SPECIAL REPORT
The following summarizes some of the key data on ofatumumab from the American Academy of Neurology annual meeting (AAN), San Diego, CA, April 5-9, 2025.
Efficacy in early MS
First-line use of ofatumumab
Long-term efficacy and safety
Safety in pregnancy
Higher-efficacy disease-modifying therapies (DMT) are increasingly used as first-line therapies, most notably for patients with highly-active disease at presentation. This approach was prudent with therapies that had potentially severe adverse effects, however, it does not take full advantage of newer treatments with a more favourable benefit-risk profile, such as anti-CD20 agents. The early use of ofatumumab, an anti-CD20 monoclonal antibody administered by subcutaneous injection, was among the key issues addressed at the American Academy of Neurology annual meeting, held April 5-9, 2025, in San Diego, California.
Efficacy in early MS
In the ASCLEPIOS trial, patients were randomized to ofatumumab 20 mg q4weeks or teriflunomide 14 mg/day (Hauser et al. N Engl J Med 2020;383:546-557). Patients could continue on treatment in the ALITHIOS open-label extension. A post-hoc analysis of ALITHIOS examined the efficacy and safety of early ofatumumab in the subgroup of patients with non-highly active disease activity (Ziemssen et al. AAN 2025;P1.003). This subgroup comprised patients with a maximum of 1 relapse/year in the first one or two years; and EDSS score <3.0; had received <1 prior DMT; and had MS symptom onset <5 years. Mean age of the cohort was 36 years; mean baseline EDSS score was 1.82.
Early continuous ofatumumab was associated with fewer 6-month confirmed disability worsening (6M-CDW) events; the risk reduction versus the teriflunomide/ofatumumab switch group was 33.2%. A total of 83.5% in the continuous ofatumumab group were free of 6M-CDW at 6 years. Early effective treatment resulted in a higher rate of no evidence of disease activity (NEDA) at two years with ofatumumab compared to teriflunomide (92% vs. 35%). The NEDA rate for both the continuous ofatumumab and switch groups was 93% at year 6. Serum neurofilament-light chain (sNfL) concentrations were lower with ofatumumab, but were comparable after the active comparator arm was switched to ofatumumab. Serum IgG levels were generally stable during ofatumumab treatment. The rate of serious infections (excluding COVID-19) during the study was 2.3/100 patient-years.
First-line use of ofatumumab
The first-line use of ofatumumab in non-highly active MS patients was further examined in the AIOLOS study in Germany (Nelles et al. AAN 2025;P7.013). The non-interventional study compared early MS patients receiving either ofatumumab or a platform injectable therapy. In the interim analysis (n=390), the probability of remaining on treatment in the first year was higher in the ofatumumab group compared to the group receiving interferon-beta or glatiramer acetate (97% vs. 81%). The proportion of patients with serious adverse effects was 3.3% with ofatumumab and 7.3% with interferon-beta/glatiramer acetate. Adverse events leading to treatment discontinuation occurred in 0.7% with ofatumumab compared to 11.0% with a platform injectable. Serum IgG levels remained stable during ofatumumab treatment during the 18-month observation period; mean IgG was 9.7 g/L at baseline and 9.1 g/L at month 18.
Long-term efficacy and safety
Two studies at AAN reported on the long-term efficacy and safety of ofatumumab. The first analysis included patients receiving ofatumumab in clinical trials and followed for up to seven years (n=1969) (Pardo et al. AAN 2025;P7.016). In the group receiving continuous ofatumumab (n=944), the proportion of patients free of 6M-CDW was 77.3% at seven years. In the subgroup of recently-diagnosed and treatment-naïve patients (n=421), the proportion of patients free of 6M-CDW was 81.5% during the study period. The proportion free of six-month confirmed progression independent of relapse activity (PIRA) with continuous ofatumumab for seven years was 83.7%. The proportion free of 6M-PIRA was higher in the recently-diagnosed/treatment-naïve group (87.6%). No new safety signals were seen during long-term treatment. The incidence of serious adverse effects was 4.06/100 patient-years. Mean IgG levels remained above the lower limit of normal (LLN) in 96.8% of ofatumumab-treated patients.
A separate study examined the risk of serious infections in the long-term cohort from clinical trials (n=1969) (Wiendl et al. AAN 2025;P8.017). Cumulative drug exposure was 8042.7 patient-years. Overall, 5.84% experienced a serious infection over six years. The annualized rate of infections (excluding COVID-19) declined from 1.22% in year 1 to 0.68% in year 6. Most infections were grades 1-3 in severity; 93.9% fully recovered, are recovering or recovering with sequelae. The most common serious infection was COVID-19 (2.49%). There were five deaths attributed to COVID-19 or COVID-19 pneumonia, and one death due to pneumonia and septic shock. In the group with IgG < LLN at any time (55/1969), 48 of 55 (87.3%) did not experience a serious infection.
Safety in pregnancy
Recent studies have reported minimal drug exposure and little impact on neonatal B cell counts with anti-CD20 therapy administered in the first trimester (Hellwig et al. ACTRIMS Forum;P106. Bove et al. ECTRIMS 2024;O039). The most recent study looked at pregnancy outcomes in 32 neonates exposed to ofatumumab in the German MS and Pregnancy Registry (Dost-Kovalsky et al. AAN 2025;P10.008). Exposure was defined as ofatumumab use after the first day of the last menstrual period or within six months of the last menstrual period. Mean maternal age was 31.8 years. The median duration of ofatumumab exposure during pregnancy was 15 days. Neonatal outcomes (e.g. birth weight) following ofatumumab exposure (n=23) were comparable to those seen in the general population. There were no cases of B cell depletion in umbilical cord blood. There were four cases of lymphopenia or B cell lymphopenia in infants exposed to ofatumumab in the first trimester. Most infants (87%) were vaccinated according to the normal scheduling. The use of live attenuated vaccines was delayed in three infants with lymphopenias. The group concluded that lymphocyte and B cell counts should be monitored in neonates exposed to ofatumumab during pregnancy. Live attenuated vaccines may be administered once B cell counts have normalized.