Phase 2 Data Show Vidofludimus Calcium Suppresses MRI Lesions in Relapsing MS With Good Tolerability

Vidofludimus calcium, an investigational inhibitor of dihydroorotate dehydrogenase (DHODH), significantly reduced new MRI lesions in patients with relapsing-remitting multiple sclerosis (MS) in the phase 2 EMPhASIS trial while demonstrating a favorable safety profile relative to placebo.

The findings, published in the Annals of Clinical and Translational Neurology, set the stage for phase 3 testing of the oral compound.

A safer way to inhibit DHODH?

Inhibition of DHODH, a mitochondrial enzyme with a role in the rate-limiting step of de novo pyrimidine synthesis, has been shown to suppress MRI brain lesions and disease activity in MS.

If ultimately approved by the FDA, vidofludimus calcium would be the second DHODH inhibitor available in the U.S. and Europe for relapsing forms of MS. The first, teriflunomide (Aubagio®), has been commercially available for a decade, but its use can be limited by its side effect profile, which includes elevated rates of diarrhea, alopecia and neutropenia as well as elevated liver enzymes. These effects are believed to be due to off-target interactions with various kinases that are independent from teriflunomide’s effects on DHODH.

Vidofludimus calcium was developed as a selective inhibitor of DHODH without off-target effects. “The EMPhASIS trial was conducted to assess whether vidofludimus calcium reduces development of new active MRI lesions in patients with relapsing-remitting MS while providing a good safety profile,” says the study’s first author and coordinating investigator, Robert Fox, MD, a staff neurologist in Cleveland Clinic’s Mellen Center for Multiple Sclerosis and Vice Chair for Research in its Neurological Institute.

Study design

EMPhASIS was conducted at 38 medical centers in four European nations with limited access to approved MS therapies: Bulgaria, Poland, Romania and Ukraine. Inclusion criteria were as follows:

• Age 18 to 55
• Diagnosis of relapsing-remitting MS according to the 2017 McDonald criteria
• Expanded Disability Status Scale score of 0 to 4
• Evidence of MS disease activity, defined as two or more relapses in the prior 24 months (or one or more in the prior 12 months) and one or more MS-related gadolinium-enhancing brain lesion in the prior 6 months

Patients were randomized in a double-blind fashion and 1:1:1 ratio to 24 weeks of once-daily treatment with one of the following, all given orally:

• Vidofludimus calcium 30 mg
• Vidofludimus calcium 45 mg
• Matching placebo

Enrollees underwent standardized brain MRI scanning and clinical assessment (including routine clinical chemistries and hematology, liver function tests and urinalysis) at baseline and every 6 weeks thereafter through week 24. The primary endpoint was the difference in cumulative number of combined unique active lesions (gadolinium-enhancing lesions and new/enlarging T2 lesions) at week 24 between vidofludimus calcium 45 mg and placebo; the difference in this measure between the 30-mg dose and placebo was the leading secondary endpoint.

Results at a glance

Key results among the study’s 209-patient cohort included the following:

• Significantly fewer combined unique active lesions at week 24 with both doses of vidofludimus calcium compared with placebo — rate ratio of 0.38 (95% CI, 0.22-0.64; P = 0.0002) for the 45-mg dose (primary endpoint) and rate ratio of 0.30 (95% CI, 0.17-0.53; P < 0.0001) for the 30-mg dose (secondary endpoint). Suppression of lesions with active therapy was evident by week 6 and continued through study completion.
• Similar rates of treatment-emergent adverse events among patients randomized to placebo (44%) and both doses of vidofludimus calcium (45% in the 30-mg dose group and 41% in the 45-mg dose group). The most common events were nasopharyngitis and headache and occurred with similar frequency among the groups.
• Similar rates of serious adverse events between the placebo group (1%) and the combined vidofludimus calcium groups (1%).
• Similar rates of study discontinuation and discontinuation due to adverse events between the placebo group (7% and 4%, respectively) and the combined vidofludimus calcium groups (4% and 1%, respectively).
• No increased incidence of infectious, hepatic, renal or hematologic treatment-emergent adverse events with vidofludimus calcium therapy.

On to phase 3 testing

“These results are encouraging, as the study met its primary and secondary endpoints for suppressing combined unique active MRI lesions while showing vidofludimus calcium to be safe and well tolerated,” Dr. Fox observes.

He notes that the study also showed trends favoring vidofludimus calcium in annualized relapse rate and relevant biomarkers, such as neurofilament light chain, although the study wasn’t powered to assess many of these measures. “Longer studies in a larger patient sample are needed to determine this agent’s effect on clinical outcomes,” Dr. Fox says.

He adds that a lower daily dose, 10 mg, was subsequently evaluated in a second cohort of the EMPhASIS trial and that preliminary reports suggest this lower dose is less effective. Given the comparable safety profiles and MRI outcomes for the 30-mg and 45-mg doses of vidofludimus calcium in the current study, 30 mg will be evaluated in phase 3 trials of the compound for relapsing-remitting MS, Dr. Fox notes.

The study was funded by Immunic, Inc., which is developing vidofludimus calcium. Dr. Fox reports receiving consulting fees for serving as an advisor to Immunic.