IMU-838 is a small molecule investigational drug (vidofludimus calcium) under development as an oral tablet formulation for the treatment of relapsing-remitting multiple sclerosis (RRMS), inflammatory bowel disease (IBD) and other chronic inflammatory and autoimmune diseases. By inhibiting dihydroorotate dehydrogenase (DHODH), a key enzyme of pyrimidine de novo biosynthesis, metabolically activated T and B immune cells experience metabolic stress, and the release of Th1 and Th17 key cytokines including IL-17A, IL-17F and IFNg is inhibited, thereby reducing the inflammation associated with IBD. 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’ 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, or RNA, and deoxyribonucleic acid, or DNA, production), DHODH inhibition also leads to a direct antiviral effect, which has been demonstrated in various virus infected cells, such as influenza virus infections, cytomegolvirus infections and even hemorrhagic fever-causing viruses, such as Lassa virus. Treatment with IMU-838 may avoid virus reactivation, one of the major drawbacks of the long-term use of traditional immunomodulators in IBD patients. Efficacy of vidofludimus, the active moiety and free acid form of IMU-838, has been demonstrated in several animal disease models for IBD, as well as systemic lupus erythematosus and transplant rejection.
Initial clinical trials were conducted by 4SC using a free acid formulation of the active moiety of IMU-838, vidofludimus, and an amorphous material. In total, 4SC’s clinical trial data encompasses more than 250 patients treated with the active moiety, helping generate a safety database to encourage further development of IMU-838. After the consummation of the asset acquisition from 4SC, Immunic developed and patented a new specific polymorph of the calcium salt formulation of vidofludimus, IMU-838, which Immunic believes exhibits improved physicochemical and pharmacokinetic properties.
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. A phase 2 study in patients with RRMS is currently ongoing, with enrollment completed in October 2019 and top-line data expected to be available in the third quarter of 2020. A second phase 2 study in patients with UC is also ongoing, with enrollment initiated in April 2018 and top-line data expected to be available during the fourth quarter of 2021. A third phase 2 trial in patients with CD is planned. Furthermore, Immunic’s collaboration partner, Mayo Clinic, has started an investigator-sponsored proof-of-concept clinical trial testing IMU-838 activity in patients with primary sclerosing cholangitis, or PSC.