Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: a focus on phase II and III trials
Creators: name: Hof, Willemien F.J.
name: de Boer, Jan Freark
name: Verkade, Henkjan J.
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Cancer
subject: Virology

description: Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by inappropriate bile formation, causing hepatic accumulation of bile acids and, subsequently, liver injury. Until recently, no approved treatments were available for these patients. Recent clinical trials for PFIC treatment have focused on intestine-restricted ileal bile acid transporter (IBAT) inhibitors. These compounds aim to reduce the pool size of bile acids by interrupting their enterohepatic circulation. Other emerging treatments in the pipeline include systemic IBAT inhibitors, synthetic bile acid derivatives, compounds targeting bile acid synthesis via the FXR/FGF axis, and chaperones/potentiators that aim to enhance the residual activity of the mutated transporters. Substantial progress has been made in drug development for PFIC patients during the last couple of years. Although data concerning long-term efficacy are as yet only scarcely available, new therapies have demonstrated robust efficacy in a considerable fraction of patients at least on the shorter term. However, a substantial fraction of PFIC patients do not respond to these novel therapies and thus still requires surgical treatment, including liver transplantation before adulthood. Hence, there is still an unmet medical need for long-term effective medical, preferably non-surgical, treatment for all PFIC patients. Normally, the liver produces bile which is a route of secretion of waste products from the body and also helps in the intestinal absorption of fats from the diet. The bile goes from the liver, through the bile duct to the intestines and components are taken up again at the end of the intestine and transported back to the liver. However, progressive familial intrahepatic cholestasis (PFIC in short) is a group of diseases where bile stays in the liver and damages it. PFIC often causes symptoms already in very young children, like itch and jaundice (getting a slight yellow color). Patients get more and worse symptoms over time and may eventually need a liver transplantation. This review discusses what drugs have been developed for PFIC recently and what drugs are in development now. Two new drugs for PFIC have been developed and approved in the last few years: odevixibat and maralixibat. These drugs help bile in the intestines leave the body via the stool and prevent bile from going back to the liver instead. Drugs in development aim to either 1) do the same, 2) make the bile less toxic, 3) reduce the production of bile, or 4) help bile go from the liver into the bile ducts. There has been a lot of progress in drug development for PFIC in the last few years. The new drugs have helped a considerable number of patients, but many patients still do not respond to these new drugs, keep having symptoms and may need surgery. Therefore, despite considerable progress, research needs to continue for an effective treatment for all PFIC patients.