Targeting DHODH

IMU-838 is an inhibitor of the intracellular de-novo biosynthesis of pyrimidines which are important for several metabolic processes during T-cell differentiation, maturation, and effector function e.g. production of relevant cytokines. The compound blocks the biochemical function of dihydroorotate dehydrogenase (DHODH), which is involved in the de-novo pyrimidine biosynthesis and highly expressed and metabolically important in activated lymphocytes. Resting lymphocytes are not affected, as they are able to meet their pyrimidine needs through the DHODH-independent salvage pathway. As a result, DHODH inhibition provides an immunomodulatory effect selective towards activated immune cells.

In pathological conditions like chronic inflammatory and autoimmune diseases, the metabolic activation and control of the intracellular ‘supply-chain’ of nucleotides are of highest importance. Disruption of the metabolic intracellular maintenance of building blocks leads to metabolic stress.  The metabolic stress secondary to DHODH inhibition leads to a reduction of pro-inflammatory cytokine release including IL‑17 (IL‑17A and IL‑17F) and interferon gamma (IFNg) by stimulated T‑cells, and to induction of apoptosis in activated lymphocytes. Thus, DHODH inhibition offers a treatment option for autoimmune or chronic inflammatory disorders characterized by an overstimulated immune system, such as inflammatory bowel disease (IBD).

IMU-838 contains a small molecule called vidofludimus calcium and can be taken as once daily tablet. The compound was discovered by 4SC AG and acquired by Immunic in 2016. Immunic has developed a new pharmaceutical form containing the calcium salt of vidofludimus in a new pharmaceutical formulation designated as IMU-838. IMU-838 was successfully tested in two phase 1 clinical trials in 2017 and is currently being tested in phase 2 trials in patients with ulcerative colitis and relapsing-remitting multiple sclerosis. Immunic intends to initiate an additional phase 2 trial in patients with Crohn’s disease later in 2019. Furthermore, Immunic’s collaboration partner, Mayo Clinic, plans to start an investigator-sponsored proof-of-concept clinical trial testing IMU-838 activity in patients with primary sclerosing cholangitis (PSC) in the first quarter of 2019.

In the indication IBD, an exploratory, open-label Phase 2 study was previously conducted by 4SC to evaluate the efficacy, safety and tolerability of vidofludimus in patients with Crohn’s disease (CD) and ulcerative colitis (UC). The study showed that vidofludimus had activity in the remission maintenance therapy of steroid-dependent patients with CD and UC.

Immunic Therapeutics - IMU-838 DHODH