IMU-838 is a small molecule investigational drug under development as an oral tablet formulation for the treatment of relapsing-remitting multiple sclerosis, or RRMS, inflammatory bowel disease, or IBD, and other chronic inflammatory and autoimmune diseases.
By inhibiting dihydroorotate dehydrogenase, or DHODH, a key enzyme of pyrimidine de novo biosynthesis, highly metabolically activated T and B immune cells experience metabolic stress, which leads to a modulation of their activity and function. Thereby, pro-inflammatory cytokines such as IFNγ, TNFα, IL-17A and IL-17F, produced by activated Th1 and Th17 cells, which represent subtypes of so-called T helper cells, are repressed and thereby reduce the inflammation associated with IBD, MS and other chronic inflammatory diseases. In preclinical studies of vidofludimus, the active ingredient of IMU-838, apoptosis (or programmed cell death) was induced in activated T cells, which Immunic believes may also play a crucial role in the activity of the drug in IBD by further dampening the inflammatory response.
Immunic believes that a key advantage of DHODH inhibition, in general, is that the sensitivity of specific immune cells to DHODH inhibition correlates with their intracellular metabolic activation state, and therefore may not negatively impact “normal” immune and bone marrow cells. In animal studies of IMU-838, animals treated with large doses of the active moiety of IMU-838 were shown to lack detrimental effects on bone marrow, supporting the lack of an unspecific anti-proliferative effect regularly seen with many traditional immunomodulators.
Based on the selectivity toward metabolically activated cells (with a high need for ribonucleic acid and deoxyribonucleic acid production), DHODH inhibition also leads to a direct antiviral effect, which has been observed in various virus infected cells, such as hepatitis C virus infections, cytomegalovirus infections and even hemorrhagic fever-causing viruses, such as Arena virus infections. Treatment with IMU-838 may avoid virus reactivation, one of the major drawbacks of the long-term use of traditional immunomodulators in IBD patients.
DHODH Targeting Leads to Metabolic Stress in Metabolically Activated Cells
In 2017, Immunic completed two phase 1 studies of single or repeated once-daily doses of IMU-838 in healthy volunteers, where Immunic observed results supporting tolerability of repeated daily dosing of up to 50 mg of IMU-838. To date, IMU-838 has been tested in more than 800 individuals and has shown an attractive pharmacokinetic, safety and tolerability profile.
Phase 2 Trial of IMU-838 in RRMS (EMPhASIS Trial)
On August 2, 2020, Immunic announced positive top-line data from its phase 2 EMPhASIS trial of IMU-838 in patients with RRMS. The trial achieved statistical significance on all primary and key secondary endpoints, indicating activity in RRMS patients. On September 11, 2020, the Company published the full unblinded clinical data set which confirmed and expanded on the previously announced top-line results. On April 15, 2021, Immunic announced an interim analysis of the additional 10 mg Cohort 2 of the EMPhASIS trial confirming IMU-838’s dose response in RRMS and supporting phase 3 dose selection. Previously published data from Cohort 1, together with the Cohort 2 data, confirmed that 30 mg once daily IMU-838 is the most appropriate dose for the company’s planned phase 3 program in RRMS.
Immunic is now in discussions with regulatory authorities, including the U.S. Food and Drug Administration and the European Medicines Agency, regarding the company’s planned phase 3 program in RRMS. Feasibility and other preparatory activities for the phase 3 program are ongoing in parallel and initiation is expected in the second half of 2021.
Phase 2 Trial of IMU-838 in UC (CALDOSE-1 Trial)
The CALDOSE-1 trial is a phase 2b, dose-finding, multicenter, double-blind, placebo-controlled study being conducted in more than 100 study centers throughout 14 countries, including the United States and countries in Western, Central and Eastern Europe. Recruitment is expected to be completed in the second half of 2021 and top-line data is expected to be available in the first half of 2022.
Phase 2 Trial of IMU-838 in Moderate COVID-19 (CALVID-1 Trial)
On February 17, 2021, Immunic announced that IMU-838 has shown evidence of clinical activity in hospitalized patients with moderate COVID-19. This planned main analysis of the Company’s phase 2 CALVID-1 trial was based on data from 204 randomized patients and included top-line clinical efficacy, safety, disease marker, and virology data. The data showed clinical activity based on multiple secondary endpoints, including (1) clinically meaningful improvements in time to clinical recovery and time to clinical improvement; (2) a substantial treatment effect on high-risk patients and those over 65 years of age; (3) an anti-viral effect of IMU-838 on SARS-CoV-2, as observed by viral titers; (4) a robust anti-inflammatory effect, based on a more effective reduction of C-Reactive Protein in treated patients, as compared to placebo; and (5) an indication, based on initial data from a post hoc analysis of “Long COVID” symptoms, that IMU-838 may have the potential to contribute to the prevention of long-term fatigue. IMU-838 was also found to be safe and well-tolerated in hospitalized patients with moderate COVID-19.
Additional available data from the full analysis of all 223 randomized patients support the conclusions made in the main analysis and have provided data on a few additional endpoints. Notably, the rate and timing of anti-SARS-CoV-2 antibodies patients are developing in response to the infection was found to be identical between the IMU-838 and placebo treatment arms. The full analysis was also able to detect a relationship between drug trough levels in blood plasma and the clinical recovery endpoint.
Phase 2 Trial of IMU-838 in Primary Sclerosing Cholangitis
On February 18, 2021, Immunic announced positive top-line data from its investigator-sponsored proof-of-concept clinical trial of IMU-838 in primary sclerosing cholangitis, or PSC, which was conducted at Mayo Clinic in Arizona and Minnesota, both of which are tertiary referral centers for PSC patients. Data showed a statistically significant decrease in serum alkaline phosphatase levels (p=0.041) in the 11-patient per-protocol population after 24-weeks of treatment, as compared to baseline. Additionally, the primary objective, a clinically relevant reduction of serum alkaline phosphatase higher than 25% without an increase in liver biochemistry of more than 33%, was achieved in 27.3% of the patients in the per-protocol population at week 24, as compared to baseline. Other liver biochemistry parameters evaluated, including aspartate aminotransferase, alanine aminotransferase, and total/direct/indirect bilirubin, remained stable, and IMU-838’s favorable safety and tolerability profile was confirmed in the patient population.
Immunic, Inc. Publishes Full Unblinded Clinical Data From Phase 2 EMPhASIS Trial of IMU-838 in Patients With Relapsing-Remitting Multiple Sclerosis and Announces Poster Presentation at the MSVirtual2020
Immunic, Inc. Announces First Patients Enrolled in Investigator-Sponsored Phase 2 Clinical Trial of IMU-838 in Combination with Oseltamivir for the Treatment of Patients with Moderate-to-Severe COVID-19
Immunic, Inc.’s Interim Dosing Analysis of IMU-838 as Part of its Ongoing Phase 2 CALDOSE-1 Study in Patients with Moderate-to-Severe Ulcerative Colitis Establishes Broad, Potentially Safe and Effective Dose Range