Vidofludimus Calcium (IMU-838): Targeting DHODH

Vidofludimus calcium (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 moiety 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 vidofludimus calcium, animals treated with large doses of the active moiety vidofludimus 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 vidofludimus calcium 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

Illustration of IMU-838 processes

This graphic illustrates the above mentioned processes.

In 2017, Immunic completed two phase 1 studies of single or repeated once-daily doses of vidofludimus calcium in healthy volunteers, where Immunic observed results supporting tolerability of repeated daily dosing of up to 50 mg of IMU-838.

To date, vidofludimus calcium has been tested in more than 1,100 individuals and has shown an attractive pharmacokinetic, safety and tolerability profile.

Vidofludimus Calcium in Relapsing-Remitting Multiple Sclerosis (RRMS)
Vidofludimus Calcium in Ulcerative Colitis (UC)
Vidofludimus Calcium in Primary Sclerosing Cholangitis (PSC)
Vidofludimus Calcium in COVID-19

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