American Academy of Neurology annual meeting – April 17-22, 2021
CONGRESS HIGHLIGHTS – WEDNESDAY EDITION
Recent studies have differentiated disability worsening, which is largely attributable to inflammatory disease activity, from disability progression that occurs independently of relapse activity, which more closely reflects the neurodegenerative component and may be the main driver of accumulating disability in relapsing and progressive MS. During treatment, an analysis of the OPERA I/II trials found that most 24-week confirmed disability accumulation events occurred independently of relapses (80.6% with interferon-β, 89.1% with ocrelizumab) (Kappos et al. JAMA Neurol 2020;77:1-9).
In the ASCLEPIOS studies of ofatumumab, there was a significant 42.5% reduction in 6-month confirmed PIRA with ofatumumab versus teriflunomide (Kappos L. EAN 2020; O2034). A new analysis of the ASCLEPIOS trials examined the effect of ofatumumab on PIRA according to patient body weight (Kappos L. AAN 2021; P.087). The risk of 6-month PIRA in the group without on-study relapses was reduced 31-37% with ofatumumab vs. teriflunomide regardless of body weight. The 6-month confirmed PIRA was reduced 56% in the newly-diagnosed subgroup. A noteworthy observation was that >50% of disability worsening events in newly-diagnosed RMS patients were PIRA.
A chart review of U.S. neurologists for 764 progressive MS patients reported that many SPMS (36%) and PPMS (56%) patients are considered not active, defined as no relapses in the previous year or no Gd+ lesions on the most recent MRI (Schobel V. AAN 2021; P.117). Neurologists were more likely to describe not-active patients as having stable disability (48% vs. 37% for active) and less disability (mean EDSS 5.8 vs. 7.3). Progression was somewhat more likely to be attributed to PIRA in not-active vs. active patients (94% vs. 86%). Not-active patients were more likely to be on their first DMT (52% vs. 37%) and were less likely to have switched DMTs in the preceding year (20% vs. 42%).
Novel therapies in development
About two dozen BTK inhibitors are in development for a variety of autoimmune and lymphoproliferative disorders, and three (evobrutinib, tolebrutinib, fenebrutinib) are in phase II or III in MS (Estupinan et al. Front Cell Dev Biol 2021;9:630942). A safety analysis of phase II studies of fenebrutinib (N=792) reported that adverse effects included nausea (5.7%) and headache (5.4%); serious infections occurred in 2.0% (vs. 1.8% with placebo) (Oh J. AAN 2021; S25.005). Liver enzyme abnormalities (grades 2 and 3) occurred in 3.7% (vs. 1.1% with placebo). Bleeding/bruising occurred in 7.7% vs. 3.2%, respectively.
The safety and efficacy of tolebrutinib were examined in a subgroup analysis of patients with high disease activity (n=61) enrolled in a phase II trial (Traboulsee A. AAN 2021;S25.004). High disease activity was defined as 1 relapse in the previous year and >1 Gd+ lesion in the prior 6 months; >9 T2 lesions at baseline; or >2 relapses in the previous year. The mean number of new Gd+ lesions was 0.82 (5 mg dose), 0.5 (15 mg), 0.38 (30 mg) and 0.08 (60 mg) with tolebrutinib at 12 weeks. The mean number of new/enlarging T2 lesions was 1.09, 0.89, 0.75 and 0.15 with the four doses, respectively.
MS prevalence has been shown to be higher with increasing latitude (Simpson Jr. et al. J Neurol Neurosurg Psychiatry 2019;90:1193-1200), an effect that is often attributed to UV-B exposure/vitamin D (Tarlinton et al. Int J Mol Sci 2019;20: 303). An analysis of the MSBase registry (N=46,128) now suggests that UV-B exposure is associated with MS severity as well as susceptibility (Vitkova M. AAN 2021; P.112). The MS Severity Scale (MSSS) was used to quantify disease severity. UV-B exposure was calculated from ozone mapping data obtained from NASA. Cumulative follow-up was >351,000 patient-years. The study found higher MSSS scores above 40 degrees latitude (which runs through New York City, Madrid, Naples, Thessaloniki and Beijing). This resulted in a mean difference of 1.3 points of MSSS between Madrid and Copenhagen (56 degrees latitude) (or New York and Fort McMurray).