Immunic, Inc. announced U.S. Food and Drug Administration (FDA) clearance of its Investigational New Drug (IND) application for the phase 3 ENSURE program of lead asset IMU-838, the company's selective oral DHODH inhibitor, in patients with relapsing-remitting multiple sclerosis (RRMS). In addition, the FDA also cleared the company's separate IND application for the supportive phase 2 CALLIPER trial of IMU-838 in patients with progressive multiple sclerosis (PMS). The ENSURE program comprises two multicenter, randomized, double-blind phase 3 trials designed to evaluate the efficacy, safety, and tolerability of IMU-838 versus placebo in RRMS patients. Based on IMU-838's robust activity in preventing lesion formation in the company's phase 2 EMPhASIS trial in RRMS, the strong and consistent correlation observed between lesion formation and clinical relapse in third-party clinical trials, and the drug's robust safety profile to date, Immunic believes that this phase 3 program provides a simple and straightforward path towards potential regulatory approval of IMU-838 in RRMS. The multicenter, randomized, double-blind, placebo-controlled phase 2 CALLIPER trial is intended to run concurrently with and to complement the phase 3 program in RRMS. In particular, CALLIPER is focused on progressive forms of multiple sclerosis (MS) and designed to corroborate IMU-838's neuroprotective potential, as exemplified by slowing of brain atrophy and delay in disability worsening. Neurodegeneration is a key concern in both PMS and RRMS, since axonal and neural damage is responsible for the increasing and often severe disability experienced by patients. Immunic believes that, if the CALLIPER trial is successful in showing a beneficial effect of IMU-838, this data, along with the ENSURE program and IMU-838's strong safety and tolerability profile, may allow for a meaningful clinical differentiation of IMU-838 from other oral MS medications and an attractive commercial positioning. Although a supportive trial, Immunic does not believe that data from the CALLIPER trial are a pre-condition for filing a New Drug Application in RRMS. Each of the identical twin phase 3 trials, titled ENSURE-1 and ENSURE-2, is expected to enroll approximately 1,050 adult patients with active RMS at more than 100 sites in 14 countries, including the United States, Latin America, Central and Eastern Europe, and India. Patients will be randomized in a double-blinded fashion to either 30 mg daily doses of IMU-838 or placebo and the primary endpoint for both trials is time to first relapse up to 72 weeks. Key secondary endpoints 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. With regard to the disability progression endpoint, the ENSURE program applies a pooled analysis of disability worsening across both trials, which may be further supported by data from the CALLIPER trial. The ENSURE trials will be run concurrently, with dosing of the first patient expected in the second half of 2021. An interim analysis to assess event rates is planned to occur after a certain number of relapses have occurred in the double-blind treatment periods. This analysis is intended to inform potential sample size adjustment and help ensure that final study readout is not planned to occur before sufficient events have been achieved. This interim analysis is not intended as a futility analysis. The phase 2 CALLIPER trial is expected to enroll approximately 450 patients at more than 70 sites in North America, Western, Central and Eastern Europe with patients randomized to either 45 mg daily doses of IMU-838 or placebo in a double-blinded fashion. The trial's primary endpoint is the annualized rate of percent brain volume change up to 120 weeks. Key secondary endpoints 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. An interim analysis comprising an unblinded analysis of serum neurofilament light chain (NfL) is planned to occur once approximately half of the enrolled patients have completed 24 weeks of treatment. NfL has been shown consistently to correlate with disease activity in neurological disorders and has become one of the most important serum biomarkers for axonal damage over the past few years. As previously reported, results of the phase 2 EMPhASIS trial of IMU-838 in RRMS showed a robust decrease in serum NfL at 24 weeks (-17.0% for 30 mg and -20.5% for 45 mg), as compared to baseline values, while the patients on placebo experienced a 6.5% increase in serum NfL over the same period.