Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ASCLEPIOS I and II trials
ECTRIMS Online Library. Hauser S. 09/13/19; 279581; 336
Stephen Hauser
Stephen Hauser
Contributions
Abstract

Abstract: 336

Type: Scientific Session

Abstract Category: Scientific Session 17: Late Breaking News

S.L. Hauser1, A. Bar-Or2, J. Cohen3, G. Comi4, J. Correale5, P.K. Coyle6, A.H. Cross7, J. de Seze8, X. Montalban9,10, K. Selmaj11, H. Wiendl12, A. Goodyear13, D.A. Häring13, C. Kerloeguen13, D. Tomic13, R. Willi13, K. Ramanathan13, M. Merschhemke13, L. Kappos14

1UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, 2Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 3Neurological Institute, Cleveland Clinic, Cleveland, OH, United States, 4University Vita-Salute San Raffaele, Milan, Italy, 5Institute for Neurological Research Dr. Raul Carrea, Buenos Aires, Argentina, 6Stony Brook University, Stony Brook, NY, 7Washington University School of Medicine, Saint Louis, MO, United States, 8University Hospital of Strasbourg, Strasbourg, France, 9St Michael's Hospital, University of Toronto, Toronto, ON, Canada, 10Center d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain, 11Center for Neurology, Lodz, Poland, 12University of Muenster, Muenster, Germany, 13Novartis Pharma AG, 14Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is under development with a monthly 20 mg subcutaneous (sc) dosing regimen for the treatment of multiple sclerosis (MS). Two Phase 3 trials of identical study design, ASCLEPIOS I (NCT02792218) and II (NCT02792231), are being conducted simultaneously to evaluate the effect of ofatumumab in patients with relapsing MS (RMS).
Objective: To investigate the efficacy and safety of ofatumumab versus teriflunomide in RMS patients.
Methods: ASCLEPIOS I and II are double-blind, double-dummy, active comparator-controlled, parallel-group, innovative, adaptive design, multicentre trials. Patients were randomised (1:1) to receive either ofatumumab 20 mg sc injections every 4 weeks (after an initial loading regimen of 20 mg sc doses on Days 1, 7 and 14) or teriflunomide 14 mg orally once daily, for up to 30 months. The studies have flexible durations, with termination occurring in the blinded core treatment epoch according to pre-specified criteria. Patients aged 18-55 years with an Expanded Disability Status Scale (EDSS) score of 0-5.5 at screening who experienced ≥1 relapse in the past year or ≥2 relapses in the past 2 years or a positive gadolinium-enhancing (Gd+) MRI scan during the year before randomisation were included. The primary endpoint is the annualised relapse rate (ARR). Key secondary endpoints include 3- and 6-month confirmed disability worsening (CDW), 6-month confirmed disability improvement (CDI), MRI-related outcomes and serum neurofilament light chain levels; safety and tolerability are also being assessed.
Results: Overall, 1881 patients were randomised in 37 countries (ASCLEPIOS I, N=927; ASCLEPIOS II, N=954). Baseline demographics and disease characteristics were previously reported (mean age, ~38 years; mean MS duration since first symptom, ~8 years; mean EDSS, 2.9; Gd+ lesions, ~40% of patients). The protocol-defined end of study (EOS) criteria were fulfilled based on blinded data: both ASCLEPIOS studies were powered to 90% for the primary endpoint, and the combined studies to 90% for 3mCDW and to 80% for 6mCDW. Hence, the EOS could be planned for beginning of July 2019. Top line efficacy and safety results will be presented at the Congress.
Conclusion: The results of these large controlled Phase 3 trials will elucidate the therapeutic potential of ofatumumab 20 mg, the first B-cell therapy that is subcutaneous and self-administered every 4 weeks, in RMS patients.
Disclosure: This study was funded by Novartis Pharma AG, Basel, Switzerland
Stephen L. Hauser serves on boards for Annexon, Alector, Symbiotix, Bionure and Neurona; he has also received travel reimbursement from F. Hoffmann-La Roche Ltd and Novartis for CD20-related meetings and presentations. Amit Bar-Or has participated as a speaker in meetings sponsored by, and received consulting fees and/or grant support from, Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, MAPI, Medimmune, Merck/EMD Serono, Novartis and Sanofi Genzyme. Jeffrey Cohen has received personal compensation for consulting for Adamas, Convelo, EMD Serono, Novartis and Pendopharm; speaking for Mylan and Synthon; and serving as a Co-Editor of Multiple Sclerosis Journal - Experimental, Translational and Clinical. Giancarlo Comi has received compensation for consulting services and/or speaking activities from F. Hoffmann-La Roche Ltd, Novartis, Teva, Sanofi, Genzyme, Merck Serono, Biogen, Bayer, Serono Symposia International Foundation, Excemed, Almirall, Chugai and Receptos. Jorge Correale is a board member of Merck Serono Argentina, Novartis Argentina, Genzyme LATAM, Genzyme Global, Biogen Idec LATAM and Merck Serono LATAM; he has received reimbursement for developing educational presentations for Merck Serono Argentina, Merck Serono LATAM, Biogen Idec Argentina, Genzyme Argentina, Novartis Argentina, Novartis LATAM, Novartis Global and Teva Argentina, as well as professional travel/accommodation stipends. Patricia K. Coyle has received consulting fees from Accordant, Alexion, Bayer, Biogen Idec, Celgene, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono and TG Therapeutics; and research support from Actelion, Alkermes, Genentech/Roche, MedDay, Novartis and NINDS. Anne H. Cross has consulted for AbbVie, Bayer, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis and Teva. Jérôme de Seze has received consultancy fees and served as an expert on advisory boards for Alexion, Allergan, Almirall, Bayer, Biogen, Chugai, CSL Behring, F. Hoffmann-La Roche Ltd, Genzyme, LFB, Merck, Novartis and Teva. Xavier Montalban has received consulting and/or speaking fees from Actelion, Biogen, Celgene, Merck, Novartis, Orzyon, Roche, Sanofi-Genzyme and Teva. Krzysztof Selmaj has received honoraria for advisory boards from Biogen, Novartis, Teva, F. Hoffmann-La Roche Ltd, Merck, Synthon, Receptos and Genzyme. Heinz Wiendl has received honoraria and consultation fees from Bayer HealthCare, Biogen, Fresenius Medical Care and GlaxoSmithKline. Ludwig Kappos' institution (University Hospital Basel) has received the following exclusively for research support: steering committee, advisory board and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB and Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi and Teva); support for educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi and Teva); licence fees for Neurostatus products; and grants (Bayer HealthCare, Biogen Idec, European Union, INNO-Swiss, Merck, Novartis, Roche Research Foundation, Swiss MS Society and Swiss National Research Foundation). Alexandra Goodyear, Dieter A. Häring, Cecile Kerloeguen, Davorka Tomic, Roman Willi, Krishnan Ramanathan and Martin Merschhemke are employees of Novartis.

Abstract: 336

Type: Scientific Session

Abstract Category: Scientific Session 17: Late Breaking News

S.L. Hauser1, A. Bar-Or2, J. Cohen3, G. Comi4, J. Correale5, P.K. Coyle6, A.H. Cross7, J. de Seze8, X. Montalban9,10, K. Selmaj11, H. Wiendl12, A. Goodyear13, D.A. Häring13, C. Kerloeguen13, D. Tomic13, R. Willi13, K. Ramanathan13, M. Merschhemke13, L. Kappos14

1UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, 2Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 3Neurological Institute, Cleveland Clinic, Cleveland, OH, United States, 4University Vita-Salute San Raffaele, Milan, Italy, 5Institute for Neurological Research Dr. Raul Carrea, Buenos Aires, Argentina, 6Stony Brook University, Stony Brook, NY, 7Washington University School of Medicine, Saint Louis, MO, United States, 8University Hospital of Strasbourg, Strasbourg, France, 9St Michael's Hospital, University of Toronto, Toronto, ON, Canada, 10Center d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain, 11Center for Neurology, Lodz, Poland, 12University of Muenster, Muenster, Germany, 13Novartis Pharma AG, 14Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is under development with a monthly 20 mg subcutaneous (sc) dosing regimen for the treatment of multiple sclerosis (MS). Two Phase 3 trials of identical study design, ASCLEPIOS I (NCT02792218) and II (NCT02792231), are being conducted simultaneously to evaluate the effect of ofatumumab in patients with relapsing MS (RMS).
Objective: To investigate the efficacy and safety of ofatumumab versus teriflunomide in RMS patients.
Methods: ASCLEPIOS I and II are double-blind, double-dummy, active comparator-controlled, parallel-group, innovative, adaptive design, multicentre trials. Patients were randomised (1:1) to receive either ofatumumab 20 mg sc injections every 4 weeks (after an initial loading regimen of 20 mg sc doses on Days 1, 7 and 14) or teriflunomide 14 mg orally once daily, for up to 30 months. The studies have flexible durations, with termination occurring in the blinded core treatment epoch according to pre-specified criteria. Patients aged 18-55 years with an Expanded Disability Status Scale (EDSS) score of 0-5.5 at screening who experienced ≥1 relapse in the past year or ≥2 relapses in the past 2 years or a positive gadolinium-enhancing (Gd+) MRI scan during the year before randomisation were included. The primary endpoint is the annualised relapse rate (ARR). Key secondary endpoints include 3- and 6-month confirmed disability worsening (CDW), 6-month confirmed disability improvement (CDI), MRI-related outcomes and serum neurofilament light chain levels; safety and tolerability are also being assessed.
Results: Overall, 1881 patients were randomised in 37 countries (ASCLEPIOS I, N=927; ASCLEPIOS II, N=954). Baseline demographics and disease characteristics were previously reported (mean age, ~38 years; mean MS duration since first symptom, ~8 years; mean EDSS, 2.9; Gd+ lesions, ~40% of patients). The protocol-defined end of study (EOS) criteria were fulfilled based on blinded data: both ASCLEPIOS studies were powered to 90% for the primary endpoint, and the combined studies to 90% for 3mCDW and to 80% for 6mCDW. Hence, the EOS could be planned for beginning of July 2019. Top line efficacy and safety results will be presented at the Congress.
Conclusion: The results of these large controlled Phase 3 trials will elucidate the therapeutic potential of ofatumumab 20 mg, the first B-cell therapy that is subcutaneous and self-administered every 4 weeks, in RMS patients.
Disclosure: This study was funded by Novartis Pharma AG, Basel, Switzerland
Stephen L. Hauser serves on boards for Annexon, Alector, Symbiotix, Bionure and Neurona; he has also received travel reimbursement from F. Hoffmann-La Roche Ltd and Novartis for CD20-related meetings and presentations. Amit Bar-Or has participated as a speaker in meetings sponsored by, and received consulting fees and/or grant support from, Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, MAPI, Medimmune, Merck/EMD Serono, Novartis and Sanofi Genzyme. Jeffrey Cohen has received personal compensation for consulting for Adamas, Convelo, EMD Serono, Novartis and Pendopharm; speaking for Mylan and Synthon; and serving as a Co-Editor of Multiple Sclerosis Journal - Experimental, Translational and Clinical. Giancarlo Comi has received compensation for consulting services and/or speaking activities from F. Hoffmann-La Roche Ltd, Novartis, Teva, Sanofi, Genzyme, Merck Serono, Biogen, Bayer, Serono Symposia International Foundation, Excemed, Almirall, Chugai and Receptos. Jorge Correale is a board member of Merck Serono Argentina, Novartis Argentina, Genzyme LATAM, Genzyme Global, Biogen Idec LATAM and Merck Serono LATAM; he has received reimbursement for developing educational presentations for Merck Serono Argentina, Merck Serono LATAM, Biogen Idec Argentina, Genzyme Argentina, Novartis Argentina, Novartis LATAM, Novartis Global and Teva Argentina, as well as professional travel/accommodation stipends. Patricia K. Coyle has received consulting fees from Accordant, Alexion, Bayer, Biogen Idec, Celgene, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono and TG Therapeutics; and research support from Actelion, Alkermes, Genentech/Roche, MedDay, Novartis and NINDS. Anne H. Cross has consulted for AbbVie, Bayer, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis and Teva. Jérôme de Seze has received consultancy fees and served as an expert on advisory boards for Alexion, Allergan, Almirall, Bayer, Biogen, Chugai, CSL Behring, F. Hoffmann-La Roche Ltd, Genzyme, LFB, Merck, Novartis and Teva. Xavier Montalban has received consulting and/or speaking fees from Actelion, Biogen, Celgene, Merck, Novartis, Orzyon, Roche, Sanofi-Genzyme and Teva. Krzysztof Selmaj has received honoraria for advisory boards from Biogen, Novartis, Teva, F. Hoffmann-La Roche Ltd, Merck, Synthon, Receptos and Genzyme. Heinz Wiendl has received honoraria and consultation fees from Bayer HealthCare, Biogen, Fresenius Medical Care and GlaxoSmithKline. Ludwig Kappos' institution (University Hospital Basel) has received the following exclusively for research support: steering committee, advisory board and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB and Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi and Teva); support for educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi and Teva); licence fees for Neurostatus products; and grants (Bayer HealthCare, Biogen Idec, European Union, INNO-Swiss, Merck, Novartis, Roche Research Foundation, Swiss MS Society and Swiss National Research Foundation). Alexandra Goodyear, Dieter A. Häring, Cecile Kerloeguen, Davorka Tomic, Roman Willi, Krishnan Ramanathan and Martin Merschhemke are employees of Novartis.

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