Selected highlights from the European Academy of Neurology annual meeting, Budapest, Hungary, July 1-4, 2023.
CONGRESS HIGHLIGHTS – TUESDAY EDITION
Update on BTK inhibitors
The first results of the phase II trial of fenebrutinib, a novel Bruton’s tyrosine kinase (BTK) inhibitor, have now been presented (Hua et al. EAN 2023;EPO-688). For the 106 evaluable RMS patients, there was a 69% reduction from baseline in Gd+ lesions at weeks 4 and 8/12 (combined) with fenebrutinib and a 74% reduction in new/enlarging T2 lesions. Relative reductions with fenebrutinib vs. placebo were 90% and 95%, respectively, for the two endpoints at week 12. No serious adverse events were reported. Phase III studies in RMS and PPMS are ongoing.
An analysis of the phase II long-term extension study of evobrutinib reported a sustained reduction in serum neurofilament light chain (NfL) with treatment for up to 144 weeks (Kuhle et al. EAN 2023;EPR-188). Lower NfL z-scores were associated with a lower incidence of disease activity (Gd+ lesions, new/enlarging T2 lesions, relapses). NfL data were previously presented at AAN 2023 (see AAN 2023 Highlights – Tuesday, April 25). A separate study examined the response to COVID-19 vaccination in the subgroup of patients receiving evobrutinib 75 mg BID during the open-label extension (Bar-Or et al. EAN 2023;EPO-103). A total of 43 of 45 patients demonstrated an anti-S1/S2 (CoV2 spike domains) IgG antibody response post-vaccination. Eighty percent demonstrated a 10-100-fold increase in anti-S1/S2 antibody levels, suggesting that evobrutinib does not impair the humoral response to vaccination.
Remibrutinib is a BTK inhibitor in development for MS and various autoimmune disorders. A pooled analysis of safety data from phase II trials in chronic spontaneous urticaria, Sjogren syndrome and asthma (n=363) reported no increase in infection rates with treatment (Airas et al. EAN 2023;EPO-146). Skin disorders were more common due to an increase in skin reactions in the urticaria trial. Treatment was well-tolerated for up to 52 weeks.
A novel role for BTK inhibition was proposed by a group from the Netherlands (Bogers et al. EAN 2023;EPR-161). The in vitro study determined that Epstein-Barr virus (EBV) may act as a trigger, promoting the expression of proinflammatory interferon-gamma by B cells. IFN-gamma in turn induced the trafficking chemokine CXCR3. IgG+ B cells with a high EBV load and high CXCR3+ expression preferentially entered the CNS and produced antibodies. This process was attenuated by the BTK inhibitor evobrutinib.
Adding OCT to the McDonald criteria
The Vienna group has proposed adding optical coherence tomography (OCT) of the optic nerve to the dissemination in space (DIS) criteria in the next iteration of the McDonald criteria (Bsteh et al. EAN 2023;EPR-092). The study analysed data for 267 patients with a first demyelinating event over a mean 59-month period. Adding the optic nerve improved the diagnostic accuracy (DIS+OCT 81.2% vs. DIS 65.6%) and sensitivity (84.2% vs. 77.9% respectively) with comparable specificity (52.2%). Fulfilling the DIS+OCT criteria was associated with a 3.6-fold increased risk of a second clinical attack compared to a 2.5-fold increased risk with the McDonald 2017 DIS criteria.
A separate study by the same group reported that OCT findings within 90 days of an MS diagnosis were highly predictive of disability worsening (Bsteh et al. EAN 2023;OPR-008). Over a median observation period of 61 months, EDSS ≥3 was predicted in patients with ganglion-cell-and inner-plexiform layer (GCIPL) thickness <77 mcm (hazard ratio 2.7) and retinal nerve fibre layer (RNFL) thickness ≤ 88 mcm (HR 2.0). During the observation period, 12.1% of patients reached EDSS 3.0 after a median of 49 months.
How does cognitive impairment progress?
An Italian study examined the time course of cognitive impairments in 1243 patients with pediatric-onset, adult-onset or late-onset MS (De Meo et al. EAN 2023;EPR-037). Cognitive testing included the Brief Repeatable Battery and the Stroop Color Word Test. The first domain showing impairment in all three groups was semantic fluency. The sequence of cognitive domains affected thereafter in adult-onset MS patients was verbal memory, attention, information processing speed, executive function and visuo-spatial memory. In pediatric-onset MS, the next domains affected were executive function, attention, verbal memory, information processing speed and visuo-spatial memory. In late-onset MS, the sequence was information processing speed, attention, executive function and visuo-spatial memory. It remains to be determined if impairment differences are influenced by brain and immune-system development and/or other factors.
Clinical tip of the day
The metric of no evidence of disease activity (NEDA) may not adequately capture the functional changes that occur in early MS patients with minimal disability, according to a new analysis (Solaro et al. EAN 2023;EPO-650). The study examined functional outcomes at two years in 57 patients (mean age 38.9 years, mean EDSS 1.4) with and without NEDA. Tests included the 6-minute walking test (6MWT), the Timed Up and Go (TUG), the Timed 25-foot walk (T25FW), the Fatigue Severity Scale (FSS), the Twelve-Multiple Sclerosis Walking Scale (MSWS-12), the Fullerton Advanced Balance-short (FAB-s), the 9-Hole Peg Test (9-HPT), Manual Ability Measure-36 (MAM-36), and the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). In the group with NEDA, 70% showed worsening on the 9-HPT, 47% on the 6MWT and T25FW, 43% on FSS, 40% on the SDMT, and 30% on TUG. Overall, MS patients with NEDA demonstrated an impairment in at least one domain of functioning at two years.