The Safety and Efficacy of Daclizumab HYP inRelapsing-Remitting Multiple Sclerosis in theSELECTION Extension Study: Primary ResultsDr Gavin Giovannoni, MBBCh, PhD, FRCP, FRCPathJune 10, 2013Gavin Giovannoni1, Ralf Gold2, Krzysztof Selmaj3, Eva Havrdova4,Xavier Montalban5, Ernst-Wilhelm Radue6, Dusan Stefoski7,Manjit McNeill8, Jitesh Rana8, Jacob Elkins8, and Gilmore O’Neill81Queen Mary University of London, Barts and The London School of Medicine andDentistry, 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, USAEuropean Neurological Society23rd MeetingBarcelona, Spain
Disclosures2 This study was supported by Biogen Idec and AbbVieBiotherapeutics. Gavin Giovannoni: Has received research grantsupport from Bayer Schering Healthcare, BiogenIdec, GW Pharma, Merck Serono, Merz, Novartis,Teva and sanofi-aventis. Dr Giovannoni has receivedpersonal compensation for participating on AdvisoryBoards in relation to clinical trial design, trial steeringcommittees and data and safety monitoringcommittees from: Bayer Schering Healthcare, BiogenIdec, Eisai, Elan, Five Prime Therapeutics, Genzyme,Genentech, GSK, Ironwood Pharma, Merck Serono,Novartis, Pfizer, Roche, sanofi-aventis, Synthon BV,Teva, UCB Pharma and Vertex Pharmaceuticals. Ralf Gold: Has received speakers’ honoraria andresearch grant support from Bayer ScheringHealthcare, Biogen Idec, Merck Serono, Merz,Novartis, Teva and sanofi-aventis. Dr Gold hasreceived compensation for Advisory Board activitiesfrom Biogen Idec, Merck Serono, Novartis and TEVA Krzysztof Selmaj: Has received speaker’s honorariafrom Novartis, Merck Serono, Gedeon Richter, ONOPharma, and Biogen Idec. Dr Selmaj has receivedpersonal compensation for participation in AdvisoryBoards and steering committees from Biogen Idec,Roche, Genzyme, ONO Pharma, Merck Serono, andNovartis. Eva Havrdova: Has received speakers’ honorariaand research grant support from Bayer ScheringHealthcare, Biogen Idec, Genzyme, Merck Serono,Novartis, and Teva. Dr Havrdova has receivedcompensation for Advisory Board activities fromBiogen Idec, Genzyme, Merck Serono, Novartis andTEVA. Xavier Montalban: Has received speaking honorariaand travel expenses for speaking and scientificmeetings, has been a steering committee member ofclinical trials or participated in advisory boards ofclinical trials in the past years with Bayer ScheringPharma, Biogen Idec, EMD Merck Serono,Genentech, Genzyme, Novartis, sanofi-aventis, TevaPharmaceuticals, Almirall and BTG. Ernst-Wilhelm Radue: Has received researchsupport (mainly for MS projects) and lecture feesfrom: Actelion, Basilea, Bayer Schering, Biogen Idec,Merck Serono, Novartis and others. Lecture feeshave been mainly used for research funding at theMedical Image Analysis Center (former MS MRIEvaluation Center), University Hospital Basel Dusan Stefoski: Has received research funding andsupport, and speaker bureau honoraria from: BiogenIdec, EMD Serono, Teva, Pfizer, Elan, and Novartis. Manjit McNeill, Jitesh Rana, Jacob Elkins, andGilmore O’Neill: Full-time employees of Biogen Idec.
Hypothesized ImmunomodulatoryEffect of Daclizumab Treatment31. Bielekova B, et al. Proc Natl Acad Sci USA 2006;103: 5941–5946. 2. Martin J, et al. J Immunol 2010;185:1311–1320.
Study Design of SELECT and SELECTION4 All DAC HYP treatments were subcutaneous (SC) injections every 4 weeks.SELECT: n=621 SELECTION: n=517PlaceboDAC HYP 150mg SC every 4 weeksDAC HYP 300mg SC every 4 WeeksYear 1DAC HYP 150mgDAC HYP 300mgDAC HYP 150mgDAC HYP 300mgDAC HYP 150mgYear 2DAC HYP 300mg24wk wash out24wk wash outDouble-blind Treatment**** RandomizationContinuous 2 y DAC HYP 150mgFirst year of DAC HYPtreatmentContinuous 2 y DAC HYP 300mgWashout/ ReinitiationWashout/ ReinitiationYear 1 Year 2Baseline End of washoutDAC HYP, daclizumab high-yield process
Three Key Objectives in SELECTION51. Safety / Efficacy of DAC HYP in subjects initiating treatment- How does MS activity in year 2 after starting DAC HYP compare to year 1 onplacebo?2. Safety / Efficacy of DAC HYP in subjects treated continuouslyfor 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?PlaceboDAC HYP 150mg SC every 4 weeksDAC HYP 300mg SC every 4 WeeksYear 1DAC HYP 150mgDAC HYP 300mgDAC HYP 150mgDAC HYP 300mgDAC HYP 150mgYear 2DAC HYP 300mg24wk wash out24 wk wash out
Reduced Confirmed Disability Progression after1-year of DAC HYP9Reduction = 54%P = 0.03318 subjectswith progressionYear 1 Year 28 subjectswith progressionPlacebon=163DAC HYPn=163PercentofpatientswithconfirmeddisabilityprogressionSustained 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 froma 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 Lesionsafter 1-year of DAC HYP101.4 (2.4)2.1 (3.7)8.0 (9.5)0.2 (0.8)Year 1 Year 2 Year 1 Year 2Placebon=162DAC HYPn=156Placebon=163DAC HYPn=163New/enlarging T2 lesions New Gd+ T1 lesionsReduction inGd+ Lesions= 86%Gd+, gadolinium enhancing T1 lesionsReduction innew ornewly enlargingT2 Lesions= 74%
Efficacy of DAC HYP in Subjects TreatedContinuously for 2 years11SELECT SELECTIONDAC HYP 150mg SC every 4 weeksDAC HYP 300mg SC every 4 weeksWeeks 0-52 Weeks 0-52DAC HYP 300mg SC every 4 weeksDAC HYP 150mg SC every 4 weeks
Reduction in ARR was Sustained duringYear 2 of DAC HYP Treatment120.434(0.347, 0.544)Year 2 of DAC HYP62% reduction vs.SELECT placeboYear 1 of DAC HYP66% reduction vs.SELECT placebo0.148(0.096, 0.229)Placebon=163Year 1 Year 1 Year 2DAC HYPn=129DAC HYPn=129AnnualizedRelapseRate
Confirmed Disability Progressionover 2 Years of DAC HYP Treatment1350% risk reduction(95% CI, 12-71%; P=0.015)0.00.10.20.3DAC HYP continuous0 12 2463 9 15 18 21DAC HYPPlaceboPlacebo16%12%DAC HYPDAC HYP after placebo6%13%Placebo patients startDAC HYPTime on study (months)ProportionofpatientswithconfirmeddisabilityprogressionDAC HYPSustained 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 froma 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 LesionsDuring Year 2 of DAC HYP treatment142.0 (4.0)1.7 (3.6)1.4(5.3)1.0 (3.1)8.2 (9.3)Year 176% reduction vs.SELECT placeboYear 283% reduction vs.SELECT placeboYear 179% reduction vs.SELECT placeboYear 288% reduction vs.SELECT placeboFewer new T2 lesions in Year 2 vs.Year 1 of DAC HYP (P=0.032)DAC HYP 150 mgYear 1n=195Year 1n=64Year 2n=63Year 1n=64Year 2n=65Placebo DAC HYP 300 mgNumbernewT2lesions(mean)
Impact of Washout / Re-initiation of DAC HYP15SELECT SELECTIONDAC HYP 150mg SC every 4 weeksDAC HYP 300mg SC every 4 weeksWeeks 0-52 Weeks 0-52DAC HYP 150mgWashoutDAC HYP 300mgWashout
After 24-Week Washout from DAC HYP,Gd+ Lesions were Below Pre-treatment Baseline184.108.40.206.220.127.116.11.90.2 0.200.20.40.60.818.104.22.168.82 BaselineWk 24Wk 52End of 24-wk washout32-wks after restartDAC HYP 300 mgDAC HYP 150 mgEnd of 24 week washoutEnd of 24 week washoutNumberNewGd+Lesions(mean)Year 1 Year 2 Year 1 Year 2
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 1placebo phase (P=0.033)Evidence for sustained efficacy in subjects continuing on DACHYP 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 treatmentand 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 2of 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-Caen24This study was supported by Biogen Idec and AbbVie Biotherapeutics. Ed Parr of UBC ScientificSolutions provided editorial support to the authors in the development of this presentation, whichwas funded by Biogen Idec and AbbVie Biotherapeutics.