9th Joint ECTRIMS-ACTRIMS meeting – 11-13 October 2023
The following summarizes some of the highlights from Day 3 of ECTRIMS-ACTRIMS 2023.
October 12 Edition
October 11 Edition
Update on BTK inhibitors
Effect of anti-CD20s on IgG
Low T cell count after switching off fingolimod
Novel therapy in development
Tracking eye movements as a biomarker of progression
Clinical tip of the day
CONGRESS HIGHLIGHTS – FRIDAY EDITION
Update on BTK inhibitors
Three studies have reported on the long-term efficacy and safety of Bruton’s tyrosine kinase (BTK) inhibitors in MS. In the open-label extension of the evobrutinib phase II trial, patients were initially randomized to one of three doses of evobrutinib (25mg QD, 75mg QD, or 75mg BID), placebo (evobrutinib 25 mg after week 24) or dimethyl fumarate. For the extension, all patients received 75 mg OD for a mean of 50.6 weeks before switching to the 75 mg BID dose (Montalban et al. ECTRIMS/ACTRIMS 2023;P706). The annualized relapse rate was 0.11 with BID dosing vs. 0.20 with 75 mg QD. At week 240, the proportion with no evidence of clinical worsening was 87%. The incidence of serious adverse events was 2.4%. An integrated safety analysis for evobrutinib was published earlier this year (Montalban et al. J Neurol Neurosurg Psychiatry 2023;94:1-9).
In the phase II trial of tolebrutinib, patients received 12 weeks of tolebrutinib (5, 15, 30, or 60 mg/day) and four weeks of placebo in a crossover design (Reich et al. Lancet Neurol 2021;20:729-738). In the open-label extension, patients continued in their assigned dosing group before switching to the 60 mg dose in weeks 15-47 (Oh et al. ECTRIMS/ACTRIMS 2023;P278). ARR was 0.23 for patients receiving tolebrutinib 60 mg for >8 weeks; 68.5% were relapse-free. EDSS scores remained stable to week 144. The incidence of elevated liver enzymes was 5%. MRI outcomes were reported separately (Reich et al. ECTRIMS/ACTRIMS 2023;P684). For the group on continuous tolebrutinib 60 mg, the mean number of new Gd+ lesions from the previous scan was 0.48 at week 144; 79.3% had no new Gd+ lesions. Mean T2 volume was reduced from 12.74 cm3 to 0.42 cm3. Paramagnetic rim lesions (PRL) were examined in 20 patients. PRL count was unchanged in 15 patients, two had one lesion that resolved by week 144 and three patients had new PRLs at endpoint.
Effect of anti-CD20s on IgG
IgG levels appear to decline during treatment with ocrelizumab but generally remain above the lower limit of normal (LLN), according to the ACAPELLA real-world study (O’Shea et al. ECTRIMS/ACTRIMS 2023;P315). IgG levels were evaluated at baseline and over a five-year course of therapy in 434 MS patients. Mean IgG levels decreased 12.17% over 9 treatment cycles (-10.82% at 11 cycles). A total of 5.7% experienced hypogammaglobulinemia; levels remained >LLN in 94.3% of patients. The infection rate was slightly higher in patients with a low IgG level vs. normal level at baseline (46.0 vs. 44.1 cases/100 patient-years).
An analysis of the ALITHIOS open-label study (N=1969) evaluated the long-term effect of ofatumumab on immunoglobulin levels (Wiendl et al. ECTRIMS/ACTRIMS 2023;P709). Overall, IgG levels remained >LLN at all time points in 98% of patients for up to five years after initiating ofatumumab. The mean change from baseline in IgG was -2%. The rate of serious infections was similar in patients with IgG <LLN vs. >LLN. Mean IgM levels declined but remained >LLN; IgM levels were >LLN at all time points in 69.4% of patients.
Low T cell count after switching off fingolimod
Patients switching from fingolimod to ocrelizumab or natalizumab have low CD4+ T cell counts that persist for up to 48 months, according to a retrospective Italian study (Rolando et al. ECTRIMS/ACTRIMS 2023;P683). The study examined 336 patients who switched treatments. A lower absolute lymphocyte count (ALC) and CD4+ lymphocyte count were seen at all time points in patients switching from fingolimod to either ocrelizumab or natalizumab. No effect was seen on CD8+ T cells or NK cells. ALC was not affected when switching from other DMTs to ocrelizumab or natalizumab. A number of recent studies have raised concerns about the impact of prior therapies on ocrelizumab efficacy (Abbadessa et al. J Neuroimmunol 2023;378:578072).
The efficacy of ocrelizumab was reduced in patients switching from fingolimod in a German real-world cohort (Wolff et al. ECTRIMS/ACTRIMS 2023;P279). Interestingly, a loss of efficacy was not seen in patients switching from fingolimod to ofatumumab although the reasons for this are unclear.
Novel therapy in development
CD40 ligand (aka CD154) is a costimulatory protein expressed on activated T cells that facilitates T and B cell interactions and promotes B cell maturation. Frexalimab is a monoclonal antibody that targets CD40L and is currently in phase II testing. According to the preliminary unpublished results (N=129), high-dose frexalimab was associated with an 89% reduction in Gd+ lesions at week 12 in patients with RMS. During the open-label 12-week extension, 125 patients received high- or low-dose frexalimab (Vermersch et al. ECTRIMS/ACTRIMS 2023;P275). The mean number of new Gd+ lesions was reduced from 0.3 at week 12 to 0.1 at week 24 in the continuous high-dose group; 96% had no new Gd+ lesions. The lesion count was 0.6 and 0.5 at the two time points in the low-dose group; 80% had no new Gd+ lesions. Lesion counts were substantially reduced from 2.8 to 0.7 in placebo patients switched to high-dose frexalimab. The most common adverse events were COVID-19, nasopharyngitis and headache. The rate of serious adverse events was 4.0%.
Tracking eye movements as a biomarker of progression
A novel eye-movement tracking tool may help to identify subtle changes in physical and cognitive disability, according to an interim analysis of a study at McGill University (Giacomini et al. ECTRIMS/ACTRIMS 2023;P1427). Eye-movement metrics were correlated with EDSS, SDMT and BICAMS. Click here to listen to a NeuroSound podcast with lead author Dr. Paul Giacomini.
Clinical tip of the day
Anti-CD20 therapy in the months before pregnancy is associated with a lower relapse rate in the pregnancy/postpartum period compared to prior treatment with natalizumab or fingolimod (Sahloul et al. ECTRIMS/ACTRIMS 2023;P062). An analysis of 66 consecutive pregnancies also reported that MRI activity during pregnancy/postpartum occurred in 5.2% of the ocrelizumab group vs. 63.1% for natalizumab and 72.2% for fingolimod. Median disability scores were stable with ocrelizumab during pregnancy/postpartum but increased 1 point in the natalizumab group and 0.5 points in the fingolimod groups. These findings suggest that women who discontinue natalizumab or fingolimod due to pregnancy are at risk of rebound disease activity during pregnancy/postpartum.
October 12 Edition
October 11 Edition