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The following summarizes some of the highlights from Day 2 of the American Academy of Neurology annual meeting (AAN), San Diego, CA, April 5-9, 2025.

Ofatumumab long-term data
KFLC a long-term predictor of disability worsening
BAFF a potential predictor of low Ig
Tolebrutinib in SPMS
Clinical tip of the day

CONGRESS HIGHLIGHTS – TUESDAY EDITION

Ofatumumab long-term data
A total of 77.3% of patients receiving continuous ofatumumab were free of six-month confirmed disability worsening at 7-year follow-up, according to the latest analysis of the ALITHIOS extension study (Pardo et al. AAN 2025;P7.016). In the recently diagnosed and treatment-naive (RDTN) subgroup, the proportion free of 6M CDW was 81.5%. Also noteworthy was that 83.7% of patients on continuous ofatumumab and 87.6% of the RDTN group were free of six-month confirmed progression independent of relapse activity (PIRA) at seven years. No new safety signals were identified in the safety analysis (N=1969). The most common adverse effect was infections with an incidence of 37.12 per 100 patient-years.

KFLC a long-term predictor of disability worsening
Kappa free light chain (KFLC), now incorporated into the new McDonald diagnostic criteria, is a predictor of disease activity in the short term but long-term data are lacking. A new study examined the prognostic value of KFLC in 64 patients (median age 32 years) with a first demyelinating event (Hegen et al. AAN 2025;P6.004). Overall, 72% had a relapse and 47% had worsening disability at 10-year follow-up. KFLC index was predictive of time to relapse (HR 1.45) and disability worsening (HR 1.86). With a higher vs. lower baseline KFLC index, the likelihood of remaining relapse-free or free of disability worsening at 10 years was 40% and 27% lower, respectively.

BAFF a potential predictor of low Ig
B cell activating factor (BAFF) is a cytokine involved in B cell proliferation and differentiation. A retrospective study at the University of California-Irvine profiled BAFF and other disease activity biomarkers in stable MS patients (Chumakova et al. AAN 2025;P5.011). As expected, BAFF levels increased during treatment with B cell depleting therapies. However, it was noted that BAFF levels were significantly higher with ocrelizumab compared to ofatumumab despite similar mechanisms of action. Moreover, BAFF levels were correlated with the duration of treatment with ocrelizumab but not with ofatumumab. In addition, BAFF was negatively correlated with IgG levels in ocrelizumab-treated patients. The researchers concluded that BAFF may be a predictor of hypogammaglobulinemia in ocrelizumab-treated patients.

Tolebrutinib in SPMS
Tolebrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that has been studied in the phase III HERCULES trial of SPMS and the GEMINI I/II trials of RMS. In HERCULES, 1131 patients with SPMS were randomized to tolebrutinib or placebo. Mean age was 48.9 years; mean baseline EDSS score was 5.0 (Fox et al. AAN 2025;PL5.003). The cumulative incidence of 6M CDP was 26.9% with tolebrutinib versus 37.2% with placebo, a 31% reduction. Treatment was also associated with a 38% reduction in the annualized rate of new/enlarging T2 lesions compared to placebo (1.8 vs. 2.9). There was a slowing of progression on the Timed 25-Foot Walk but not on the 9-Hole Peg Test. There was a minimal impact of treatment on brain volume loss. A total of 3.9% of tolebrutinib-treated patients discontinued therapy due to adverse effects. The most common adverse effects included COVID-19 (25.5%) and nasopharyngitis (9.3%). The incidence of elevated liver enzymes was 4.0% (3xULN); 0.5% had very high liver enzymes (20xULN). One patient died following liver transplantation. Results were previously presented last year (Fox et al. ECTRIMS 2024;O136). Full results have now been published for HERCULES and GEMINI I/II (N Engl J Med 2025; epublished April 8, 2025).

Clinical tip of the day
A majority of MS patients may experience frequent headaches. A Harvard study reported that 55.6% of patients had at least one headache per month (Balshi et al. AAN 2025;P1.001). Risk factors for frequent headache included non-white race (odds ratio 3.65), family history of MS (OR 2.59), female sex (OR 2.56) and a history of smoking (OR 1.91).

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