First Patient Enrolled in Primary Sclerosing Cholangitis Trial

Immunic announced enrollment of the first patient in an investigator-sponsored proof-of-concept clinical trial of IMU-838 for the treatment of patients with primary sclerosing cholangitis (PSC). IMU-838 is an orally available, next-generation selective immune modulator that inhibits the intracellular metabolism of activated immune cells by blocking the enzyme dihydroorotate dehydrogenase (DHODH). PSC is a progressive disease of the liver with unknown cause and a prevalence of about 4.15 per 100,000 in the United States. Other than liver transplantation, there are currently no approved therapies that have been shown to improve survival in patients with PSC.

Keith Lindor, M.D., Senior Advisor to the Provost and Professor of Medicine, College of Health Solutions, Arizona State University, and Principal Investigator for the trial, was awarded a grant from the National Institutes of Health (NIH) for the study. The study will be sponsored by Elizabeth Carey, M.D., Professor of Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, who has received Investigational New Drug (IND) approval from the U.S. Food & Drug Administration (FDA) and has been granted Institutional Review Board (IRB) approval to conduct the study. The study will be conducted at Mayo Clinic in Arizona (Dr. Carey) and Minnesota (John E. Eaton, M.D.), both of which are tertiary care centers for PSC patients.

The proof-of-concept study, for which Immunic is providing the study medication, is a single-arm, open-label, exploratory study planning to enroll a total of 30 patients with PSC, aged 18 to 75 years, who will receive 30mg IMU-838 once daily for a period of six months. The trial's primary endpoint is the change in serum alkaline phosphatase (ALP) at six months compared to baseline. In previous trials, a biochemical endpoint such as change in serum ALP has been an accepted biomarker of disease progression in PSC patients.

"Recent studies indicate that the proinflammatory cytokine interleukin 17, or IL-17, may play a central role in the pathogenesis of PSC, as well as ulcerative colitis. Significant increases in IL-17-expressing lymphocytes are found in the livers of PSC patients," Dr. Keith Lindor said. "These findings speak to the strong possibility of an overlap in therapeutic approaches to the two diseases. Our goal with this study is to examine the safety, tolerability, and efficacy of daily dosing of IMU-838, an orally available, small molecule inhibitor of DHODH, a target known for its effect on Th17 cells, in order to establish proof-of-concept that IMU-838 shows activity for the treatment of PSC. Establishing such a baseline should enable the design of more comprehensive clinical studies."

"We are honored to be collaborating with such prominent institutions and investigators, including Drs. Lindor, Carey and Eaton on this important clinical trial," said Daniel Vitt, Ph.D., Chief Executive Officer and President of Immunic. "Certainly, the available data, including the mode of action of IMU-838, which already is commercially proven in other indications, compels us to support their work to address the unmet medical need of patients affected by PSC, whose current options include only supportive care or, ultimately, liver transplantation. With the potential for a best-in-class DHODH inhibitor safety profile, and an IND for IMU-838 in inflammatory bowel disease, or IBD, already established, positive data from this investigator-sponsored trial should enable Immunic to approach the regulatory authorities about the possibility of an accelerated regulatory pathway in this orphan indication."

PSC is a very rare liver disease with a prevalence of about 4.15 per 100,000 in the United States, in which the bile ducts in the liver become inflamed, narrow and prevent bile from flowing properly. The exact cause and disease mechanism are still unknown but an autoimmune mechanism may play a role. There is an association with inflammatory bowel diseases, most often with ulcerative colitis and less commonly with Crohn's disease. PSC is a progressive disease and the estimated time from diagnosis of PSC to death or liver transplant has been shown to be less than 15 years.

IMU-838 is an orally available, next-generation selective immune modulator that inhibits the intracellular metabolism of activated immune cells by blocking the enzyme dihydroorotate dehydrogenase (DHODH). IMU-838 acts on activated T and B cells while leaving other immune cells largely unaffected and allows the immune system to stay functioning, e.g. in fighting infections. In previous trials, IMU-838 did not show an increased rate of infections compared to placebo. In addition, DHODH inhibitors such as IMU-838 are known to possess a direct antiviral effect. 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 relapsing-remitting multiple sclerosis and ulcerative colitis. 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, has started an investigator-sponsored proof-of-concept clinical trial testing IMU-838 activity in patients with primary sclerosing cholangitis.

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