Phase 3 ENSURE Program of Vidofludimus Calcium Continues Following Positive Futility Analysis

Andreas Muehler, MD, MBA, chief medical officer at Immunic

According to an announcement from Immunic, an Independent Data Monitoring Committee (IDMC) review of unblinded, interim data from the phase 3 ENSURE program assessing vidofludimus calcium in patients with relapsing multiple sclerosis (RMS) was positive, advising that the trials continue as planned. ENSURE, which includes 2 phase 3 trials (ENSURE-1; ENSURE-2), uses time to first relapse up to 72 weeks as the primary end point.¹

ENSURE 1 and 2 are 2 identical multicenter, randomized, double-blind trials expected to enroll approximately 1050 adults with RMS representing 15 different countries. ENSURE-1 is anticipated to be completed in the second quarter of 2026, while ENSURE-2 is expected to complete in the second half of 2026. The trials test the efficacy and safety of 30 mg daily doses of vidofludimus calcium, a small molecule drug that is designed to activate the neuroprotective transcription factor nuclear receptor related 1 (Nurr1), which is associated with direct neuroprotective properties.

In the program, an unblinded IDMC committee performed the interim futility analysis based on a pre-specified assessment after approximately half of the planned first relapse events occurred in the double-blind treatment periods of each of the twin studies. The analysis aimed to guide potential sample size adjustments and ensure the final study readout occurs after sufficient events, with the unblinded IDMC determining that futulity criteria had not been met.

"While Immunic remains blinded to all data, the IDMC's favorable recommendations in this interim analysis corroborate our initial assumptions for the design, powering and relapse rate of the twin phase 3 trials of vidofludimus calcium in RMS, and suggest that they are in line with the data observed so far,” Andreas Muehler, MD, MBA, chief medical officer at Immunic, said in a statement.¹ "In particular, the planned sample size seems appropriate to address the primary endpoint of time to first relapse. As the IDMC recommends, we are continuing the ENSURE trials unchanged, with completion expected in 2026."

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.

"I am particularly excited about the positive outcome of the interim analysis of our phase 3 ENSURE trials, marking the successful achievement of a critical milestone for the program," Daniel Vitt, PhD, chief executive officer at Immunic, said in a statement.¹ "We are confident in vidofludimus calcium's potential to transform the oral MS market and continue to believe that the phase 3 program provides a clear and straightforward path towards seeking potential regulatory approval in RMS."

Vidofludimus calcium, otherwise known as IMU-838, is a highly selective inhibitor of the enzyme dihyroorotate dehydrogenase (DHOD), a key enzyme in the metabolism of overreactive immune cells and virus-infected cells. It was previously studied in the phase 2 EMPhASIS trial (NCT03846219), a placebo-controlled study of 268 patients with relapsing-remitting MS. Data published earlier this year showed that daily doses of 30-mg and 45-mg of the drug, but not 10-mg, decreased the cumulative number of active lesions compared with placebo, thus establishing the lowest efficacious dose.²

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In the cohort, the mean cumulative combined unique active (CUA) lesions was 5.8 (95% CI, 4.1-8.2) for placebo (n = 81), 5.9 (95% CI, 3.9-9.0) for 10-mg treatment group (n = 47), 1.4 (95% CI, 0.9-2.1) for 30-mg treatment group (n = 71), and 1.7 (95% CI, 1.1-2.5) for 45-mg treatment group (n = 69) over 24 weeks. Researchers reported a decrease in serum neurofilament light chain decreased in a dose-dependent manner. Notably, only 3 patients in the placebo group (3.7%) and 3 patients in any dose group of IMU-838 (1.6%) had confirmed disability worsening after 24 weeks.

Vidofludimus calcium is also being investigated for its neuroprotective effects in the phase 2 CALLIPER trial (NCT050541140) of patients with progressive MS. The study featured 467 randomized patients with primary progressive MS (35.2%), non-active secondary progressive MS (59.5%), and active secondary progressive MS (7.9%) to vidofludimus calcium or placebo over 120 weeks. In the trial, investigators performed a preplanned interim analysis assessing serum neurofilament light (sNfL) after half of the participants completed 24 weeks of the treatment and had biomarker data available at baseline and week 24.³

The interim data, presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, showed that serum NfL levels were reduced by 22.4% (P = .01) after 24 weeks of treatment, with consistent treatment effects seen across each progressive MS subtype. Notably, the vidofludimus calcium group displayed a 10% decrease compared with a 20% increase sNfL for placebo among those with an Expanded Disability Status Scale no more than 5.5. During the meeting, study author Robert Fox, MD, along with Muehler, sat down to discuss the therapeutic potential of the treatment and its dual mechanism of action. In the clip below, the duo also talked about the significance of sNfL reduction, as well as other notable points regarding the CALLIPER study.

REFERENCES
1. 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 October 22, 2024. https://finance.yahoo.com/news/immunic-announces-positive-outcome-interim-103000104.html
2. Fox RJ, Wiendl H, Wolf C, et al. Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial. Neurol Neuroimmunol Neuroinflamm. 2024;11(3):e200208. doi:10.1212/NXI.0000000000200208
3. Fox RJ, Wolf C, Ondruš M, et al. Serum Neurofilament Changes in Progressive MS: Exploring the Impact of Vidofludimus Calcium by Age and Disability in the CALLIPER Study Interim Analysis. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark. Abstract 686.