by Isabella Colonna
For November we have selected Montalban X, Vermersch P, Arnold DL, Bar-Or A, Cree BAC, Cross AH, Kubala Havrdova E, Kappos L, Stuve O, Wiendl H, Wolinsky JS, Dahlke F, Le Bolay C, Shen Loo L, Gopalakrishnan S, Hyvert Y, Javor A, Guehring H, Tenenbaum N, Tomic D; evolutionRMS investigators. Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials. Lancet Neurol. 2024 Nov;23(11):1119-1132. doi: 10.1016/S1474-4422(24)00328-4. Epub 2024 Sep 19. PMID: 39307151.
…
Inflammation and neurodegeneration in the central nervous system (CNS) of multiple sclerosis (MS) patients drive neuronal damage, brain atrophy and disability. Bruton’s tyrosine kinase (BTK) is a key player in B cell signalling, as well as in other immune cells like monocytes, macrophages, and microglia. BTK inhibitors not only suppress B cells but also target CNS innate immune cell inflammation by affecting microglia and macrophages. Evobrutinib, a highly selective BTK inhibitor, showed encouraging clinical and imaging effects in a phase 2 trial for relapsing MS.
Our paper of the month presents the findings from two large multicentre, double-blind, phase 3 trials (EvolutionRMS1 and EvolutionRMS2), which compared the safety and efficacy of evobrutinib with teriflunomide in adults aged 18-55 and with a diagnosis of relapsing MS.
A total of 1,124 and 1,166 participants were enrolled in the two trials, respectively, and were randomly assigned (1:1) to receive either evobrutinib (45 mg twice daily with placebo once per day) or teriflunomide (14 mg once daily with placebo twice per day). Both treatments were taken orally in an unfasted state, and the median treatment duration was 109.6 weeks.
Evobrutinib did not show any superiority over teriflunomide in reducing the annualised relapse rate up to week 156 (primary outcome). Likewise, it did not outperform teriflunomide in any secondary clinical or imaging efficacy secondary endpoints. With regard to safety, the occurrence of treatment-emergent adverse events was similar between the two groups, with the most common being COVID-19 infection, liver enzyme elevations, and headaches. However, the incidence rates of serious adverse events were more frequent in the evobrutinib group (7.5% vs. 5.6%), and liver enzyme elevations above five times the normal limit occurred more often with evobrutinib than with teriflunomide.
In conclusion, these phase 3 trials indicate that evobrutinib is not superior to teriflunomide in terms of clinical, imaging, or biomarker outcomes in patients with relapsing MS. Moreover, these efficacy findings, in association with the liver-related side effects, do not support the use of evobrutinib in patients with relapsing MS.
