Nurr1 activation: A novel approach to preventing neurodegeneration in MS

Presented by

Prof. Robert Fox , Cleveland Clinic, OH, USA

Conference

ECTRIMS 2025

Outcomes of the phase 2 CALLIPER trial of vidofludimus calcium in progressive MS (PMS) support the hypothesis that activation of the neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) may represent a new therapeutic avenue to prevent neurodegeneration in MS. The treatment also demonstrated a favourable safety and tolerability profile.

Vidofludimus calcium is a first-in-class Nurr1 activator. Prof. Robert Fox (Cleveland Clinic, OH, USA) outlined its multiple mechanisms-of-action:

Enhances neuronal survival in vitro.
Reduces microglial activation in vitro.
Selectively inhibits dihydroorotate dehydrogenase (DHODH), thereby reducing focal inflammation and associated MRI activity.
Reduces Epstein-Barr virus (EBV) reactivations in vitro.

Based on this mechanism, vidofludimus calcium is designed to address both neurodegenerative and inflammatory processes in MS. While its efficacy has been previously explored in relapsing-remitting MS (RRMS), the phase-2 trial CALLIPER trial (NCT05054140) evaluated its effects in patients with progressive forms of the disease [1].

A total of 467 participants from 13 countries with primary progressive MS (PPMS) or secondary progressive MS (SPMS) were enrolled. Eligible participants were <65 years old, had no relapse in the preceding 24 months, evidence of disability worsening, and a baseline Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5. The mean age was 49.7 years, with 64% of the participants being female. Participants were randomised 1:1 to receive vidofludimus calcium (n=235) or placebo (n=232). The primary endpoint was the annualised rate of percent brain volume change (PBVC). Secondary outcomes were time to 24-week confirmed EDSS and composite disability worsening.

“There was no effect of vidofludimus calcium on whole brain atrophy in this PMS cohort,” Prof. Fox reported. The absolute difference in PBVC after 30 months was 4.7% (95% CI -0.285 to 0.379; P=0.78). Although the study was underpowered for disability outcomes, consistent trends suggested a potential benefit on disability progression, as measured by the Composite Disability Worsening (CDW) at week 24:

Overall population: HR 0.859 (95% CI 0.576-1.282; P=0.455)
PPMS: HR 0.778 (95% CI 0.405-1.494; P=0.450)
Non-active SPMS: HR 0.812 (95% CI 0.462-1.428; P=0.470)
Participants without Gd+ at baseline: HR 0.663 (95% CI 0.394-1.115; P=0.121)

“The consistent effect on 24-week CDW among participants without Gd+ lesions supports the presumed clinical neuroprotective role of Nurr1 activation,” Prof. Fox commented.

At 24 weeks, confirmed disability improvement was better in the vidofludimus calcium group than in the placebo group (P<0.034), without adjustment for multiple comparisons.

“Vidofludimus calcium showed a favourable safety and tolerability profile, with adverse event rates similar to placebo. At a daily dose of 45 mg, no new safety signals were identified.”

Prof. Fox concluded: “These data support advancing vidofludimus calcium into a phase 3 trial in PMS.”

Fox RJ, et al. Efficacy and safety of vidofludimus calcium, a novel nurr1 activator and dhodh inhibitor, in progressive multiple sclerosis: data from the phase 2 CALLIPER trial. O024, ECTRIMS 2025 Congress, 24-26 September 2025, Barcelona, Spain.

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