Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Studies to Assess the Safety and Efficacy of Elezanumab when Added to Standard of Care in Relapsing and Progressive Forms of Multiple Sclerosis

Abstract

Objective: Elezanumab is a monoclonal antibody that binds repulsive guidance molecule a (RGMa), an inhibitor of central nervous system regeneration after inflammation or injury. The aim was to assess the safety and efficacy of elezanumab in relapsing and progressive forms of multiple sclerosis (MS).

Methods: RADIUS-R and RADIUS-P were phase 2 trials in relapsing (RADIUS-R) or progressive (RADIUS-P) MS. Participants were randomized to intravenous elezanumab 400mg, 1800mg, or placebo every 4 weeks through week 48. The primary endpoint was the mean Overall Response Score (ORS).

Results: In RADIUS-R, 208 participants received elezanumab 400mg (n = 69), elezanumab 1800mg (n = 69), or placebo (n = 70). In RADIUS-P, 123 participants received elezanumab 400mg (n = 40), elezanumab 1800mg (n = 40), or placebo (n = 43). The primary endpoint of ORS was not met in either study. For RADIUS-R, mean ORS was -0.2 with effect size of -0.2 for elezanumab 400mg and -0.2 with effect size of -0.2 for elezanumab 1800mg. For RADIUS-P, mean ORS was 0.0 with effect size of 0.0 for elezanumab 400mg and 0.1 with effect size of 0.1 for elezanumab 1800mg. Elezanumab was well tolerated; the rate of serious adverse events was similar across treatment groups in both studies. Adverse events with ≥10% of elezanumab population were falls, urinary tract infections, headaches in RADIUS-R and RADIUS-P, and also fatigue, infusion-related reactions, and muscular weakness in RADIUS-P.

Interpretation: Elezanumab was safe and well tolerated, but did not meet the primary endpoint in either study. ANN NEUROL 2025;98:590-602.

FIGURE 1

Trial profile. (A) RADIUS‐R enrolled participants with relapsing forms of multiple sclerosis (RRMS and rSPMS). (B) RADIUS‐P enrolled participants with progressive forms of multiple sclerosis (includes PPMS and nrSPMS), respectively. ^aPrimary reason for discontinuation, participants may have more than one reason for discontinuation. ^bAll randomized participants who received at least 1 dose of study drug were included in the mITT populations. COVID‐19 = coronavirus disease 19; mITT = modified intent‐to‐treat; nrSPMS = non‐relapsing secondary progressive multiple sclerosis; PPMS = primary progressive multiple sclerosis; RRMS = relapsing remitting multiple sclerosis; rSPMS = relapsing secondary progressive multiple sclerosis.

FIGURE 2

ORS in the mITT population. LS mean ORS in the mITT population based on MMRM in (A) RADIUS‐R and (B) RADIUS‐P. Error bars are 95% confidence intervals. The ORS was scored relative to baseline at each assessment and summed for a possible range of −4 (worsening in all components) to +4 (improvements in all components). LS = least squares; mITT = modified intent‐to‐treat; MMRM = mixed‐effect model for repeated measures; ORS = Overall Response Score. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 3

Overall Response Score by subgroups. Subgroup analysis of the primary endpoint (Overall Response Score at week 52) in the modified intent‐to‐treat population based on MMRM. Placebo versus elezanumab (A) 400mg and (B) 1800mg in RADIUS‐R and placebo versus elezanumab (C) 400mg and (D) 1800mg in RADIUS‐P. There is some imbalance in the numbers of participants by median EDSS because of the small number of study participants in each trial that were randomized to 3 treatment groups. ^aThe background immunotherapy subgroup included those taking any of the MS immunotherapies (not just ocrelizumab) outlined in the inclusion criteria for RADIUS‐R and RADIUS‐P at baseline. CI = confidence interval; EDSS = expanded disability status scale; LS = least squares; MMRM = mixed‐effect model for repeated measures; MS = multiple sclerosis; PPMS = primary progressive MS; rSPMS = relapsing secondary progressive MS.