Vidofludimus for Progressive MS: No Impact on Brain Atrophy but Hints of a Role for Disability

In the phase 2 CALLIPER trial, vidofludimus calcium showed no effect on the primary endpoint of whole brain atrophy in progressive multiple sclerosis (MS) but demonstrated consistent trends suggesting reduction in disability progression across various outcomes, patient populations and patient subgroups.

The results support advancing the novel oral compound to phase 3 trials in progressive MS, investigators with the multicenter CALLIPER trial concluded.

“These findings bolster the hypothesis that the mechanism of vidofludimus calcium — Nurr1 activation combined with DHOD inhibition — may represent a novel means of preventing neurodegeneration in MS,” says first author Robert Fox, MD, a neurologist with Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research who presented the CALLIPER results in an oral presentation at ECTRIMS 2025. “New mechanisms are highly welcome as we strive to address the unmet therapeutic needs of patients with progressive forms of MS.”

A dual mode of action

Vidofludimus calcium (IMU-838) is an investigational small-molecule drug administered orally. It offers a dual mode of action as both an activator of the putative neuroprotective transcription factor Nurr1 (nuclear receptor-related 1) and a selective inhibitor of the pyrimidine biosynthesis enzyme DHODH (dihydroorotate dehydrogenase).

The compound’s Nurr1 activation has been shown to produce direct and indirect neuroprotective effects in vitro through improving neuronal survival and by reducing microglial activation. Its DHODH inhibition has been shown to reduce focal inflammation and associated MRI activity as well as to reduce Epstein-Barr virus reactivation in vitro.

The drug is currently in phase 3 trials for treatment of relapsing MS after phase 2 testing in this patient population showed significant reduction of the development of new brain lesions and trends toward favorable effects on relapse rate and related biomarkers.

Another DHODH inhibitor, teriflunomide, has been commercially available for more than a decade for treating relapsing forms of MS, but it does not share the Nurr1 activation mechanism of vidofludimus calcium. Use of teriflunomide can be limited by its side effect profile, which includes increased rates of diarrhea, alopecia and neutropenia as well as elevated liver enzymes. These unwanted effects of teriflunomide are believed to be due to its interactions with various other kinases separate from DHODH.

The phase 2 EMPhASIS trial for relapsing MS found similar rates of serious adverse events between vidofludimus calcium and placebo, with no clear increase in the rate of infectious, hepatic, renal or hematologic events with active treatment. The CALLIPER trial aimed to assess the drug’s safety and tolerability in patients with progressive MS along with its therapeutic effects in this patient population.

Study design

The CALLIPER investigators randomized 467 patients in a double-blind manner to 120 weeks of treatment with vidofludimus calcium 45 mg once daily (n = 235) or placebo (n =232). Patients were 18 to 65 years old and had an Expanded Disability Status Scale (EDSS) score from 3.0 to 6.5 (mean 5.2, median 5.5), no evidence of relapse in the prior 24 months, and evidence of disability worsening (as judged by an independent reviewer) in the prior 24 months. Randomization was stratified by MS type (primary progressive, nonactive secondary progressive or active secondary progressive) and by baseline EDSS score (≤5.5 or >5.5).

“The treatment and placebo groups were well balanced, and the study population represented the general population of people with progressive MS,” Dr. Fox observes. Similar shares of patients completed the study’s double-blind treatment period per protocol (82.6% of treatment group and 83.6% of placebo group).

Efficacy and safety findings

On the study’s primary endpoint, percent brain volume change on MRI, there was no significant difference between the treatment and placebo groups through 30 months.

The study’s key secondary endpoint was a composite measure of confirmed disability worsening at 24 weeks, comprising scores on the EDSS, the 9-hole peg test and the timed 25-foot walk. “As is typical of phase 2 MS trials, these outcomes were not powered for statistical significance but provide a glimpse into the possible clinical efficacy of this agent,” Dr. Fox notes. On the key secondary outcome, results through 120 weeks showed a trend favoring vidofludimus calcium, although the difference was not statically significant.

Similarly, active treatment showed a favorable trend over placebo on the secondary endpoint of 24-week confirmed disability worsening based solely on EDSS score, although this was not statistically significant. This trend was also observed in subanalyses among patients without gadolinium-enhancing lesions at baseline. “Seeing a similar trend in patients without active lesions at baseline shows that it’s not just through focal inflammation that vidofludimus calcium is working, but also supports the hypothesis that this agent has neuroprotective effects,” Dr. Fox says.

Vidofludimus calcium showed superior effects over placebo on two exploratory endpoints related to disability:

• Change in mean EDSS score through 120 weeks (P < .01)
• Time to 24-week confirmed disability improvement (based on EDSS score) (P = .034)

In the trial’s safety analysis, no new safety signals emerged, and rates of treatment-emergent and serious adverse events were comparable between the treatment and placebo arms. There was no evidence of increased rates of elevated liver enzymes, renal events or infections, which are commonly seen with the approved DHODH inhibitor teriflunomide. “The safety profile in this study was similar to that of previous clinical trials of vidofludimus calcium,” Dr. Fox says.

Bottom line

“Although it was disappointing to see no effect of vidofludimus calcium on brain volume, this has been seen in other progressive MS trials recently and suggests that brain volume may not be the right MRI biomarker for trials in progressive MS,” Dr. Fox says.

“This trial was not adequately powered for disability outcomes,” he adds, “so its disability-related findings should not be overinterpreted.” He notes, however, that the consistent trends in disability findings observed across outcomes (mean EDSS score, both composite and EDSS confirmed disability worsening, and EDSS confirmed disability improvement), patient populations (primary progressive MS and nonactive secondary progressive MS) and subgroups (patients without baseline gadolinium-enhancing lesions) warrant further investigation of vidofludimus calcium for treating disability in progressive MS.

“Additionally,” he says, “the ongoing phase 3 trial program for vidofludimus calcium in relapsing MS should further illuminate the drug’s effect in the relapsing MS patient population.”

The study was sponsored by Immunic Therapeutics.

Dr. Fox reported personal consulting fees from Astoria Biologica, Biogen, Bristol Myers Squibb, Cognito, EMD Serono, Galvani, Immunic, INmune Bio, Kiniksa, Novartis, Sanofi, Siemens and TG Therapeutics. He has served on advisory committees for AB Science, Biogen, Immunic, Novartis and Sanofi, and has received clinical trial contract and research grant funding from Biogen, Novartis and Sanofi.