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ABSTRACT
Introduction
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.
Areas covered
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.
Expert opinion
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 does not respond to these novel therapies and thus still requires surgical treatment, including liver transplantation before adulthood. Hence, there is still an unmet medical for long-term effective medical, preferably non-surgical, treatment for all PFIC patients.
Plain Language Summary
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.
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4-PB, 4-phenylbutyrate; AAV, adeno-associated virus; ABCB11, ATP-binding cassette sub-family B member 11 protein; ALT, alanine aminotransferase; ASBT, apical sodium-dependent bile acid transporter; AST, aspartate aminotransferase; ATP8B1, ATPase phospholipid transporting 8B1; BSEP, bile salt export pump; CFTR, cystic fibrosis transmembrane conductance regulator; FIC1, familial intrahepatic cholestasis 1; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; GGT, gamma-glutamyl transferase; IBAT, ileal bile acid transporter; KIF12, kinesin family member 12; MDR3, multidrug resistance protein 3; MVID, microvillus inclusion disease; MYO5B, myosin 5B; MASLD, metabolic-dysfunction associated steatotic liver disease; NAPPED, NAtural course and Prognosis of PFIC and Effect of biliary Diversion; MASH, metabolic dysfunction-associated steatohepatitis; NLS, native liver survival; norUDCA, norursodeoxycholic acid; OCA, obeticholic acid; PBC, primary biliary cholangitis; PBD, partial biliary diversion; PEBD, partial external biliary diversion; PFIC, progressive familial intrahepatic cholestasis; PSC, primary sclerosis cholangitis; sBA, serum bile acids; SBD, surgical biliary diversion; TJP2, tight junction protein 2; UDCA, ursodeoxycholic acid; USP53, ubiquitin specific peptidase 53.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728214.2024.2336986
Declaration of interest
HJ Verkade has been a consultant for Ausnutria, Albireo AB/Ipsen, Mirum, Vivet, Intercept and Orphalan (each on ad interim basis) and has received unrestricted research grants from Albireo AB/Ipsen and Mirum. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
A reviewer on this manuscript has disclosed that they are a Consultant for IPSEN, CAMP4 therapeutics and SIGNANTHEALTH. They have also received speaker’s fee from ADVANZ. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.