Focus on ofatumumab
There is a growing body of evidence supporting the use of high-efficacy disease-modifying therapies (DMT) as first-line agents in the treatment of multiple sclerosis. Since the TRANSFORMS trial over a decade ago, numerous pivotal trials have demonstrated the superiority of higher-efficacy DMTs over lower-efficacy agents (Cohen et al. N Engl J Med 2010;362:402-415). The concern with this more aggressive approach was safety. However, the accumulation of long-term safety data, most notably for anti-CD20 agents, has demonstrated the low risk of serious adverse events with sustained exposure to selected high-efficacy DMTs in clinical practice.
Long-term data on the efficacy and safety of subcutaneous ofatumumab 20 mg/month in the first-line setting were presented at the American Academy of Neurology (AAN) annual meeting, held April 13-18, 2024, in Denver, Colorado. The findings were a continuation of a subgroup analysis of newly-diagnosed and treatment-naïve patients in the ASCLEPIOS I/II trials (Gartner et al. Mult Scler 2022;28:1562-1575). In that original analysis, first-line ofatumumab reduced the annualized relapse rate (ARR) by 50% versus teriflunomide (0.09 vs. 0.18). The proportion of patients with 6-month confirmed disability worsening (CDW) events was 46% lower (5.4% vs. 10.0%) with ofatumumab. With respect to progression independent of relapse activity (PIRA), the proportion with 6-month PIRA events was significantly lower with ofatumumab compared to teriflunomide (3.6% vs. 7.7%) in this patient population.
Patients in ASCLEPIOS were subsequently enrolled in the ALITHIOS open-label extension (n=465) and results at six years are now available (Pardo et al. AAN 2024;S31.003). Mean age was about 36 years; mean body-mass index was about 26 kg/m2; and mean EDSS was about 2.30. ARR was 0.05 in the continuous ofatumumab group at Year 6. There was near-complete suppression of Gd+ lesions (0.001 lesions/scan) with continuous ofatumumab. The annualized rate of new T2 lesions was also low (0.07). The teriflunomide group saw substantial improvements in all endpoints after switching to ofatumumab. ARR was reduced 71% from 0.228 in the core phase to 0.065; the number of Gd+ lesions/scan was reduced 98% from 0.319 to 0.005; and the annualized rate of new T2 lesions was reduced 93% from 4.39 to 0.31.
What was most noteworthy, however, was the cumulative rate of three-month CDW. The CDW event rate was 16.6% with continuous ofatumumab versus 23.7% in the switch group at six years. While the slope of progression was comparable between the two groups post-switch, patients who started treatment with a modest-efficacy DMT did not regain what had already been lost. Moreover, the rate of six-month PIRA events remained higher in the switch group (16.8%) compared to patients initiating treatment with ofatumumab (11.1%), suggesting that early immunosuppression with a more potent agent is a more effective strategy than escalation in slowing neurodegeneration and disability progression.
Long-term safety
The long-term safety of ofatumumab was examined using the ALITHIOS database of patients initially enrolled in the ASCLEPIOS I/II, APOLITOS and APLIOS studies (Wiendl et al. AAN 2024;P9.010). The exposure-adjusted incidence rate (EAIR) for infections declined from 51.14/100 patient-years in the ASCLEPIOS core period to 38.86/100 PY at year 6. The rate of serious infections (excluding COVID-19) also declined during long-term follow-up (1.55 to 0.90/100 PY). The EAIR for malignancies was stable from the core studies (0.32/100 PY) to year 6 (0.34/100 PY).
Serum immunoglobulins remained above the lower limit of normal (LLN) in a majority of patients during long-term treatment with ofatumumab. The mean IgG level declined slightly from 10.31 g/L to 9.97 g/L; IgG was >LLN in 97.2% of patients. Mean IgM levels were reduced from 1.34 g/L to 0.63 g/L; IgM was >LLN in 65.9% of patients. The level of IgG/IgM did not appear to be associated with infection risk.
Also noteworthy was retrospective study of treatment persistence in real-world practice (Hersh et al. AAN 2024;P5.012). Patients (mean age 47 years) received either a platform injectable (glatiramer acetate, interferon-β, n=592), an oral DMT (fumarate, fingolimod, teriflunomide, cladribine, siponimod, ozanimod, n=576) or ofatumumab (n=576). At one year, the persistence rate was 74.5% with ofatumumab versus 43.2% with an injectable. In a second comparison, persistence was 76.3% with ofatumumab versus 64.6% with oral DMTs at 12 months. These results suggest that ofatumumab is well-tolerated and would have an acceptable adherence rate during long-term therapy.