Phase 3 ENSURE Program of IMU-838 in Relapsing Multiple Sclerosis Cleared

Robert J. Fox, MD

The FDA has cleared the investigational new drug application (IND) for the phase 3 ENSURE program, which will evaluate Immunic’s investigational agent IMU-838 in patients with relapsing-remitting multiple sclerosis (RRMS). Immunic also announced that a separate IND application for the supportive phase 2 CALLIPER trial of IMU-838 in patients with progressive multiple sclerosis (PMS) has been cleared as well.¹

The ENSURE program is comprised of 2 identical, double-blind, twin phase 3 trials, titled ENSURE-1 and ENSURE-2, designed to evaluate the efficacy, safety, and tolerability of IMU-838 in a 30-mg daily dose versus placebo in patients with RRMS. Approximately 1050 adult patients with active RRMS are expected to be enrolled in the studies and will be evaluated on time to first relapse as the primary end point. Both trials will run concurrently, with dosing of the first patient expected in the second half of 2021.

"IMU-838’s phase 2 results in relapsing-remitting multiple sclerosis showed an encouraging balance between efficacy, safety, and tolerability and I look forward to the phase 3 program in this indication,” Robert J. Fox, MD, neurologist, Mellen Center for Multiple Sclerosis, and Vice-Chair for Research, Neurological Institute, Cleveland Clinic, said in a statement. “There is a clear unmet need for new therapeutic options which can help delay or arrest this process and I look forward to seeing data on IMU-838’s neuroprotective potential.”

Key secondary end points include volume of new T2-lesions, time to confirmed disability progression, time to sustained clinically relevant changes in cognition, and percentage of whole brain volume change, grey matter volume, and white matter volume. The ENSURE program will also apply a pooled analysis of disability worsening across both trials, which may be further supported by data from the CALLIPER trial.

READ MORE: Specific Structural Damage Linked to Worsened Disability Milestones in MS

The company decided to move IMU-838 to a phase 3 setting after it previously showed robust results in the phase 2 EMPhASIS trial (NCT03846219). Topline results from that study presented at the 2021 American Academy of Neurology (AAN) Annual Meeting, April 17-22, showed that the drug reduced combined unique active (CUA) MRI lesions in patients with RRMS.²

The EMPhASIS study consisted of a blinded main treatment period of 24 weeks followed by an optional extended, unblinded treatment period for up to 9.5 years to evaluate long-term safety. MRIs were conducted every 6 weeks. Researchers studied 2 dosages, 30 mg (n = 71) and 45 mg (n = 69) compared to placebo (n = 69). The trial met its primary end point, with 45 mg of IMU-838 showing a 62% reduction in CUA lesions over 24 weeks compared to placebo (P = .0002), as well as its secondary end point, with 30 mg of IMU-838 showing a 70% reduction in CUA lesions over 24 weeks compared to placebo (P <.0001). The time course of CUA lesion reduction was constant throughout follow-up.

CALLIPER, on the other hand, is a multicenter, randomized, double-blind, placebo-controlled phase 2 trial, is intended to run concurrently with and to complement the phase 3 ENSURE program. It is expected to enroll approximately 450 patients at more than 70 sites, with patients randomized to either 45-mg daily doses of IMU-838 or placebo for up to 120 weeks. Investigators will use annualized rate of percent brain volume change as the primary end point. Secondary end points include the annualized rate of change in whole brain atrophy and time to 24-week confirmed disability progression based on the Expanded Disability Status Scale (EDSS). Dosing of the first patient is expected in the third quarter of 2021.

"In our discussions with regulatory authorities, including the FDA and the European Medicines Agency, testing IMU-838 against placebo was viewed as a reasonable approach for our phase 3 program, from both a regulatory and scientific perspective, as placebo provides the cleanest comparator to show proof-of-efficacy and to underline IMU-838’s existing safety and tolerability profile,” Andreas Muehler, MD, chief medical officer, Immunic, said in a statement.

Fox recently sat down with NeurologyLive to provide background on the topline results from the EMPhASIS trial. Watch below as he discusses the potential advantages the drug has over teriflunomide (Aubagio; Sanofi), as well as the relatively low prevalence of adverse events seen within the trial.

REFERENCES

1. Immunic announces FDA clearance to begin IMU-838 phase 3 ENSURE studies in relapsing-remitting multiple sclerosis and phase 2 CALLIPER study in progressive multiple sclerosis. News release. July 1, 2021. Accessed July 8, 2021. https://www.immunic-therapeutics.com/2021/07/01/immunic-inc-announces-fda-clearance-to-begin-imu-838-phase-3-ensure-studies-in-relapsing-remitting-multiple-sclerosis-and-phase-2-calliper-study-in-progressive-multiple-sclerosis/

2. Fox RJ, Wiendl H, De Stefano N, Sellner J, Muehler A. Efficacy and safety of the selective oral DHODH modulator vidofludimus calcium (IMU-838) in relapsing multiple sclerosis (EMPhASIS): a randomized, placebo-controlled phase 2 trial. Presented at 2021 American Academy of Neurology Annual Meeting; April 17-22. Abstract P15 085