ECTRIMS 2022 HIGHLIGHTS – FRIDAY, OCTOBER 28 EDITION

 

38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis – October 26-28, 2022

The following summarizes some of the highlights from Day 2 of ECTRIMS 2022.

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Siponimod effects in active and inactive SPMS patients
Update on BTK inhibitors
Role of fluid biomarkers
Clinical tip of the day

CONGRESS HIGHLIGHTS – FRIDAY EDITION

Siponimod effects in active and inactive SPMS patients
A new analysis examined data for 632 SPMS patients in the global siponimod managed access program (BAF2001M) (de las Heras et al. ECTRIMS 2022; P325). The program enables access to siponimod in countries where the drug is not yet approved. Patients with nonactive SPMS were included prior to January 2021. Mean age was 52 years. The mean EDSS score was unchanged from baseline to month 24. EDSS scores were stable or improved in 94% of patients, suggesting a treatment benefit even in nonactive SPMS.

Update on Bruton’s tyrosine kinase (BTK) inhibitors
The evobrutinib phase II trial compared three doses (25 or 75 mg OD, 75 mg BID) with placebo and dimethyl fumarate (Montalban et al. N Engl J Med 2019;380:2406-2417). Through weeks 12-24, the number of Gd+ lesions reportedly significantly decreased only in the evobrutinib 75 mg arm. There were no significant differences in annualized relapse rate (ARR) or disability progression with any dose. Following a 24-week blinded extension, patients remained in their initial dose group (with placebo switched to evobrutinib 25 mg) (Vermersch et al. ECTRIMS 2022; P731). At week 48, patients entered the open-label extension and received evobrutinib 75 mg/day for 49.8 weeks before switching to evobrutinib 75 mg BID. During the 75-mg OD phase, the mean number of Gd+ lesions increased, but declined after switching to 75 mg BID. The authors noted that 75 mg BID was the fasting dose, which corresponds to a 45 mg BID fed dose.

A separate study provided an update on the effect of evobrutinib on neurofilament-light chain (Kuhle et al. ECTRIMS 2022; EP1021). Preliminary results were presented last year (Kuhle et al. ECTRIMS 2021; 116). NfL Z-scores were significantly reduced from week 12 with evobrutinib 75 mg BID. The effect was sustained to week 48.

Results from the phase IIb trial of tolebrutinib (5, 15, 30 or 60 mg/day) were reported last year (Reich et al. Lancet Neurol 2021;20:729-738). Patients received tolebrutinib for 12 weeks followed by four weeks of placebo (cohort 1), or four weeks of placebo followed by 12 weeks of tolebrutinib (cohort 2). The reduction in Gd+ lesions was dose-dependent; the reduction was 85% versus placebo with tolebrutinib 60 mg after 12 weeks of active treatment.

Long-term data are now available. At the end of the 16-week trial there was a treatment gap (0-21 weeks) before starting the long-term extension (Reich et al. ECTRIMS 2022; P297). In Part A, patients received the original study dose (5-60 mg/day); at 48 weeks (Part B), all patients received the 60-mg dose. In the continuous 60-mg group, the mean number of Gd+ lesions, new/enlarging T2 lesions and change in T2 lesion volume were low through to week 96. A total of 11 patients discontinued treatment due to lack of efficacy, adverse effects or other reasons (Oh et al. ECTRIMS 2022; P308). The most common adverse effects were COVID-19 (20.8%), headache (13.6%), nasopharyngitis and upper respiratory tract infection (11.2%), bacterial cystitis (7.2%), pharyngitis (5.6%) and arthralgia (5.6%). Similar results were reported for the subgroup with highly-active disease (Fox et al. ECTRIMS 2022; P292).

Role of fluid biomarkers
The prognostic value of fluid biomarkers is uncertain, as shown by several reports at ECTRIMS. An analysis of 1716 MS patients on different DMTs found that changes in neurofilament-light (NfL) levels were not useful in predicting treatment response, as determined by relapses, disability progression or disability improvement (Moradi et al. ECTRIMS 2022; P352). A separate study reported that sNfL was only prognostic for disability worsening in patients >60 years who also had elevated levels of glial fibrillary acidic protein (GFAP) (Barro et al. ECTRIMS 2022; P254). GFAP alone performed better in predicting six-month confirmed disability progression (hazard ratio 1.41), notably in patients aged 40-50 years (HR 1.93).

In the CLIMB study, a change from baseline in GFAP in the first few months of starting a high-efficacy DMT was predictive of time to new T2 lesions and time to disability progression (Moreira Ferreira et al. ECTRIMS 2022; P327). NfL was generally uninformative. The prognostic value of NfL in CSF was improved when used in conjunction with measures of intrathecal IgM synthesis, which has been proposed as a biomarker of disease severity in RRMS (Rosenstein et al. ECTRIMS 2022; P257). The combined measure was strongly associated with early progression to EDSS >3 (HR 4.6) or EDSS >6 (HR 8.2).

In the OBOE study of CSF biomarkers in ocrelizumab-treated patients, GFAP and neurofilament-heavy chain (NfH) were correlated with higher EDSS score, T2 lesion volume and SELs (Cross et al. ECTRIMS 2022; P449). cNfL was correlated with Gd+ lesion count and SEL count. The findings suggest that GFAP is primarily associated with neurodegenerative processes whereas NfL mostly reflects inflammation. Further complicating the picture, however, were findings from the ASCEND trial of natalizumab, which found that GFAP changes were only weakly correlated with progression (EDSS, T25FW, 9HPT) if acute inflammation (relapses, MRI lesions) was absent (Jiang et al. ECTRIMS 2022; EP1019).

Clinical tip of the day
Bowel/bladder symptoms may indicate the presence of progression independent of disease activity (PIRA) (Portaccio et al. ECTRIMS 2022; P051). In an analysis of 8998 patients in the Italian MS Registry over a 12-year period, 55.8% experienced at least one confirmed disability accumulation (CDA) event. PIRA accounted for 68.5% of first CDA events. Most events involved >2 functional systems, most commonly bowel/bladder (odds ratio 1.29) and cerebral function (OR 1.54). Pyramidal or sensory involvement was more commonly associated with relapse-associated worsening (RAW).

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