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Randomized Controlled Trial
. 2023 Oct;29(11-12):1452-1464.
doi: 10.1177/13524585231195346. Epub 2023 Sep 11.

Efficacy and safety of four-year ofatumumab treatment in relapsing multiple sclerosis: The ALITHIOS open-label extension

Stephen L Hauser  1 , Ronald Zielman  2 , Ayan Das Gupta  3 , Jing Xi  4 , Dee Stoneman  5 , Goeril Karlsson  5 , Derrick Robertson  6 , Jeffrey A Cohen  7 , Ludwig Kappos  8
Affiliations
Randomized Controlled Trial

Efficacy and safety of four-year ofatumumab treatment in relapsing multiple sclerosis: The ALITHIOS open-label extension

Stephen L Hauser et al. Mult Scler. 2023 Oct.

Abstract

Background: Ofatumumab has demonstrated superior efficacy and favorable safety for up to 2.5 years versus teriflunomide in relapsing multiple sclerosis (RMS).

Objective: Further characterize efficacy and safety of ofatumumab in RMS.

Methods: Efficacy set: patients randomized to ofatumumab/teriflunomide in ASCLEPIOS I/II (core). Safety set: patients who received ⩾ 1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS (all core), or ALITHIOS (umbrella open-label extension). Patients received continuous ofatumumab or were newly switched from teriflunomide. Data cut-off: 25 September 2021.

Results: In the efficacy set (n = 1882), the continuous ofatumumab group had a low annualized relapse rate (ARR 0.05 (95% confidence interval: 0.04-0.07)), low numbers of gadolinium-enhancing (Gd+) T1 lesions (0.01 lesions/scan) and fewer new/enlarging T2 lesions (annualized rate 0.08). Overall, 78.8% met three-parameter "no evidence of disease activity" criteria through 4 years. Switching from teriflunomide led to reduced ARR, risk of confirmed disability worsening (CDW), new/enlarging T2 lesions, Gd+ T1 lesions, and serum neurofilament light chain. In the continuous and newly switched ofatumumab groups, cumulative 3- and 6-month CDW rates remained low. In the safety set (n = 1969), the most frequently reported adverse events were infections and infestations (58.35%). No new safety signals were identified.

Conclusion: Ofatumumab has a favorable longer-term benefit-risk profile in RMS.

Trial registry: ALITHIOS (NCT03650114): https://clinicaltrials.gov/ct2/show/NCT03650114.

Keywords: Relapsing-remitting multiple sclerosis; follow-up; monoclonal antibodies; ofatumumab; treatment.

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Conflict of interest statement

Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All support for the present manuscript (e.g. funding, provision of study materials, medical writing, article processing charges) and the studies were sponsored and funded by Novartis Pharma AG, Basel, Switzerland. Novartis Pharma AG supported the development of this manuscript, provided data analyses according to the direction of the authors, and provided funding for medical writing support. Open access fee was paid by Novartis. Medical writing support for the development of this publication, under the direction of the authors, was provided by James Currie (BSc, Hons; PhD.), Laura Crocker (BMedSci, Hons), and Philippa Lloyd (BSc, Hons) of Ashfield MedComms, an Inizio company, and was funded by Novartis Pharma AG. Stephen L Hauser currently serves on the scientific advisory board of ACCURE, Alector, Annexon, board of directors of Neurona, and has previously consulted for BD, Moderna, and NGM Bio. Dr Hauser also has received travel reimbursement and writing support from F. Hoffmann-La Roche and Novartis AG for anti-CD20-therapy-related meetings and presentations. Grants: NIH/NINDS (R35NS111644) and Valhalla Foundation; within the past 36 months, no longer active: National Multiple Sclerosis Society (RR 2005-A-13). Ronald Zielman is a full-time employee of Novartis. Ayan Das Gupta is a paid and permanent employee of Novartis. Jing Xi is an employee of Novartis. Dee Stoneman is a full-time employee of Novartis. Goeril Karlsson is a full-time salaried employee of Novartis. Derrick Robertson declares grants or contracts from Anokion, Atara Biotherapeutics, Biogen, GW Pharmaceuticals, Novartis, PRIME CME, TG Therapeutics, CorEvitas, EMD Serono, Genentech, Janssen, PCORI and Sanofi; consulting fees from Biogen, Genentech, EMD Serono, Janssen, Bristol Myers Squibb, Horizon, Novartis, Sanofi, TG Therapeutics, Alexion, Greenwich Biosciences and Mallinckrodt; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen, EMD Serono, Genentech, TG Therapeutics, Bristol Myers Squibb, Janssen, PRIME CME, Sanofi, Alexion and Horizon. Jeffrey A Cohen declares consulting fees from Biogen, Convelo, EMD Serono, Gaossamer Gio, Mylan and PSA; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for ACTRIMS; other financial or non-financial interests for Sage—serving as an Editor of Mult Scler J. Ludwig Kappos declares grants or contracts from any entity (payments made to institution) from Novartis, Roche, and Innosuisse; consulting fees (payments made to institution) from AurigaVision AG, Bayer AG, df-mp Molnia & Pohlman, Genentech, Glaxo Smith Kline, Janssen LLC, Japan Tobacco Inc., Merck, Novartis, Roche, Senda Biosciences Inc., Shionogi BV, Wellmera AG; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (payments made to institution) from BMS, Celgene, Janssen Pharmaceuticals, Merck, Novartis and Roche; support for attending meetings and/or travel (payments made to institution) from MH Consulting, Österreichische Gesellschaft für Neurologie, Novartis Biocieˆncias S.A. and Eli Lilly; participation on a Data Safety Monitoring Board or Advisory Board (AB, payments made to institution) from Actelion, Merck Healthcare KGaA, Novartis, Roche, Sanofi and TG Therapeutics and (DSMB, payments made to institution) from Minoryx Therapeutics S.L. and Santhera Pharmaceuticals; leadership or fiduciary role in other board, society, committee or advocacy group paid or unpaid from Neurostatus-UHB AG—Supervisory Board (unpaid), payment to institution; (charitable) Foundation Clinical Neuroimmunology and Neuroscience Basel (“RC2NB”)—CEO (employment by University Hospital Basel); MAGNBIMS Steering Committee, EUROPEAN CHARCOT FOUNDATION (Board membership)—no payment.

Figures

Figure 1.
Figure 1.
Analysis sets and time periods. *The “newly switched ofatumumab group” comprised patients randomized to teriflunomide in ASCLEPIOS I/II (those who completed treatment were eligible to enter ALITHIOS and be switched to ofatumumab); the “continuous ofatumumab group” comprised patients randomized to ofatumumab in ASCLEPIOS I/II (those who completed treatment were eligible to enter ALITHIOS). All patients who completed study treatment in the core period were eligible to enter ALITHIOS but could withdraw prior to treatment. The efficacy analysis set comprised all patients randomized to ofatumumab or teriflunomide in ASCLEPIOS I/II, regardless of whether they completed/discontinued study treatment. The safety analysis set comprised patients who received ≥1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS, or ALITHIOS. Percentages based on the number of randomized patients. The open-label extension period was defined as following the first dose of ofatumumab in ALITHIOS (below the dashed line); the core period is prior to the open-label extension (above the dashed line). Reasons for the discontinuation of study treatment are presented in Supplementary Table 1.
Figure 2.
Figure 2.
Relapse data: (a) within-group comparison of ARR during the core and open-label extension periods; (b) between-group comparison of total confirmed relapses up to 4 years in the newly switched ofatumumab group and continuous ofatumumab group (efficacy analysis set). Data from the efficacy analysis set. Adjusted ARR presented as ARR (95% CI). aConfirmed relapses are those accompanied by a clinically relevant change in the EDSS. Comparisons obtained from fitting a piecewise negative binomial model for the core period and open-label extension time periods with log-link, adjusted for treatment and region as factors, number of relapses in previous year, baseline EDSS score, baseline number of Gd+ lesions and the patient’s age at baseline as covariates. The natural log of the time-in-study (in years) by time period is used as offset to annualize the relapse rate in each time period. Baseline variables are from the core period baseline. P values in panel A are nominal P values; P value in panel B is from a Wilcoxon Rank Sum test. ARR: annualized relapse rate; CI: confidence interval; EDSS, Expanded Disability Status Scale; Gd+, gadolinium-enhancing; RR: rate ratio.
Figure 3.
Figure 3.
Kaplan–Meier estimates of cumulative event rates (% patients) for confirmed disability worsening (left-hand panel) and cumulative number of confirmed disability worsening events (right-hand panel): (a) 3mCDW and (b) 6mCDW (efficacy analysis set). Data from the efficacy analysis set. Superior efficacy of ofatumumab in the core period was established previously versus teriflunomide (for more information, refer to Hauser, et al.). Cut-off for core and open-label extension periods based on the first dose of ofatumumab in the open-label extension period. “Difference” refers to the difference in KM estimates (newly-switched ofatumumab group minus continuous ofatumumab group). aP value is a Log-Rank test. 3mCDW: 3-month confirmed disability worsening; 6mCDW: 6-month confirmed disability worsening; CI: confidence interval; HR, hazard ratio; KM: Kaplan–Meier.
Figure 4.
Figure 4.
Lesion activity on MRI in the core and extension periods: (a) within-group comparison, mean number of Gd+ T1 lesions/scan; (b) between-group comparison, mean number of Gd+ T1 lesions; (c) within-group comparison, mean annualized rate of neT2 lesions; and (d) between-group comparison, mean number of neT2 lesions (efficacy analysis set). Data from the efficacy analysis set. Panels A and C: data are presented as mean (95% CI). Data were estimated from fitting a piecewise negative binomial model for the core and open-label extension time periods with log-link, adjusted for treatment and region as factors for panels A and B, and treatment for panels C and D. For panels A and B, baseline number of T1 Gd+ lesions and patient’s age at baseline were covariates; the natural log of the number of scans with evaluable Gd+ lesion counts by period is used as offset to obtain the lesion rate per scan in each period. For panels C and D, baseline volume of T2 lesions and patient’s age at baseline were covariates; the natural log of the time-in-study (in years) by period is used as offset to annualize the lesion rate in each period. Baseline variables are from the core period baseline. P values in panels A and C are nominal P values; P values in panels B and D are from a Wilcoxon Rank Sum test. CI: confidence interval; Gd+: gadolinium-enhancing; neT2: new/enlarging T2; RR, rate ratio.
Figure 5.
Figure 5.
No evidence of disease activity (NEDA-3): (a) core period, open-label extension period and overall; (b) during the first year of treatment and after first year of treatment, by study period (efficacy analysis set). Data from the modified efficacy analysis set for NEDA-3. All P values are nominal. The statistical model used logistic regression to adjust for treatment and region as factors, and for age, baseline EDSS score, number of Gd+ lesions at baseline as covariates. N=total patients in each treatment group. aRe-baseline was performed at entry to the extension period. CI: confidence interval; EDSS, Expanded Disablity Status Scale; Gd+, gadolinium-enhancing; M: month; NEDA-3: three-parameter no evidence of disease activity; OR: odds ratio.
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