Redefining Relapse in Efficacy Measures for Multiple Sclerosis Treatments: Stephen Krieger, MD; Enrique Alvarez, MD, PhD

WATCH TIME: 3 minutes

"We've changed the way relapse is being looked at which could have implications for how we analyze our data, and even how trials are done in the future."

In relapsing multiple sclerosis (MS) trials, the key objective centers around diminishing the annualized relapse rate (ARR). Nevertheless, high efficacy therapies, as observed in the phase 3 ULTIMATE studies (NCT03277261; NCT03277248), present a perplexing scenario for clinicians. Despite achieving a significant 90% reduction in new/enlarging (n/e)T2 lesions, the reduction in relapses held at 54.2%. Researchers suggested that this apparent contradiction may be attributed to potential confounding factors stemming from pseudoexacerbations.¹ These events involve the resurgence of symptoms that meet relapse criteria without the accompanying focal inflammation.

Presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 29 to March 2, by senior author Stephen Krieger, MD, and lead author Enrique Alvarez, MD, PhD, new findings from an analysis suggested that pseudoexacerbations are expected to contribute equally to both arms in clinical trials which can influence the primary outcome.¹ In this study, investigators compared the proportion of patients with relapses to those with n/eT2 MRI lesion in the ublituximab (Briumvi; TG Therapeutics) and teriflunomide (Aubagio; Sanofi) arms from the ULTIMATE trials. Researchers applied a stricter relapse definition, requiring n/eT2 lesions on MRI after the relapse event, during the analysis for both arms.

In the ULTIMATE trials, the ratio of ublituximab-treated participants with n/eT2 lesions to those with a relapse was 3.32, similar to teriflunomide-treated participants at 3.04. After rebaselining this ratio for teriflunomide-treated participants, the ratio was stable at 3.13 at week 24 while the ratio flipped to 0.27 for those on ublituximab. Following the application of the redefined relapse criteria using MRI-supported relapses, 75 out of 97 relapses (77.3%) in the ublituximab-treated participants and 38 of the 213 (17.8%) of the relapses in the teriflunomide-treated participants were not confirmed. The ublituximab ARR reduction increased to 87.6% (R, 0.124 [0.074, 0.209]; P <.0001), with ARR at 0.190 for teriflunomide and 0.024 for ublituximab.

At the forum, Krieger, associate professor of neurology at Icahn School of Medicine at Mount Sinai, and Alvarez, associate professor of neurology, University of Colorado School of Medicine, sat down with NeurologyLive® to discuss how redefining relapse may impact the outcome measures for therapies in MS. The experts in MS also talked about the percentage qualified that met the relapse definition, and how many were determined as pseudo-relapses. In addition, the duo spoke about how the larger effect size observed in the study may contribute to the potential reduction in the number of patients required for future trials.

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REFERENCES
1. Alvarez E, Bodhinathan K, Xu Y, Miskin H, Lee L, Krieger S. MS Relapse Redefined: Addressing the Radiological/Pseudoexacerbation Paradox With High Efficacy Therapy in the ULTIMATE I and II Trials. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. P110.