Selected highlights from the American Academy of Neurology annual meeting, Boston, MA, 22-27 April 2023.
April 26 Edition
April 24 Edition
Bruton’s tyrosine kinase (BTK) inhibitors – an update
EBV antibodies not useful for prognosis
Novel imaging studies in RIS
CONGRESS HIGHLIGHTS – TUESDAY EDITION
Bruton’s tyrosine kinase (BTK) inhibitors – an update
Tolebrutinib: In the phase IIb trial of tolebrutinib, 130 RMS patients received one of four doses (5, 15, 30 or 60 mg/day) for 12 weeks and four weeks of placebo (Reich et al. Lancet Neurol 2021;20:729-738). Results showed a dose-dependent reduction in new Gd+ lesions at the end of the treatment period. The mean reduction in the number of Gd+ lesions/scan was 85% (0.13 lesions/scan with TOL 60 mg vs. 1.03/scan with placebo). In the long-term safety study, the number of Gd+ lesions/scan was 0.31 with TOL 60 mg/day at week 96 (Reich et al. AAN 2023;S6.012). New/enlarging T2 lesion counts also remained low. Safety results at 2.5 years were also reported (Oh et al. AAN 2023;S16.010). The most common adverse events included COVID-19 (24.8%), headache (13.6%) and upper respiratory tract infection (11.2%). No new safety signals were seen.
Evobrutinib: In the phase II trial of evobrutinib, 267 RMS patients received one of three doses of the BTK inhibitor (25 mg/day, 75 mg/day or 75 mg BID), dimethyl fumarate or placebo (Montalban et al. N Engl J Med 2019;380:2406-2417). In weeks 12-24, the number of Gd+ lesions was reduced 70% vs. placebo with EVO 75 mg/day and 56% with EVO 75 mg BID. For the open-label extension, patients were maintained on EVO 75 mg/day starting at week 48; this dose was continued for a mean of 50 weeks prior to switching to 75 mg BID (Montalban et al. AAN 2023;S16.008). A total of 155 patients (72.8%) completed 228 weeks of treatment. During the extension, the annualized relapse rate (ARR) was reduced from 0.18 to 0.10 after switching to the 75 mg BID dose. The overall ARR from weeks 48-228 was 0.13. The rate of serious adverse events was 3.3%. Severe infections (≥grade 3) occurred in 5.2%. A separate analysis reported a sustained reduction in serum NfL levels up to week 144 (Kuhle et al. AAN 2023;P1.011). Lower NfL levels were associated with better MRI and clinical outcomes.
Comparing BTK inhibitors: A pharmacologic study compared the effects of three BTK inhibitors (tolebrutinib, evobrutinib, fenebrutinib) in the CNS in non-human primates (Turner et al. AAN 2023;S46.007). The three drugs achieved similar levels in the CSF after a single oral dose. However, only tolebrutinib CSF exposure exceeded the 90% inhibitory concentration (IC90); evobrutinib and fenebrutinib did not reach IC50. Kinase assays also showed a 65-fold more rapid interaction with BTK with tolebrutinib vs. evobrutinib.
EBV antibodies not useful for prognosis
Epstein-Barr virus (EBV) infection reportedly precedes neuroaxonal damage as evidenced by elevated NfL levels only after seroconversion (Bjornevik et al. Science 2022;375:296-301). Higher EBV antibody titres have been associated with more severe white- and gray-matter damage (Jakimovki et al. Mult Scler 2020;26:322-332). However, a review of 35 studies found that EBV titres were not consistently associated with neurological disability or the development of MS in CIS patients (Bose et al. AAN 2023;P1.007). The authors concluded that EBV antibodies are not useful as a prognostic biomarker. The pooled analysis was hampered by differing assay methods and heterogeneous study populations indicating a need to standardize study methodologies.
A Canadian-led study reported that the presence of paramagnetic rim lesions (PRL) may be a useful prognostic biomarker for the development of MS in individuals with radiologically isolated syndrome (RIS) (Oh et al. AAN 2023;S27.003). 3T-MRIs of the brain and cervical spinal cord were obtained in 36 persons with RIS. Median age was 43 years; 70% were female. During the observation period, 25% developed clinical MS (67% RRMS, 33% PPMS) after a median of 5.2 years. RIS subjects who later developed MS had a significantly higher median number of PRLs (11 vs. 1) and central-vein sign lesions (34 vs. 10) at baseline compared to individuals who did not develop MS. The PRL count at baseline and during follow-up was the best predictor of MS. The group previously reported that PRLs and central-vein sign lesions were predictive of cognitive impairment (verbal memory, processing speed) in individuals with RIS (Oh et al. Mult Scler 2021;27:2199-2208).
Also noteworthy was a separate pilot study that found that plasma GFAP levels correlated with PRLs, central-vein sign lesions and the number of black holes in persons with RIS (Schneider et al. AAN 2023;P1.003). While the results are preliminary, they may suggest that high GFAP levels may be a useful prognostic biomarker in individuals with RIS.
A separate Canadian study used 3T myelin water imaging (MWI) to investigate the extent of myelin damage in the brain and corticospinal tract in 27 persons with RIS vs. 20 healthy controls (Keane et al. AAN 2023;S27.005). The myelin water fraction (MWF) was significantly lower in the corticospinal tract and corpus callosum in persons with RIS. No differences were seen in the cingulum and superior longitudinal fasciculus. MWF values in the corticospinal tract and corpus callosum were correlated with performance on the Timed 25-Foot Walk but not on the 9-Hole Peg Test or the Symbol Digit Modalities Test. The findings suggest that regional myelin damage and ambulatory impairment occur early in individuals with RIS.
April 26 Edition
April 24 Edition