Primary sclerosing cholangitis (PSC) is an idiopathic disease of the liver characterized by ongoing
inflammation of the intrahepatic and/or extrahepatic bile ducts. PSC is a rare, but debilitating disease, with a
prevalence of roughly 50,000 patients in the United States. The outcome in patients with PSC is highly
unsatisfactory, with many cases ultimately leading to cirrhosis, cancer of the liver or bile duct, or end-stage
liver disease. PSC is one of the leading indications for liver transplantation in the US and many European
countries, with a median time from diagnosis to death or liver transplantation of only 8 years. To date, no
medical therapies other than liver transplantation have been proven to halt the progression of the disease.
PSC often exhibits comorbidity with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). IBD
is present in 70%-80% of PSC patients, with 90% of that in the form of UC. PSC and IBD share a strong link
to the proinflammatory cytokine IL-17 and Th17 cells, IL-17-producing lymphocytes. In IBD, Th17 cells
massively infiltrate the inflamed intestine and UC patients demonstrate greatly increased expression of IL-17 in
colonic mucosa. Recent studies now also indicate a central role of IL-17 in the pathogenesis of PSC.
The investigational new drug vidofludimus calcium (VC) is a new small molecule immune modulator that has
been shown to induce apoptosis in proliferating lymphocytes and reduce release of the proinflammatory
cytokines IL-17 and IFN¿. This is accomplished through its potent inhibition of the mitochondrial enzyme
dihydroorotate dehydrogenase (DHODH), which catalyzes the rate-limiting step in the pyrimidine synthesis
pathway. Metabolic stress secondary to this inhibition leads to these key immunomodulatory effects. As
DHODH is highly expressed in activated lymphocytes, whereas resting lymphocytes are able to meet their
pyrimidine needs through the DHODH-independent salvage pathway, VC selectively affects activated immune
cells. In a recent clinical trial, vidofludimus has demonstrated a strong positive effect in patients with
ulcerative colitis, and a series of clinical trials have demonstrated a highly favorable safety profile.
Based on the above evidence, we believe that VC is likely to serve as a safe and effective therapy in patients
with PSC, and that a small-scale trial to test this hypothesis is warranted. Here we propose a 30 patient, open-
label, single-arm 6-month study of VC in PSC patients. The study will be conducted by a team of investigators
with a long history of involvement in PSC research and clinical trials. The trial will be carried out at two sites,
each of which is recognized as a tertiary referral center for PSC. Success in this trial would motivate larger,
more comprehensive clinical trials. This may eventually lead to an effective therapy for this rare but deadly
disease where one does not currently exist, significantly improving patient outcome and quality of life.