The raft of disease-modifying therapies for multiple sclerosis (MS) looks set to expand further in light of phase III trial results presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress in September 2019. The most notable trials were the OPTIMUM study of the sphingosine-1-phosphate (S1P) receptor 1 (S1P1) inhibitor ponesimod and the ASCLEPIOS I and II trials of the monoclonal antibody ofatumumab.

Ludwig Kappos presented results of the OPTIMUM study, in which ponesimod was compared with teriflunomide for the treatment of relapsing–remitting MS in 1,113 patients. Ponesimod reduced the annualized relapse rate (ARR) by 30.5% and active MRI lesions by 56% compared with teriflunomide. No significant effect was seen on disability progression over 6 months. Fatigue also stabilized with ponesimod but worsened over time with teriflunomide. This trial was the first in which fatigue was a secondary end point.

Ponesimod is selective for S1P1, in contrast to fingolimod and siponimod, which also affect other S1P receptors. Ponesimod also has few active metabolites. These characteristics did not benefit the safety profile, but Kappos says the new drug offers a cleaner pharmacological approach, meaning that ponesimod could be a better candidate than the other S1P1 inhibitors for combination therapies.

In the ASCLEPIOS I and II trials, which were identical in design, ofatumumab was compared with teriflunomide for the treatment of relapsing–remitting MS. Ofatumumab reduced the ARR by 50.5% and 58.5% in the two trials, and reduced active MRI lesions by 82.0–97.5%. Disability worsening was also reduced by >30%. Ofatumumab depletes B cells via the same mechanism as ocrelizumab. Stephen Hauser, who presented the results, said that the efficacies of the two antibodies seem similar, but ofatumumab is a fully human, rather than humanized, antibody and can be administered via subcutaneous injection rather than intravenous infusion, giving it considerable clinical advantages.

Perhaps the most scientifically exciting aspect of the ASCLEPIOS trials was the use of serum levels of neurofilament light (sNfL) as a secondary end point. Ofatumumab reduced sNfL to a significantly greater extent than did teriflunomide, indicating that sNfL will be a useful measure of treatment response in future trials. However, rates of whole-brain atrophy did not differ between the two treatments, raising questions about what biological processes whole-brain atrophy and sNfL are measuring.

Another study of neurofilament created waves at the ECTRIMS meeting by demonstrating that sNfL is increased up to 6 years before clinical onset of MS. This finding indicates that MS has a prodromal phase that lasts several years, and that neuronal damage is already occurring at this stage. The study, by Bjornevik et al., is now published in JAMA Neurology.