Investigating IMU-838 for Relapsing MS

Robert Fox, MD, Vice-Chair for Research at the Cleveland Clinic Neurological Institute, discussed the findings of the phase 2 EMPhASIS trial of this investigational MS therapy.

Data 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 topline 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 studied 2 dosages, 30 mg (n = 71) and 45 mg (n = 69), and compared them 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).

NeurologyLive spoke with Fox to learn more about the advantages that IMU-838 offer over other treatments for RMS. He also gave an overview of the trial’s findings so far and further ongoing research.

NeurologyLive: What advantages does IMU-838 offer over other DMTs for multiple sclerosis?

Robert Fox, MD: IMU-838 is a next-generation small molecule dihydroorotate dehydrogenase (DHODH) inhibitor. It is similar to teriflunomide, which is a currently approved therapy for MS, but lacks the off-target effects on kinases, so we think it may have a better safety and tolerability profile than the currently available teriflunomide.

There are a couple potential advantages of IMU-838 over teriflunomide. It’s a once daily oral-available and orally absorbed therapy, and it has a short half-life of only about 30 hours, and it gets to a steady state in about 6 to 8 hours. As a result, it's eliminated from the body within about 10 days without the need for the accelerated elimination procedure with activated charcoal or cholestyramine that is needed to accelerate the removal of teriflunomide.

Some of the side effects that are known to be associated with teriflunomide include liver irritation, so elevation of liver enzymes, renal injury, also hair loss and lowering of the white blood cell count. What was found in this trial was that none of those were seen with IMU-838. Very little hair loss of any kind was seen. There was not a reduction in white blood cell count, and there did not appear to be an elevation in the rate of liver enzyme irritation or renal impairment.

Could you give an overview of the EMPhASIS trial’s finding?

The emphasis trial was a placebo-controlled dose finding trial in relapsing-remitting MS (RRMS). And like most RRMS trials, the primary endpoint was MRI, so CUA lesions, which are gadolinium enhancing lesions or new/enlarging T2 lesions, both collected on serial brain MRIs. Two doses were evaluated: 30 mg a day of IMU-838 and 45 mg a day of IMU-838 compared to placebo. Over the course of the 24-week trial, what was found is there was a 62 to 70% reduction in CUA lesions in the 45 mg and the 30 mg dose groups and there wasn't much difference between the dose groups either, suggesting similar efficacy of the 2 doses, 30 and 45 mg.

One of the questions that was raised in this trial is what the minimally effective dose is, since both 30 mg and 45 mg seem to be similarly active in reducing the new/enlarging MRI lesions by about two-thirds. So, there is a third cohort that is being evaluated with 10 mg. That will help us identify the minimally effective dose, and based on the results of that additional cohort, we will then be able to decide what dose to take into a phase 3, clinically powered trial.

Transcript edited for clarity. For more coverage of AAN 2021, click here.

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