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New Phase 2 Data of IMU-838 Confirms Long-Term Benefits, Safety in Relapsing Multiple Sclerosis

SAP Partner | <b>Cleveland Clinic</b>

After 24 weeks of treatment, the adjusted mean annualized relapse rates were 0.53 with placebo vs 0.39 and 0.48 for the 30- and 45-mg groups of IMU-838.

Immunic recently announced new supportive data from its phase 2 EMPhASIS trial (NCT03846219) of vidofludimus calcium formulation (IMU-838), with results that showed reductions in MRI lesions in patients with relapsing multiple sclerosis (MS) that was paired with a favorable safety profile.1,2

The findings were consistent with previously published data, including that presented at the 2021 American Academy of Neurology (AAN) Annual Meeting. Led by Robert Fox, MD, neurologist, Mellen Center for Multiple Sclerosis, and Vice-Chair for Research, Neurological Institute, Cleveland Clinic, results showed a total of 6.4 (95% CI, 0.17-0.53; P <.001) combined unique active (CUA) lesions for those on placebo vs 2.4 (95% CI, 1.1-4.9) for those on 45 mg of IMU-838 after 24 weeks of treatment (62% reduction; rate ratio [RR], 0.38; 95% CI, 0.22-0.64; P = .0002).

Developed by Immunic, IMU-838 is a next-generation, small-molecule dihydroorate dehydrogenase (DHODH) inhibitor that has a more selective mechanism and shorter half-life than other DHODH inhibitors. EMPhASIS was a double-blind, placebo-controlled study that enrolled patients 18-55 years with relapsing MS who were assigned 1:1:1 to either once-daily IMU-838 in 30-mg or 45-mg doses, or placebo.

"The results from this phase 2 trial of vidofludimus calcium in patients with RRMS are encouraging, as the trial met its primary and key secondary end points for suppressing the number of combined unique active magnetic resonance imaging lesions," Fox said in a statement.1 "Importantly, vidofludimus calcium was found to be safe and well-tolerated as compared to placebo, with no increase in the rate of infections, effects on liver or blood cell laboratory parameters, and with a very low treatment discontinuation rate."

Patients underwent standardized brain MRI scans at baseline and every 6 weeks after the first day of dosing until week 24. The difference in the number of CUA lesions between the 45-mg and placebo groups was the primary end point, while the key secondary end point was the same outcome for the 30-mg group. In total 95% (198 of 209) of patients completed the study, with completion rates that were similar between the placebo (n = 64; 93%) and the 30 mg (n = 69; 97%) and 45 mg (n = 65; 94%) IMU-838 dosed groups.

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The key secondary outcome showed an adjusted mean CUA lesions of 13.2 (95% CI, 6.6-26.4) for placebo and 4.0 (95% CI, 2.2-7.2) for the 30-mg group of IMU-838 (70% reduction; RR, 0.30; 95% CI, 0.17-0.53; P <.0001). No notable difference was observed in the adjusted mean CUA at 24 weeks between vidofludimus calcium 30 mg and 45 mg. Lower adjusted mean cumulative number of CUA in either IMU-838 dosed groups compared with placebo was evident as early as week 6 and continued through week 24.

The cumulative number of new gadolinium-enhancing lesions up at week 24 was 13.0 (95% CI, 6.8-24.5) for placebo, 4.5 (95% CI, 2.7-7.7), and 4.0 (95% CI, 2.1-7.8) for the 30- and 45-mg IMU-838 dosed groups, respectively. Additionally, the adjusted mean annualized relapse rates were 0.53 (95% CI, 0.32-0.89) for placebo compared with 0.39 (95% CI, 0.22-0.69) for the 30 mg group of IMU-838 and 0.48 (95% CI, 0.28-0.82) for the 45-mg dosed group. Median change in neurofilament light chain in serum from baseline to week 24 was 6.5%, –17.0%, and –20.5% for placebo, vidofludimus calcium 30 mg, and vidofludimus calcium 45 mg, respectively.

In total, 44% of those on placebo experienced at least 1 treatment-emergent adverse event (AE) throughout the study, which was similar to those on 30 mg (45%) or 45 mg (41%) of IMU-838. Alopecia, fatigue, rash, and cystitis were treatment-emergent AEs that occurred in greater than 1% of IMU-838-treated patients that were not found in the placebo group. Three patients experienced four serious adverse events occurred in the vidofludimus calcium 30 mg (n  = 2) and the placebo group (n  = 1) and were considered unrelated to treatment: hydronephrosis and ureterolithiasis (vidofludimus calcium 30 mg), open fracture (vidofludimus calcium 30 mg), and squamous cell carcinoma of the cervix (placebo).

Three (4%) patients on placebo and 6 (4%) patients in either of the IMU-838 dosed groups experienced hepatic treatment-emergent AEs. Rises in aminotransferase or aspartate aminotransferase greater than 5 times the upper limit of normal occurred in 2 (3%) patients with placebo vs 1 (1%) patient and 3 (4%) patients in the 30- and 45-mg IMU-838 groups, respectively. Of the 5 patients who discontinued treatment due to treatment-emergent adverse events, 1 in the placebo group and 2 in the vidofludimus calcium 45 mg group met hepatotoxicity stopping rules.

"Based on these strong data, we have enrolled patients in our phase 2 CALLIPER trial in progressive multiple sclerosis patients to further explore vidofludimus calcium's neuroprotective potential, as exemplified by a slowing of brain atrophy and delay in disability worsening, which are often caused by axonal and neural damage," Daniell Vitt, PhD, chief executive officer and President, Immunic, said in a statement.1 "Equally exciting, we have also been enrolling patients in our phase 3 ENSURE program of vidofludimus calcium as a treatment for relapsing MS. We remain highly enthusiastic about the potential for this novel therapeutic to become a best-in-class DHODH inhibitor in relapsing MS."

In July 2021, the FDA cleared an investigational new drug application for the CALLIPER trial (NCT05054140) to evaluate IMU-838 in patients with progressive MS. The trial is a multicenter, randomized, double-blind, placebo-controlled study that will run concurrently with the phase 3 ENSURE program, enrolling a total of 450 patients with progressive MS at more than 70 sites. Patients will be randomized to either 45-mg daily doses of IMU-838 or placebo for up to 120 weeks. Investigators will then use annualized rate of percent brain volume change as the primary end point, while secondary end points include annualized rate of change in whole brain atrophy, as well as time to 24-week confirmed disability progression, based on the Expanded Disability Status Scale. The first patient was enrolled in September 2021.3

REFERENCES
1. Immunic announces publication of data from its phase 2 EMPhASIS trial of vidofludimus calcium in relapsing-remitting multiple sclerosis in peer reviewed journal, Annals of Clinical and Translational Neurology. News release. Immunic. June 15, 2022. Accessed June 20, 2022. https://www.prnewswire.com/news-releases/immunic-announces-publication-of-data-from-its-phase-2-emphasis-trial-of-vidofludimus-calcium-in-relapsing-remitting-multiple-sclerosis-in-peer-reviewed-journal-annals-of-clinical-and-translational-neurology-301568317.html
2. Fox RJ, Wiendl H, Wolf C, et al. A double-blind, randomized, placebo-controlled phase 2 trial evaluating the selective dihydroorotate dehydrogenase inhibitor vidofludimus calcium in relapsing-remitting multiple sclerosis. Ann Clin Transl Neurol. doi:10.1002/acn3.51574
3. Immunic, Inc. enrolls first patient in its phase 2 CALLIPER trial of IMU-838 in progressive multiple sclerosis. September 30, 2021. Accessed June 30, 2022. https://www.prnewswire.com/news-releases/immunic-inc-enrolls-first-patient-in-its-phase-2-calliper-trial-of-imu-838-in-progressive-multiple-sclerosis-301388669.html