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IMU-838 Efficacious and Well-Tolerated in Relapsing Multiple Sclerosis

The therapy has fewer off-target effects on kinases and may be better-tolerated than other DHODH inhibitors for patients with relapsing MS.

Topline results from the phase 2 double-blind, placebo-controlled, randomized, parallel-group EMPhASIS trial (NCT03846219) suggest that oral vidofludimus calcium (IMU-838) reduced combined unique active (CUA) magnetic resonance imaging (MRI) lesions in patients with relapsing multiple sclerosis (RMS).

These results were presented at the 2021 American Academy of Neurology (AAN) Annual Meeting, April 17-22, by Robert J. Fox, MD, neurologist, Mellen Center for Multiple Sclerosis, and Vice-Chair for Research, Neurological Institute, Cleveland Clinic. Fox and colleagues sought to evaluate the safety, tolerability, and efficacy of IMU-838, a next-generation, small-molecule dihydroorotate dehydrogenase (DHODH) inhibitor that has a more selective mechanism and shorter half-life than other DHODH inhibitors.

“[IMU-838] is in the same class as teriflunomide but lacks off-target effects on kinases which may reduce side effects,” Fox said during his presentation. “Patient disposition shows excellent study retention with little dropout.”

The EMPhASIS study consists 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). Five patients (7.2%) discontinued in the placebo group due to liver enzyme elevations (n = 2), cervix carcinoma (n = 1), and hematuria (n = 1). Two (2.8%) discontinued in the 30-mg group for no reported reasons and 4 (5.8%) discontinued in the 45-mg group for liver enzyme elevations (n = 2) and rash (n = 1).

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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.

Fox and colleagues also found that the 30-mg group had an adjusted mean annualized relapse rate (ARR) of 0.39, compared to the ARR of 0.48 in the 45-mg group, and 0.53 in the placebo group. The mean percentage change from baseline to week 24 in serum neurofilament light (NfL) was –17.0% in the 30-mg group, –20.5% in the 45-mg group, and 6.5% in the placebo group. Expanded Disability Status Scale score remained constant in both treatment groups.

Safety profiles were similar across all groups, with 70 treatment-emergent adverse events (TEAEs) in 32 patients (75.1%) in the 30-mg group, 59 TEAEs in 29 patients (40.6%) in the 45-mg group, and 62 TEAEs in 30 patients (43.5%) in the placebo group. Three serious AEs occurred: squamous cell carcinoma of the cervix in placebo, an open fracture, and ureterolithiasis, all in the 30-mg group. Altogether, researchers saw no differences between groups in AEs as well as no concerns with renal and hepatic toxicity.

“Overall, these results compare quite favorably with other first-line and oral therapies in RMS. A phase 3 program is being planned,” Fox said. The phase 3 program is expected to start in the second half of 2021.

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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