B cells play an important role in the pathogenesis of multiple sclerosis (MS), hence immunosuppressive therapy employing B-cell depletion is an important milestone in MS management.¹ Ofatumumab is a fully human B-cell depleting, anti-CD20 monoclonal antibody approved in 2020 for treating adults with relapsing MS.² Ofatumumab has been shown to be safe, efficacious and have significant benefits over teriflunomide, a mitochondrial enzyme inhibitor, in relapsing MS patients in the phase 3 ASCLEPIOS I and II trials.¹ However, its long-term safety and efficacy as well as the increased risks associated with coronavirus disease 2019 (COVID-19) for MS patients has to be monitored further.⁴ Recently, interim data on the long-term (up to 4 years) safety of ofatumumab in relapsing MS from the ALITHIOS study were presented at the American Academy of Neurology (AAN) Annual Meeting.³ Additionally, interim analysis from another prospective open-label study, KYRIOS, also evaluated the T- and B-cell responses in COVID-19 vaccinated relapsing MS patients on ofatumumab.⁵

ALITHIOS is an ongoing single-arm, open-label phase 3b extension study that evaluates the long-term (5 years) safety, tolerability and efficacy of ofatumumab in relapsing MS patients.² This study recruited patients from the APLIOS, APOLITOS, and ASCLEPIOS I/II phase 2 and 3 studies.² APLIOS (n=284) and APOLITOS (n=62) were single-arm studies evaluating ofatumumab in relapsing MS.3 In the ASCLEPIOS I/II comparative studies, patients were randomized 1:1 to receive either subcutaneous ofatumumab (20mg every 4 weeks after appropriate loading doses, n=946) or oral teriflunomide (14mg daily, n=936) for up to 30 months.¹ The relapse rates and disability worsening confirmed at 3 and 6 months were lower with ofatumumab.¹ Only those who enrolled for the ALITHIOS study (n=1,703) continued on ofatumumab (n=1,026), or switched from teriflunomide to ofatumumab (n=677) in the extension study.² Hauser et al. analyzed 4-year cumulative safety data (data cut off on September 25, 2021) in the overall safety population (n=1,969), which included a total sum of patients from all 3 previous studies who were on ofatumumab (n=1,291), and those who newly switched to ofatumumab (n=677).³ The outcome measures included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), serious infections, COVID-19 infections, malignancies, and the levels of serum immunoglobulin G (IgG), immunoglobulin M (IgM), neutrophils and lymphocytes.³

Results showed no new safety concerns, and that the rates of adverse events (AEs), SAEs and serious infections were similar to those in the initial studies, with infections as the most common AE.³ Of note, total serious infections (4%) were of grade 4 and below.³ The most common serious infections were COVID-19 (n=23) and appendicitis (n=13), but notably that most (94%) were resolved without ofatumumab discontinuation.³ The rate of malignancies and the mean levels of IgG, neutrophils and lymphocytes remained stable throughout 4 years, while the mean IgM levels decreased but remained above the lower limit of normal.³ Most COVID-19 cases (91%) were mild-to-moderate and the majority (98%) recovered, without any interruption in ofatumumab treatment (83%), and most importantly, there were no reinfections.³ Only 1.5% of fully (n=476) and 2% of partially (n=559) vaccinated patients had COVID-19, which was moderate; and all recovered.³

The ongoing KYRIOS study (n=33) by Ziemssen et al. compared immune response in patients receiving SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccination before starting ofatumumab (cohort 1, n=14) with patients vaccinated during stable ofatumumab treatment for at least 4 weeks (cohort 2, n=19).5 B-cell depletion was verified in cohort 2 before vaccination.⁵ Neutralizing antibodies (Nab) and SARS-CoV-2 specific T-cells (SSTC) were analyzed.⁵ Interim results showed that all vaccinated patients (n=5) in cohort 2 had increased Nab and developed SSTC (with an extent comparable with cohort 1) and peaked at 1-week post-vaccination.⁵ One patient in each cohort developed COVID-19; one in cohort 2 had an MS relapse, but all recovered.⁵ These results were consistent with the previously observed mild COVID-19 in relapsing MS patients.²

These data demonstrated that ofatumumab has long-term safety benefits and does not interfere with the immune response elicited by COVID-19 mRNA vaccinations in relapsing MS patients.^3,5