Vidofludimus Calcium Demonstrates Therapeutic Potential in Latest Phase 2 CALLIPER Trial Data of Progressive Multiple Sclerosis

Daniel Vitt, PhD

Newly announced data from the phase 2 CALLIPER trial (NCT05054140) showed that treatment with investigational vidofludimus calcium (Immunic) led to a 20% risk reduction in confirmed disability worsening (CDW) events among patients with progressive multiple sclerosis (PMS) relative to placebo. In addition, the therapy was safe and led to modest benefits on the exploratory primary MRI end point of brain volume change, further supporting the therapy’s development in this patient population.¹

CALLIPER was a double-blind, placebo-controlled exploratory study featuring patients with primary PMS (PPMS; n = 152) and non-active secondary PMS (naSPMS; n = 268) who received 45 mg daily doses of vidofludimus calcium or placebo for up to 120 weeks. All told, results revealed a 20% relative risk reduction of 24-week CDW events in the overall population, with an even greater effect observed in the PPMS group (30% reduction). Those with naSPMS also saw benefits from treatment, with a respective 15% reduction in comparison with placebo.

Vidofludimus calcium, a nuclear receptor related 1 (Nurr1) activator, reduced the relative risk of 24-week CDW events in patients without gadoliunium-enhancing lesions by 29% compared with placebo. While the trial enrolled patients with lower evidence of focal inflammatory disease and on-study relapses, a consistent reduction of disability worsening was observed across various subpopulations, regardless of inflammatory gadolinium-enhancing lesion activity at baseline or during the study.

"The tremendous reduction of confirmed disability worsening in PMS patients is a wonderful confirmation of the objectives of this exploratory phase 2 trial. CALLIPER was designed to evaluate the clinical efficacy, safety and tolerability of vidofludimus calcium in a broad set of PMS patients to determine the suitability of advancing to a confirmatory phase 3 program," Daniel Vitt, PhD, chief executive officer at Immunic, said in a statement.¹

He added, "We are particularly thrilled to see such a clinically meaningful effect in the PPMS population, with a 30% reduction in the relative risk of 24-week confirmed disability worsening events, which would be the endpoint of a future phase 3 registration study, outperforming historic trials in PPMS regarding numerical reduction of disability progression events. We believe that vidofludimus calcium may represent a novel and exciting approach for people living with PMS, where there continues to be a huge unmet medical need given only one approved therapy. We look forward to discussing these results with healthcare authorities to determine appropriate next steps for vidofludimus calcium in PMS."

On MRI end points, the most notable difference came on thalamic brain volume, where treatment with vidofludimus calcium resulted in a 20% reduced annualized rate relative to placebo. Annualized rate of percent brain volume change, another end point, was less pronounced, with 5% improvement for those on active treatment vs placebo. Furthermore, treatment with active therapy showed a significant reduction in new or enlarging T2 lesions compared with placebo over time, with a mean percent change of -0.22% for vidofludimus calcium versus +2.97% for placebo at month 24, reflecting a 3.19% benefit.

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Andreas Muehler, MD, MBA

"The most significant unmet need in MS continues to be the lack of safe and effective therapies that can slow or halt disease progression, especially in PPMS and non-active SPMS," Andreas Muehler, MD, MBA, chief medical officer at Immunic, said in a statement. "Vidofludimus calcium is the only medicine in development for MS that has been shown to be a potent activator of Nurr1, which plays a key role in neuroprotection. With this unique mode of action, vidofludimus calcium could become the first real neuroprotective treatment option for patients with progressive forms of MS."¹

He added, "We believe today’s exciting results of the phase 2 CALLIPER trial further validate vidofludimus calcium’s scientific rationale, specifically driven by the impressive numerical benefit in reducing disability worsening, which deserves to be further tested in a phase 3 registration trial. Since almost all disability events in a non-active PMS population are known to be progression independent of relapse activity (PIRA), we believe the CALLIPER results also corroborate the benefit on disability progression expected for people suffering from relapsing forms of MS, allowing for a beneficial read-through to our ongoing phase 3 ENSURE trials."

Overall, the safety profile of vidofludimus calcium was consistent with previous trials, with no new emerging signals observed. The incidence of treatment-emergent adverse events (TEAEs) were similar between the cohorts: 69.4% of those on vidofludimus calcium vs 68.5% of those on placebo. Serious adverse events also occurred at a similar rate, with 8.1% and 6.5% of those in the vidofludimus calcium and placebo groups, respectively, experiencing these.

As Muehler alluded to, vidofludimus calcium is currently being examined in 2 phase 3 trials of relapsing MS, expected to be completed in 2026. The studies, dubbed ENSURE-1 and ENSURE-2, are 2 identical, randomized, double-blind trials testing the efficacy and safety of 30 mg daily doses of vidofludimus calcium in a cohort of 1050 adults with relapsing MS.²

In October 2024, Immunic announced the positive futility analysis of the ENSURE trials by an Independent Data Monitoring Committee (IDMC), which deemed the studies may proceed as planned. The IDMC also was questioned on whether the sample size of the trial should be increased, to which they answered the trial should “continue as planned.” Both the decision to keep the cohort size, as well as whether the findings were futile, were based on the conditional power of the trials at the time of the interim analysis. To date, Immunic has remained blinded during the interim analysis and has not seen any of the data available to the IDMC to make their recommendation.

REFERENCES
1. Immunic Announces Vidofludimus Calcium Reduced Risk of Disability Worsening by 30% in Primary Progressive Multiple Sclerosis Patients from Phase 2 CALLIPER Trial. News release. Immunic. April 30, 2025. Accessed April 30, 2025. https://imux.com/immunic-announces-vidofludimus-calcium-reduced-risk-of-disability-worsening-by-30-in-primary-progressive-multiple-sclerosis-patients-from-phase-2-calliper-trial/
2. Immunic Announces Positive Outcome of Interim Analysis of Phase 3 ENSURE Program of Vidofludimus Calcium in Relapsing Multiple Sclerosis. News release. Immunic. October 22, 2024. Accessed April 30, 2025. https://finance.yahoo.com/news/immunic-announces-positive-outcome-interim-103000104.html