Table 4.

Potential novel therapeutic drugs for treatment of progressive familial intrahepatic cholestasis

Drug	Mechanism of action	Clinical trials and current status	Notes
Maralixibat/LUM001	Apical sodium-dependent bile acid transporter inhibitor	NCT04185363: Open label phase III trial; Recruiting patients; NCT03905330: MARCH-PFIC trial; Randomized controlled trial, recruiting patients; NCT04729751: RISE trial in infants; Open label phase II safety study; NCT04168385: Long term safety study; NCT02057718; Open label phase II trial; Completed	Orphan drug designation by FDA; Breakthrough therapy for PFIC2
Odevixibat/A4250	Selective inhibitor of ileal bile acid transporter	NCT03566238: PEDFIC 1 study; Phase III, open label, randomized controlled trial; Ongoing; NCT04483531: Expanded access study including patients not enrolled in PEDFIC 1 study	Orphan drug designation by FDA; Fast track designation for PFIC
4-PB/GPA	Prolongs degradation rate & increases cell surface expression of BSEP & functions as a chemical chaperone to correct the misfolded proteins	Leads to long term reduction in serum BA, improvement in liver biochemistry as well as relief of pruritus; Increased canalicular localization of E297G and D482G BSEP mutants; GPA more palatable, has lower sodium, doesn’t interact with rifampicin; Doses: 4-PB: 500 mg/kg/d; GPA: 8 g/m2/d	4-PB FDA approved for urea cycle defect
Ivacaftor	Rescues the function of missense mutations in the nucleotide binding domains of BSEP & MDR3	In vitro correction of binding domain missense mutation (T463I) of BSEP; Improved phospholipid secretion activity in mutant ABCB4	In vitro studies; Animal studies
Oxcarbazepine	Nerve stabilizing effect; Enzyme inducer – possible role in potentiating action of 4-PB	Single case report on its combined use with 4-PB and maralixibat
Gentamicin	Induce readthrough in nonsense mutation	In vitro increased readthrough in 6 common nonsense mutation of BSEP leading to increased canalicular expression of bile salt transporter
FXR agonist (Obeticholic acid)	Farsenoid X receptor agonist	No trials in PFIC; Safe and efficacious in treatment of PSC and non-alcoholic steatohepatitis	FDA approved for PSC
Nor-UDCA	Side-chain-shortened derivative of UDCA; Increases cholehepatic shunt	No trials in PFIC; NCT03872921: Ongoing phase III randomized controlled trial in PSC
Steroids	Possible upregulation of BSEP transporter? Up-regulation of sodium taurocholate copeptide transporterproviding increased gradient for BSEP	Only case reports and animal studies
NGM282	FGF19 analogue	NGM282 inhibited bile acid synthesis and decreased fibrosis markers, without change in alkaline phosphatise level
Bezafibrate	Peroxisome proliferator activated receptor agonist	Bezafibrate reduced pruritus and cholestasis in 2 out of 3 children with PFIC1 and improved lipid profile in all

PFIC: Progressive familial intrahepatic cholestasis; BSEP: Bile salt export pump; FGF: Fibroblast growth factor; NGM282: Codename of drug which is an engineered analogue of fibroblast growth factor - 19; UDCA: Ursodeoxycholic acid; PSC: Primary sclerosing cholangitis; FDA: Food and drug administration; PB: Phenyl-butyrate; MDR3: Multidrug-resistant type 3; ABCB: ATP-binding cassette subfamily B; GPA: Glycerol phenylbutyrate; BA: Bile acids.