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Clinical Trial
. 2019 May;266(5):1182-1193.
doi: 10.1007/s00415-019-09248-6. Epub 2019 Feb 28.

Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis

Benjamin Turner  1 , Bruce A C Cree  2 , Ludwig Kappos  3 , Xavier Montalban  4   5 , Caroline Papeix  6 , Jerry S Wolinsky  7 , Regine Buffels  8 , Damian Fiore  9 , Hideki Garren  9 , Jian Han  9 , Stephen L Hauser  2
Affiliations
Clinical Trial

Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis

Benjamin Turner et al. J Neurol. 2019 May.

Abstract

Objective: The efficacy and safety of ocrelizumab, versus interferon (IFN) β-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations.

Methods: Patients with RMS were randomized to either ocrelizumab 600 mg administered by intravenous infusion every 24 weeks or subcutaneous IFN β-1a 44 µg three times per week throughout the 96-week treatment period. Relapse, disability, and MRI outcomes were analyzed for predefined and post hoc subgroups based on demographic and disease characteristics along with prior treatment using appropriate statistical tests to determine the treatment effect in subgroups and treatment-by-subgroup interactions.

Results: The significant treatment benefit of ocrelizumab, versus IFN β-1a, observed in the overall OPERA I and OPERA II pooled populations was maintained across most subgroup strata for all endpoints, including annualized relapse rate, disability progression, and MRI outputs.

Conclusions: The treatment effect of ocrelizumab versus IFN β-1a, measured by clinical and MRI outcomes, was maintained across most of the subgroups and strata of interest, and the pattern of treatment benefit across all subgroups was consistent with that from the pooled OPERA studies.

Keywords: Interferon β-1a; Multiple sclerosis; Ocrelizumab; Phase 3; Relapsing; Subgroup.

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Conflict of interest statement

Conflicts of interest

B. Turner has received honoraria, travel grants and been a member of advisory boards for Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Roche. C. Papeix has received speaking honoraria and travel expense reimbursement for participation in scientific meetings, and has participated in advisory boards in the past years with Biogen, MedDay, Merck Serono, Novartis, Roche, and Sanofi Genzyme. B. Cree has received personal compensation for consulting from AbbVie, Akili, Biogen, EMD Serono, GeNeuro, Novartis, and Sanofi Genzyme. L. Kappos’s institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof. Kappos’s activities as principal investigator and member or chair of planning and steering committees or advisory boards in trials sponsored by Actelion, Addex, Almirall, Bayer HealthCare Pharmaceuticals, CSL Behring, Genentech, Inc., GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Ono Pharma, Pfizer, Receptos, F. Hoffmann-La Roche Ltd, Sanofi, Santhera, Siemens, Teva, UCB, and XenoPort; license fees for Neurostatus products; and research grants from the Swiss MS Society, the Swiss National Research Foundation, the European Union, the Gianni Rubatto Foundation, the Novartis Research Foundation and the Roche Research Foundation. X. Montalban has received speaking honoraria and travel expense reimbursement for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Octapharma, Receptos, F. Hoffmann-La Roche Ltd, Sanofi, Teva, and Trophos. J.S. Wolinsky has served on advisory boards, data monitoring or steering committees, has consulting agreements, or received speaker honoraria from the following entities: AbbVie, AcademicCME, Actelion, ACTRIMS, Alkermes, Bayer HealthCare, Biogen, Bionest, Celgene, Clene Nanomedicine, CMSC, ECTRIMS, EMS Serono, Forward Pharma A/S, France Foundation, GeNeuro, MA’s Communications, Masters MS, MedDay Pharmaceuticals, McDonnell Boehnen Hulbert & Berghoff, Novartis Pharmaceuticals, Otsuka, PlatformQ Health Education, PRIME, PTC Therapeutics, Roche Genentech, Sanofi Genzyme, Strategic Consultants International, Takeda, Teva Pharmaceuticals, and WebMD; royalties are received for out-licensed monoclonal antibodies through UTHealth from Millipore Corporation. R. Buffels is an employee of F. Hoffmann-La Roche Ltd. H. Garren is an employee of Genentech, Inc., and a shareholder of F. Hoffmann-La Roche Ltd. D. Fiore is an employee of Genentech, Inc., and a shareholder of F. Hoffmann-La Roche Ltd. J. Han is an employee of Genentech, Inc. S.L. Hauser serves on the board of trustees for Neurona and on scientific advisory boards for Annexon, Symbiotix, Bionure, Alector, and Molecular Stethoscope; he has also received travel reimbursement from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations.

Ethical standards

This trial was conducted in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice and the Declaration of Helsinki.

Informed consent

All patients provided written informed consent.

Figures

Fig. 1
Fig. 1
Annualized relapse rate by subgroup in the pooled OPERA I and OPERA II intent-to-treat population. Subgroup-level and treatment-by-subgroup interactions were assessed by the negative binomial method, or quasi-Poisson model if appropriate (where indicated). ARR annualized relapse rate, CI confidence interval, IFN interferon, OCR ocrelizumab, ROW rest of world. aA significant treatment-by-subgroup interaction was observed for age (< 40 versus ≥ 40 years; p = 0.006) and for baseline T1 gadolinium-enhancing lesion status (0 versus ≥ 1; p < 0.001); p values < 0.05 from the treatment-by-subgroup interaction test indicate that the treatment effect of OCR versus IFN is not the same at each subgroup-level. bEstimated by quasi-Poisson model
Fig. 2
Fig. 2
Disease progression confirmed at Week 12 by subgroup in the pooled OPERA I and OPERA II intent-to-treat population. Subgroup-level and treatment-by-subgroup interactions were assessed by the Cox proportional hazards method. CI confidence interval, IFN interferon, OCR ocrelizumab, ROW rest of world. aA significant treatment-by-subgroup interaction was observed for BMI (< 25 kg/m2 versus ≥ 25 kg/m2; p = 0.026); p values < 0.05 from the treatment-by-subgroup interaction test indicate that the treatment effect of OCR versus IFN is not the same at each subgroup-level
Fig. 3
Fig. 3
T1 gadolinium-enhancing lesions by subgroup in the pooled OPERA I and OPERA II intent-to-treat population. Subgroup-level and treatment-by-subgroup interactions were assessed by the negative binomial method, or quasi-Poisson model if appropriate (where indicated). CI confidence interval, IFN interferon, MRI magnetic resonance imaging, OCR ocrelizumab, ROW rest of world. aA significant treatment-by-subgroup interaction was observed for age (< 40 versus ≥ 40 years; p = 0.030) and for baseline T1 gadolinium-enhancing lesion status (0 versus ≥ 1; p = 0.001); p values < 0.05 from the treatment-by-subgroup interaction test indicate that the treatment effect of OCR versus IFN is not the same at each subgroup-level. bEstimated by quasi-Poisson model
Fig. 4
Fig. 4
New/enlarging T2 lesions by subgroup in the pooled OPERA I and OPERA II intent-to-treat population. Subgroup-level and treatment-by-subgroup interactions were assessed by the negative binomial method, or quasi-Poisson model if appropriate (where indicated). CI confidence interval, EDSS Expanded Disability Status Scale, IFN interferon, MRI magnetic resonance imaging, OCR ocrelizumab, ROW rest of world. aA significant treatment-by-subgroup interaction was observed for baseline BMI (< 25 versus ≥ 25 kg/m2; p = 0.043) and baseline EDSS score (< 4.0 versus ≥ 4.0; p = 0.007); p values < 0.05 from the treatment-by-subgroup interaction test indicate that the treatment effect of OCR versus IFN is not the same at each subgroup-level
Fig. 5
Fig. 5
Change from baseline brain volume (%) by subgroup in the pooled OPERA I and OPERA II intent-to-treat population. Subgroup-level and treatment-by-subgroup interactions were assessed by the mixed-effect model of repeated measures model. CI confidence interval, IFN interferon, LS least square, OCR ocrelizumab, ROW rest of world. aA significant treatment-by-subgroup interaction was observed for normalized baseline brain volume (< 1500 cm3 and ≥ 1500 cm3; p = 0.002); p values < 0.05 from the treatment-by-subgroup interaction test indicate that the treatment effect of OCR versus IFN is not the same at each subgroup-level
Fig. 6
Fig. 6
Subgroup analyses of the proportion of patients with NEDA in the pooled OPERA I and OPERA II mITT population. Subgroup-level testing used the Cochran–Mantel–Haenszel test and treatment-by-subgroup interactions were assessed by the Breslow–Day test. CI confidence interval, EDSS Expanded Disability Status Scale, IFN interferon, mITT modified intent-to-treat, NEDA no evidence of disease activity, OCR ocrelizumab, ROW rest of world. aA significant treatment-by-subgroup interaction was observed for baseline EDSS score (< 4.0 versus ≥ 4.0; p = 0.022); p values < 0.05 from the treatment-by-subgroup interaction test indicate that the treatment effect of OCR versus IFN is not the same at each subgroup-level
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References

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