 th percentiles) 80 60 40 20 0 0 1 2 4 6 8 12 13 14 18 26 Time (months)
  • 23. SummaryEvidence for high efficacy in subjects initiating DAC HYP• 59% reduction in ARR after treatment start vs. year 1 pbo phase (p<0.001)• 50% reduction in EDSS progression after treatment start vs. year 1 pbo 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 washoutPharmacodynamic changes plateau by second year of treatmentSafety 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 150mg continuous group
  • 24. 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 Abbott Biotherapeutics Corp. 24

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