Long-term treatment with ofatumumab, a fully human anti-CD20 monoclonal antibody, is associated with a favourable safety profile and sustained efficacy, according to a newly-published analysis of the ALITHIOS long-term extension (Hauser et al. Mult Scler 2023; epublished September 11, 2023). The study is the most recent to support the earlier use of high-efficacy therapy in patients with multiple sclerosis.
The safety analysis comprised MS patients who had been exposed to ofatumumab in the ASCLEPIOS I/II, APLIOS, APOLITOS studies and the ALITHIOS extension (N=1969, ofatumumab exposure 4032.5 patient-years). Overall, serious adverse events occurred in 12.3% of patients receiving ofatumumab. The most frequent adverse event was infection. The exposure-adjusted incidence rate (EAIR) for serious infections was similar in the core studies and the long-term safety analysis (1.44 vs. 1.53). The most common infection was COVID-19.
Immunoglobulin levels were stable during long-term treatment. Mean IgG levels remained above the lower limit of normal (LLN); this included patients with low IgG levels at treatment start. IgM levels decreased but remained above the LLN. There was no apparent association between Ig levels and the rate of serious infections. These results were consistent with the findings of a recent systematic review of immunoglobulin changes during anti-CD20 therapy (Saidha et al. Neurol Sci 2023;44:1515-1532). The mean level of lymphocytes and neutrophils remained stable and above the LLN. The incidence of malignancies was 0.86%; the EAIR for malignancies was unchanged in the safety dataset compared to the ofatumumab group in the ASCLEPIOS core study (0.33 vs. 0.32).
The efficacy analysis (N=1882) included patients receiving ofatumumab 20 mg SC q4wk or teriflunomide 14 mg/day in the ASCLEPIOS I/II trials. The annualized relapse rate remained low during the extension (0.05) among patients receiving continuous ofatumumab. The mean number of Gd+ lesions was 0.01 lesions/scan during the extension, a 65% reduction from the core study period. There was also an 87.9% reduction in the annualized rate of new T2 lesions (0.66 to 0.08 lesions/scan) during the extension compared to the core period.
In the teriflunomide-ofatumumab switch group, there was a delay in achieving the benefits seen with continuous ofatumumab. After two years of ofatumumab (month 48), some outcomes, such as ARR (0.06 vs. 0.05) and the number of Gd+ lesions/scan (0.01 vs. 0.01), were comparable in the switch vs. continuous group. Two notable exceptions were the number of new T2 lesions/scan, which remained higher in the switch vs. continuous ofatumumab group (0.58 vs. 0.08) during the extension; and confirmed disability worsening (CDW). At months 36 and 48, the rate of 3-month CDW was 17.9% and 19.1%, respectively, with continuous ofatumumab, compared to 21.9% and 23.1% for the switch group. Thus, the slope of progression was comparable in the two groups once the switch group started ofatumumab, but the long-term outcome was poorer due to the delay in initiating a higher-efficacy therapy.
The benefit of earlier use of ofatumumab was evaluated in a subgroup analysis of recently-diagnosed and treatment-naïve subjects (n=615) in the ASCLEPIOS I/II studies and followed for up to four years in the ALITHIOS extension (Gartner et al. ECTRIMS 2022;P052). Overall, there were 42% fewer relapses with continuous ofatumumab compared to the teriflunomide/ofatumumab switch group. With respect to confirmed disability worsening (CDW), there were 41.4% fewer 3-month CDW events with continuous ofatumumab. Following the switch from teriflunomide to ofatumumab, the proportion with 3-month CDW stabilized (20.6% at month 33, 21.6% at month 48), but remained higher than in the continuous ofatumumab group (12.6% at both time points).
Earlier use of ofatumumab was also associated with a 96% reduction in the cumulative number of Gd+ lesions (mean 0.0 lesions/scan at endpoint), and an 83.4% reduction in the cumulative number of new T2 lesions compared to the switch group.
Ofatumumab was generally well-tolerated in this treatment-naïve group. The most common adverse effects were nasopharyngitis, injection-related reactions, headache and upper respiratory tract infections. The incidence of serious infections was comparable in the continuous ofatumumab and teriflunomide/ofatumumab switch groups (EAIR 1.73 vs. 1.51). The incidence of malignancies was low (EAIR 0.41).
These results suggest a favourable benefit-risk profile when ofatumumab is employed as a starting therapy in newly-diagnosed MS patients. Treatment is generally well-tolerated and the early benefits of reduced disease activity and slowed disability worsening are sustained for up to four years.