SPECIAL REPORT

While there is a growing consensus on the benefits of initiating treatment with a higher-efficacy (HE) disease-modifying therapy (DMT) in MS, there are a few considerations in clinical practice that need to be addressed. The key issues include the efficacy of HE DMTs relative to lower-efficacy therapies in slowing disability worsening; whether anti-CD20 monoclonal antibody agents (e.g. ofatumumab, ocrelizumab), which primarily target inflammatory disease activity, have an impact on progression independent of relapse activity (PIRA); how switching therapies may optimize outcomes; and whether long-term drug exposure is safe.

These issues were addressed in new studies on ofatumumab, a fully human anti-CD20 monoclonal antibody, presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held 18-20 September 2024 in Copenhagen, Denmark.

Efficacy – CDW and PIRA
Six-year data were presented for ALITHIOS, the open-label extension of the ASCLEPIOS I/II trials that compared ofatumumab with teriflunomide (Hauser et al. N Engl J Med 2020;383:546-557). The analysis (n=1367) included patients on continuous ofatumumab versus patients switching from teriflunomide to ofatumumab in the open-label phase (Bar-Or et al. ECTRIMS 2024;P058). The ofatumumab initiation group was numerically superior to the switch group with respect to six-month confirmed disability worsening (CDW, 21.1% vs. 24.8%), six-month PIRA (15.45% vs. 16.56%) and six-month relapse-associated worsening (RAW, 5.24% vs. 5.81%). Overall, among patients receiving continuous ofatumumab, 78.9% of were free of 6M-CDW and 84.6% were free of 6M-PIRA at six years.

The treatment effect was greater in the subgroup of recently diagnosed/treatment naïve patients (n=615). The rate of 6M-CDW was significantly lower with continuous ofatumumab vs. switch patients (16.6% vs. 23.7%). The 6M-PIRA rates were 11.1% vs. 16.7%, respectively. The findings support the benefit of ofatumumab as a first-choice therapy.

The MSBase group examined the effect of treatment initiation with a HE DMT on PIRA rates (Spelman et al. ECTRIMS 2024;P842). The first part of the analysis compared patients in the Swedish MS registry who started treatment with a HE vs. low/moderate efficacy DMT (N=4358). There were fewer CDW events in the HE DMT group (982 vs. 1474); most of these events were PIRA. In the propensity score analysis, there was a 21% reduction in the risk of PIRA in the group initiating HE DMTs.

These data suggest that high-efficacy DMTs may delay the development of PIRA when initiated early in the disease course.

Also noteworthy was a real-world study of the impact of ofatumumab on MS fatigue in 70 patients (mean age 38 years; 81.8% with spinal cord lesions) with RRMS or SPMS (Ramirez et al. ECTRIMS 2024;P1774). Most were switched to ofatumumab due to lack of efficacy. There was a significant improvement in the Modified Fatigue Impact Scale (MFIS) score at 6 and 12 months (45.0 and 22.5 vs. baseline 47.5). The median EDSS score improved from 2.5 to 1.5 at one year post-switch.

Switching DMTs
While switching studies typically investigate escalation strategies, numerous real-world studies at ECTRIMS 2024 reported on lateral switches among higher-efficacy agents to optimize efficacy and/or safety.

Three studies investigated switching from natalizumab to ofatumumab in patients at risk of progressive multifocal leukoencephalopathy (PML). An Italian multicentre study switched 38 RRMS patients (mean age 38 years) to ofatumumab; mean time off treatment prior to ofatumumab initiation was 37 days (Camera et al. ECTRIMS 2024;P845). There were no cases of rebound disease activity (relapses, new T2 lesions) three months after discontinuing natalizumab. At 12 months, the annualized relapse was 0.13 compared to 0.20 in the year prior to switch; 11% had disease activity. There were no cases of new PIRA. Patients reported improved symptom scores and convenience after switching to ofatumumab.

Similar results were seen in a French study (N=32) that used a mean off-drug transition period of 40 days (de Seze et al. ECTRIMS 2024;P1708). There were no relapses or new MRI activity in patients after switching to ofatumumab. In a second Italian study of rebound after natalizumab discontinuation in 31 patients, 96.8% were relapse-free six months after starting ofatumumab, 90.3% were free of EDSS progression and 77.4% had no new MRI activity (Chisari et al. ECTRIMS 2024;P571).

A German retrospective cohort study examined the effectiveness of switching from an anti-CD20 agent to cladribine (n=30) or from cladribine to an anti-CD agent (n=38) (Konen et al. ECTRIMS 2024;P293). The proportion of patients with relapse activity declined from 57% to 17% after switching to cladribine; and from 84% to 26% after switching to an anti-CD20 treatment. The proportion of patients who were stable or clinically improved increased from 87% to 90% after switching to cladribine, and from 68% to 76% after switching to an anti-CD20 therapy.

Treatment safety
A concern with long-term B cell suppression is the risk of infections. An analysis of patients receiving ofatumumab in clinical trials (N=1969, cumulative exposure 8042.7 patient-years) examined infections over a six-year follow-up period (Wiendl et al. ECTRIMS 2024;P392). A total of 115 patients (5.8%) had a serious infection; this included 49 cases of COVID-19 (43% of all serious infections). Over 90% of patients had a full recovery. There were six deaths: five due to COVID-19 pneumonia and one due to pneumonia and septic shock. The most common non-COVID serious infections were urinary tract infections (0.91%), lower respiratory tract infections (0.81%) and appendicitis (0.76%). The annualized rate of serious infections was stable (0.013 in year 1, 0.010 in year 6) over the observation period. Interestingly, serious infections did not appear to be associated with low IgG levels. A total of 55 patients (2.8%) had at least one IgG reading below the lower limit of normal (LLN); 48 of the 55 patients (87%) did not experience a serious infection. Over the six-year period, three patients had a serious infection within 30 days of IgG <LLN and four had an infection >30 days of IgG<LLN.

Additional safety data were provided in the interim analysis of the KAIROS study of 291 treated MS patients switched to ofatumumab (Bischof et al. ECTRIMS 2024;P1744). Mean age at entry was 41 years; mean EDSS score was 2.66. The frequency of serious adverse events was 2.7%. The most common serious adverse events were COVID-19 (0.7%) infection and general physical health deterioration (0.7%); neither was considered related to treatment.