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The following summarizes some of the highlights from Day 2 of the American Academy of Neurology annual meeting (AAN), Chicago, Illinois, April 18-22, 2026.

Update on BTK inhibitors
Ofatumumab real-world efficacy
High rate of UTIs in MS
Novel anti-CD40L MAb in development
Immune checkpoint inhibitors and MS
MS fatigue: what medication works?

CONGRESS HIGHLIGHTS – TUESDAY EDITION

Update on BTK inhibitors
Three meta-analyses have investigated the efficacy and safety of Bruton’s tyrosine kinase (BTK) inhibitors in MS. The first study examined data for seven trials of evobrutinib and tolebrutinib (Ezz-Alarab et al. AAN 2026;P4.010). BTK inhibitors were superior to placebo but not tolebrutinib in the reduction of new/enlarging T2 lesions. BTK inhibitors were less effective than teriflunomide in reducing Gd+ lesions. The rate of confirmed disability progression (CDP) at 42 months was 10% with teriflunomide, 15% with BTK inhibitors and 45% with placebo. Ther was no increase in adverse events or serious adverse events with BTK inhibitors versus comparators. There was a lower risk of alopecia and GI effects and a higher risk of ALT elevations with BTK inhibitors compared to teriflunomide. Somewhat different results were seen in a second meta-analysis of 13 trials (N=6360) (Zafar et al. AAN 2026;P4.001). BTK inhibitors were associated with a 20% improvement in 3-month CDP and a reduction in Gd+ lesions, but showed no advantage on T2 lesions.

A third meta-analysis looked at safety outcomes with BTK inhibitors versus teriflunomide (Popatbhai et al. AAN 2026;P11.003). The mortality rate was lower with tolebrutinib vs. teriflunomide (odds ratio 0.5); there was no difference with evobrutinib vs. tolebrutinib (OR 1.01). The rate of adverse events vs. teriflunomide was higher with evobrutinib (OR 1.41) but comparable with tolebrutinib (OR 1.21). ALT elevations were not increased with evobrutinib (OR 0.8) or tolebrutinib (OR 0.46). The rate of alopecia was lower with BTK inhibitors; the rates of nasopharyngitis were comparable for all three treatments.

In the failed GEMINI 1 and 2 trials, tolebrutinib showed no benefit vs. teriflunomide with respect to ARR, or number of Gd+ or new/enlarging T2 lesions (Oh et al. N Engl J Med 2025; 392:1893-904). The pooled percentage of participants with 6-month CDP (multiple imputation) was 8.3% with tolebrutinib and 11.3% with teriflunomide. A new analysis has noted that about 80% of CDP events were progression independent of relapse activity (PIRA) (Oh et al. AAN 2026;P7.001). The proportion of patients with PIRA events was 6.4% with tolebrutinib and 8.5% with teriflunomide.

A separate study analysis of data from the HERCULES and GEMINI 1 and 2 trials of tolebrutinib found that leukocyte, total lymphocyte, neutrophil, monocyte and platelet counts remained within normal ranges with tolebrutinib over 42 months (Oreja Guevara et al. AAN 2026;P9.001). Mean IgG levels were overall stable and remained within the normal range.

Ofatumumab real-world efficacy
A multicentre study examined the efficacy, safety and tolerability of ofatumumab in 329 MS clinic patients in the U.S. over a 36-month period (Arias et al. AAN 2026;P4.002). Mean age was 44 years; mean disease duration was 12 years; and 84% were previously treated. The annualized relapse rate (ARR) was reduced 79% from baseline to 0.02 at month 36. The number of new T2 lesions (odds ratio 0.08) and Gd+ lesions (OR 0.15) was also significantly reduced. IgG levels were stable but the proportion of low IgM increased over time. The median persistence was 87.8% at 36 months. The rate of infections was 26% at 12 months, 37% at 24 months and 44% at 36 months.

High rate of UTIs in MS
An analysis of the FDA Adverse Event Reporting System (FAERS) database examined the frequency of urinary tract infections (UTI) and urosepsis among MS patients on a disease-modifying therapy for the period 2003-2024 (Balshi et al. AAN 2026;S12.007). The DMT with the greatest association with UTIs/urosepsis was ocrelizumab. There were also safety signals with natalizumab, alemtuzumab and interferon-beta-1a. The authors noted that their findings likely represented immunologic effects of treatment as well as disease factors, such as the frequency of neurogenic bladder dysfunction in MS patients.

Novel anti-CD40L MAb in development
Frexalimab is a monoclonal antibody that targets the CD40-CD40L pathway involved in innate and adaptive immune activation. The 12-week phase II trial (N=129) compared placebo with frexalimab 1200 mg IV q4wk (1800 mg loading dose) or 300 mg SC q2wk (600 mg loading dose) (Vermersch et al. N Engl J Med 2024;390:589-600). Dosing was changed to 1200 mg IV q4wk and 1800 mg SC q4wk for the open-label extension (Giovannoni et al. ECTRIMS 2025;O111). The mean number of Gd+ lesions at 120 weeks was 0.2 with the 1200 mg dose and 0.1 with the 1800 mg dose. At week 112, all patients received the 1800 mg q4wk SC dose. Results at 144 weeks are now available (Vermersch et al. AAN 2026;P7.003). A total of 100 patients (76%) remained on treatment with 86% being relapse-free. The mean number of Gd+ lesions remained low (IV 0.1 vs. placebo 0.3; SC 0.0 vs. placebo 0.1). A separate study reported that frexalimab was associated with a 47-49% reduction in serum neurofilament-light (sNfL) vs. 35-45% with placebo (Granziera et al. AAN 2026;P4.009). CXCL13 levels decreased 48-61% vs. 28-34% with placebo. Brain volume loss from baseline was -0.84% at 144 weeks. Three phase III trials are planned: the FREXALT studies, which will compare frexalimab with teriflunomide in RMS (recruiting at 8 Canadian centres); and FREVIVA, a placebo-controlled trial in non-relapsing SPMS (recruiting at 14 Canadian centres).

Immune checkpoint inhibitors and MS
MS disease activity is uncommon following treatment with an immune checkpoint inhibitor (ICI), according to an analysis of 165 MS patients receiving ICI therapy (Gill et al. AAN 2026;P4.002). ICI therapies include programmed-death (PD)-1 inhibitors (e.g. pembrolizumab), cytotoxic T-lymphocyte-associated antigen (CTLA)-4 inhibitors (e.g.  ipilimumab) and lymphocyte activation gene (LAG)-3 inhibitors (e.g. relatlimab). Median age at the time of ICI initiation was 63 years; 27% continued on the DMT during ICI therapy. Four patients (2.4%) had a relapse after starting an ICI inhibitor. Following ICI therapy, two relapsed >6 months after the last ICI dose and 7 patients had new MRI lesions without relapses. About 5% showed evidence of disease activity <6 months after the last ICI dose. For immune-related adverse events, 6.7% were non-MS-related neurologic events and 21.8% were non-neurologic.

MS fatigue: what medication works?
A meta-analysis of 16 studies examined the efficacy of medications for MS fatigue, such as amantadine, amphetamine/dextroamphetamine, modafinil and methylphenidate (Ghajarzadeh et al. AAN 2026;P3.003). The study found that none of the medications was effective for fatigue severity or for improving cognitive processing speed. Amantadine was superior to placebo in improving fatigue impact. Methylphenidate had significant negative effects on SDMT scores.

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