Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II

Jutta Gärtner, Stephen L Hauser, Amit Bar-Or, Xavier Montalban, Jeffrey A Cohen, Anne H Cross, Kumaran Deiva, Habib Ganjgahi, Dieter A Häring, Bingbing Li, Ratnakar Pingili, Krishnan Ramanathan, Wendy Su, Roman Willi, Bernd Kieseier, Ludwig Kappos, Jutta Gärtner, Stephen L Hauser, Amit Bar-Or, Xavier Montalban, Jeffrey A Cohen, Anne H Cross, Kumaran Deiva, Habib Ganjgahi, Dieter A Häring, Bingbing Li, Ratnakar Pingili, Krishnan Ramanathan, Wendy Su, Roman Willi, Bernd Kieseier, Ludwig Kappos

Abstract

Background: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide.

Objectives: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS.

Methods: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events.

Results: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population.

Conclusion: The favourable benefit-risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients.ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).

Keywords: Relapsing multiple sclerosis; neurofilament light chain; no evidence of disease activity; progression independent of relapse activity; recently diagnosed; treatment-naive.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: J.G., in the past 3 years, has received fees for lectures and consultancy fees from Bayer, Biogen, Merck, Novartis and Sanofi, as well as funding for a research project from Novartis. S.L.H. has received personal compensation from Alector, Annexon Biosciences, Bionure and Neurona Therapeutics; he has also received travel reimbursement from F. Hoffmann-La Roche and Novartis for CD20-related meetings and presentations. A.B.-O. has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Janssen/Actelion, MedImmune, Merck/EMD Serono, Novartis, Roche/Genentech and Sanofi Genzyme. X.M. has received speaking fees and travel expenses for participation in scientific meetings, has been a steering committee member for clinical trials, or has participated in advisory boards for clinical trials in the past years with Actelion, Alexion Pharmaceuticals, Bayer, Biogen, Celgene, EMD Serono, EXCEMED, Genzyme, Immunic, MedDay, Merck, the MS International Federation, Mylan, NervGen Pharma, the National Multiple Sclerosis Society, Novartis, Roche, Sanofi Genzyme, Teva Pharmaceuticals and TG Therapeutics. J.A.C. has received personal compensation for consulting from Adamas Pharmaceuticals, Atara Biotherapeutics, Bristol Myers Squibb, Convelo Therapeutics, MedDay and Mylan, and for serving as an editor of the Multiple Sclerosis Journal. A.H.C. has consulted for Biogen, Celgene, EMD Serono, Genentech/Roche, Novartis and TG Therapeutics. K.D. has received personal compensation for speaker activities from Novartis and Sanofi. In the past 3 years, L.K.’s institution (University Hospital of Basel) has received steering committee, advisory board and consultancy fees used exclusively for research support in the department, as well as support of educational activities, from Actelion, Allergan, Almirall, Baxalta, Bayer, Biogen, Celgene/Receptos, CSL Behring, Desitin, Eisai, EXCEMED, F. Hoffmann-La Roche, Genzyme, Japan Tobacco, Merck, Minoryx Therapeutics, Novartis, Pfizer, Sanofi Aventis, Santhera Pharmaceuticals and Teva Pharmaceuticals, and license fees for Neurostatus-UHB products. Research at the MS Center in Basel has been supported by grants from Bayer, Biogen, the European Union, Inno-Suisse, Novartis, the Swiss MS Society, the Swiss National Research Foundation and Roche research foundations. D.A.H., K.R., R.W. and B.K. are employees of Novartis Pharma AG, Basel, Switzerland. B.L., R.P. and W.S. are employees of Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.

Figures

Figure 1.
Figure 1.
Kaplan–Meier estimates of percentage of patients with disability worsening confirmed at: (a) 3 and (b) 6 months. Disability worsening confirmed at 3 or 6 months was defined as an increase from baseline in the Expanded Disability Status Scale (EDSS) score (on a scale from 0 to 10.0, with higher scores indicating worse disability) that was sustained for at least 3 or 6 months. For patients with a baseline EDSS score of 0, an increase in the EDSS score of at least 1.5 points was required; for patients with a baseline EDSS score of 1.0 to 5.0, the criterion was an increase of at least 1.0 points; and for patients with a baseline EDSS score of at least 5.5 points, the criterion was an increase of at least 0.5 points.
Figure 2.
Figure 2.
Kaplan–Meier analyses of time to PIRA in RDTN participants: (a) time to 3mPIRA in participants without confirmed relapses on study, (b) time to 6mPIRA in participants without confirmed relapses on study, (c) time to 3mPIRA in participants without confirmed relapses on study or before 3mCDW and (d) time to 6mPIRA in participants without confirmed relapses on study or before 6mCDW. 3mCDW: 3-month confirmed disability worsening; 3mPIRA: 3-month progression independent of relapse activity; 6mCDW: 6 month confirmed disability worsening; 6mPIRA: 6-month progression independent of relapse activity; PIRA: progression independent of relapse activity; RDTN: recently diagnosed, treatment-naive.
Figure 3.
Figure 3.
Empirical lesion incidence maps for Gd+T1 lesions in all RDTN participants: (a) at baseline (N = 615); (b) 12 months after initiation of treatment with ofatumumab (N = 314); and (c) 12 months after initiation of treatment with teriflunomide (N = 301). Gd+, gadolinium-enhancing; RDTN: recently diagnosed, treatment-naive.
Figure 4.
Figure 4.
Proportion of RDTN participants with injection-related systemic reactions following the first 10 injections in the study. RDTN: recently diagnosed, treatment-naive. Only Common Terminology Criteria for Adverse Events grades that were observed in the data are shown. Only reactions/symptoms occurring within 24 hours after injections are included (i.e. time to onset of reaction ⩽ 24 hours). As teriflunomide is taken as an oral medication, injection-related systemic reactions in participants treated with teriflunomide are in response to placebo injections.

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