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 (2872)

Objective: To report efficacy, safety and tolerability of oral vidofludimus calcium (IMU-838) in EMPhASIS (NCT03846219), a phase 2 double-blind, placebo-controlled, randomized, parallel-group trial in relapsing multiple sclerosis (MS).

Background: Dihydroorotate dehydrogenase (DHODH) inhibition is an established mode of action for the disease-modifying treatment of relapsing MS. IMU-838 is a potent, selective next-generation oral DHODH modulator with no off-target effects on kinases and for which general antiproliferative effects (e.g. neutropenia or diarrhea) have not been observed in previous clinical trials.

Design/Methods: Patients with relapsing MS were enrolled at 36 centers in four European countries. A total of 210 patients were randomly assigned in a 1:1:1 ratio to receive once-daily oral doses of IMU-838 (30 or 45 mg, respectively) or placebo for 24 months. The primary endpoint was the cumulative number of combined unique active (CUA) MRI lesions. Secondary endpoints included clinical efficacy, safety and tolerability parameters.

Results: In the intention-to-treat population, significantly fewer CUA lesions were observed with both IMU-838 30 mg (−70%, p=0.0002) and 45 mg (−62%, p<0.0001) as compared to placebo. The annualized relapse rate was 0.39 with IMU-838 30 mg, 0.48 with IMU-838 45 mg, and 0.53 with placebo. In contrast to placebo, treatment with IMU-838 showed a robust decrease of serum neurofilament light levels. The overall treatment discontinuation rate was 4.3% with IMU-838 and 7.2% for placebo. Three serious treatment-emergent adverse events (TEAE) were reported in subjects assigned to 30 mg IMU-838 (open fracture, ureterolithiasis) and placebo (squamous cell carcinoma of the cervix), none was observed at the 45 mg dose. The most common TEAE were headache and nasopharyngitis.

Conclusions: Both 30 mg and 45 mg IMU-838 once daily significantly reduced CUA MRI lesions over 24 weeks compared to placebo, with a favorable safety and tolerability profile. Further assessment of this next generation DHODH modulator in Phase 3 clinical trials is warranted.

Disclosure: Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AB Science. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Janssen. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Celgene. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Immunic. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. The institution of Dr. Fox has received research support from National Institutes of Health. Dr. Fox has received publishing royalties from a publication relating to health care. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristows. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi-Aventis. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PSI CRO Deutschland GmbH. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genzyme. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi-Aventis. The institution of Dr. Wiendl has received research support from Biogen. The institution of Dr. Wiendl has received research support from Merck. The institution of Dr. Wiendl has received research support from Novartis. The institution of Dr. Wiendl has received research support from Hoffmann LaRoche. The institution of Dr. Wiendl has received research support from Deutsche Forschungsgemeinschaft. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck Healthcare KGaA. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Immunic AG. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis Pharma AG. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck Serono S.p.A. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche S.p.A.. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Celgene International II Sàrl. The institution of Dr. De Stefano has received research support from Italian MS Society. The institution of Dr. De Stefano has received research support from Merck Healthcare KGaA. Dr. Sellner has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Boehringer, Celgene, Immunic, Merck, Novartis, Roche, Sanofi. Dr. Sellner has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion, Biogen, Immunic, Merck, Novartis, Roche, Sanofi. Dr. Sellner has received personal compensation in the range of $0-$499 for serving as a Reviewer with Ethics Committtee. Dr. Muehler has received personal compensation for serving as an employee of Immunic Inc.. Dr. Muehler has received stock or an ownership interest from Immunic Inc.. Dr. Muehler has received intellectual property interests from a discovery or technology relating to health care.