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Review

Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: a focus on phase II and III trials

, &
Received 19 Dec 2023, Accepted 27 Mar 2024, Accepted author version posted online: 04 Apr 2024
Accepted author version

REFERENCES

  • Kamath BM, Stein P, Houwen RHJ, et al. Potential of ileal bile acid transporter inhibition as a therapeutic target in alagille syndrome and progressive familial intrahepatic cholestasis. Liver Int. 2020;40(8):1812–1822. doi: 10.1111/liv.14553
  • Li T, Udayan A. Bile acid metabolism and signaling in cholestasis, inflammation and cancer. Adv Pharmacol. 2015;74(1):263–302.
  • Davit-Spraul A, Gonzales E, Baussan C, et al. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis. 2009;4(1):1–12. doi: 10.1186/1750-1172-4-1
  • Ruth ND, Gray Z, McKay K, et al. P1248 identifying incidence of inherited metabolic disorders in patients with infantile liver disease. J Hepatol. 2014;60(1):S505. doi: 10.1016/S0168-8278(14)61408-2
  • Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. 1999;159(22):2647–2658. doi: 10.1001/archinte.159.22.2647
  • Stellaard F, Lütjohann D. Dynamics of the enterohepatic circulation of bile acids in healthy humans. Am J Physiol Gastrointest Liver Physiol. 2021;321(1):G55–66. doi: 10.1152/ajpgi.00476.2020
  • Keitel V, Dröge C, Häussinger D. Targeting FXR in Cholestasis. In: Handbook of Experimental Pharmacology. Springer Nature Switzerland; 2019. p. 299–324.
  • Cariello M, Piccinin E, Garcia-Irigoyen O, et al. Nuclear receptor FXR, bile acids and liver damage: introducing the progressive familial intrahepatic cholestasis with FXR mutations. Biochim Biophys Acta - Mol Basis Dis. 2018;1864(4):1308–1318. doi: 10.1016/j.bbadis.2017.09.019
  • Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by Klotho. J Biol Chem. 2006;281(10):6120–6123. doi: 10.1074/jbc.C500457200
  • Jacquemin E. Progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2012;36(SUPPL.1):S26–35. doi: 10.1016/S2210-7401(12)70018-9
  • Van Mil SWC, Houwen RHJ, Klomp LWJ. Genetics of familial intrahepatic cholestasis syndromes. J Med Genet. 2005;42(6):449–63.
  • Davit-Spraul A, Fabre M, Branchereau S, et al. ATP8B1 and ABCB11 Analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010;51(5):1645–1655. doi: 10.1002/hep.23539
  • Groen A, Romero MR, Kunne C, et al. Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology. 2011;141(5):1927–1937.e4.
  • Srivastava A. Progressive familial Intrahepatic Cholestasis. J Clin Exp Hepatol. 2014;4(1):25–36. doi: 10.1016/j.jceh.2013.10.005
  • Vitale G, Gitto S, Vukotic R, et al. Familial intrahepatic cholestasis: new and wide perspectives. Dig Liver Dis. 2019;51(7):922–933. doi: 10.1016/j.dld.2019.04.013
  • Paulusma CC, de Waart DR, Kunne C, et al. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J Biol Chem. 2009;284(15):9947–9954. doi: 10.1074/jbc.M808667200
  • Lemoine C, Superina R. Surgical diversion of enterohepatic circulation in pediatric cholestasis. Semin Pediatr Surg. 2020;29(4):150946. doi: 10.1016/j.sempedsurg.2020.150946
  • Jansen PLM, Strautnieks SS, Jacquemin E, et al.. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology. 1999;117(6):1370–1379. doi: 10.1016/S0016-5085(99)70287-8
  • Strautnieks SS, Byrne JA, Pawlikowska L, et al. Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 Families. Gastroenterology. 2008;134(4):1203–14.
  • Evason K, Bove KE, Finegold MJ, et al. Morphologic findings in progressive familial intrahepatic cholestasis 2 (PFIC2): correlation with genetic and immunohistochemical studies. Am J Surg Pathol. 2011;35(5):687–696. doi: 10.1097/PAS.0b013e318212ec87
  • van Wessel DBE, Thompson RJ, Gonzales E, et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol. 2020;73(1):84–93.
  • Crawford AR, Smith AJ, Hatch VC, et al. Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression: Visualization by electron microscopy. J Clin Invest. 1997;100(10):2562–7.
  • Alissa FT, Jaffe R, Shneider BL. Update on progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 2008;46(3):241–252. doi: 10.1097/MPG.0b013e3181596060
  • Bosma PJ, Wits M, Oude-Elferink RPJ. Gene therapy for progressive familial intrahepatic cholestasis: Current progress and future prospects. Int J Mol Sci. 2021;22(1):1–13.
  • Bull LN, Thompson RJ. Progressive familial Intrahepatic Cholestasis. Clin Liver Dis. 2018;22(4):657–669. doi: 10.1016/j.cld.2018.06.003
  • Sambrotta M, Strautnieks S, Papouli E, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet. 2014;46(4):326–328. doi: 10.1038/ng.2918
  • Xu J, Kausalya PJ, Van Hul N, et al.. Protective Functions of ZO-2/Tjp2 Expressed in Hepatocytes and Cholangiocytes Against Liver Injury and Cholestasis. Gastroenterology. 2021;160(6):2103–2118. doi: 10.1053/j.gastro.2021.01.027
  • Martínez-García J, Molina A, González-Aseguinolaza G, et al.. Gene Therapy for Acquired and Genetic Cholestasis. Biomedicines. 2022;10(6):1–20. doi: 10.3390/biomedicines10061238
  • Gomez-Ospina N, Potter CJ, Xiao R, et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun. 2016;7(1):1–8. doi: 10.1038/ncomms10713
  • Qiu YL, Gong JY, Feng JY, et al. Defects in myosin VB are associated with a spectrum of previously undiagnosed low γ-glutamyltransferase cholestasis. Hepatology. 2017;65(5):1655–1669. doi: 10.1002/hep.29020
  • Aldrian D, Vogel GF, Frey TK, et al. Congenital diarrhea and cholestatic liver disease: phenotypic spectrum associated with myo5b mutations. J Clin Med. 2021;10(3):1–15. doi: 10.3390/jcm10030481
  • Girard M, Lacaille F, Verkarre V, et al. MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease. Hepatology. 2014;60(1):301–310. doi: 10.1002/hep.26974
  • Uyar Aksu N, Görükmez O, Görükmez Ö, et al. A Novel Homozygous Mutation in the MYO5B Gene Associated With Normal-Gamma-Glutamyl Transferase Progressive Familial Intrahepatic Cholestasis. Cureus. 2021;13(11):1–5.
  • Kamath BM, Chen Z, Romero R, et al. Quality of life and its determinants in a Multicenter Cohort of Children with alagille syndrome. J Pediatr. 2015;167(2):390–396.e3. doi: 10.1016/j.jpeds.2015.04.077
  • Lee WS, Chai PF, Looi LM. Progressive familial intrahepatic cholestasis in Malaysian patients - A report of five cases. Med J Malaysia. 2009;64(3):216–9.
  • Schukfeh N, Metzelder ML, Petersen C, et al. Normalization of serum bile acids after partial external biliary diversion indicates an excellent long-term outcome in children with progressive familial intrahepatic cholestasis. J Pediatr Surg. 2012;47(3):501–505. doi: 10.1016/j.jpedsurg.2011.08.010
  • Yang H, Porte RJ, Verkade HJ, et al. Partial external biliary diversion in children with progressive familial intrahepatic cholestasis and alagille disease. J Pediatr Gastroenterol Nutr. 2009;49(2):216–221. doi: 10.1097/MPG.0b013e31819a4e3d
  • Jones-Hughes T, Campbell J, Crathorne L. Epidemiology and burden of progressive familial intrahepatic cholestasis: a systematic review. Orphanet J Rare Dis. 2021;16(1):1–14. doi: 10.1186/s13023-021-01884-4
  • Mehl A, Bohorquez H, Serrano MS, et al. Liver transplantation and the management of progressive familial intrahepatic cholestasis in children. World J Transplant. 2016;6(2):278.
  • Englert C, Grabhorn E, Richter A, et al. Liver transplantation in children with progressive familial intrahepatic cholestasis. Transplantation. 2007;84(10):1361–1363. doi: 10.1097/01.tp.0000282869.94152.4f
  • Baker A, Kerkar N, Todorova L, et al. Systematic review of progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2019;43(1):20–36. doi: 10.1016/j.clinre.2018.07.010
  • Kubitz R, Dröge C, Kluge S, et al. Autoimmune BSEP disease: disease recurrence after liver transplantation for progressive familial intrahepatic cholestasis. Clin Rev Allergy Immunol. 2015;48(2–3):273–284. doi: 10.1007/s12016-014-8457-4
  • Deeks ED. Odevixibat: First Approval. Drugs. 2021;81(15):1781–6.
  • Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis. 2001;21(4):551–562. doi: 10.1055/s-2001-19033
  • Gordo-Gilart R, Andueza S, Hierro L, et al.. Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity. Gut. 2015;64(1):147–155. doi: 10.1136/gutjnl-2014-306896
  • European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol [Internet]. 2009;51(2):237–267. Available from: http://dx.doi.org/10.1016/j.jhep.2009.04.009
  • Stapelbroek JM, van Erpecum KJ, Klomp LWJ, et al. Liver disease associated with canalicular transport defects: Current and future therapies. J Hepatol. 2010;52(2):258–271. doi: 10.1016/j.jhep.2009.11.012
  • Fickert P, Wagner M, Marschall HU, et al.. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2006;130(2):465–481. doi: 10.1053/j.gastro.2005.10.018
  • Fickert P, Hirschfield GM, Denk G, et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol. 2017;67(3):549–558. doi: 10.1016/j.jhep.2017.05.009
  • Whitington PF, Freese DK, Alonso EM, et al. Clinical and biochemical findings in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr. 1994;18(2):134–141. doi: 10.1002/j.1536-4801.1994.tb11143.x
  • Bhalerao A, Mannu GS. Management of Pruritus in chronic liver disease. Dermatol Res Pract. 2015; 2015.
  • Hegade VS, Kendrick SFW, Jones DEJ. Drug treatment of pruritus in liver diseases. Clin Med J R Coll Physicians London. 2015;15(4):351–357. doi: 10.7861/clinmedicine.15-4-351
  • Scaldaferri F, Pizzoferrato M, Ponziani FR, et al. Use and indications of cholestyramine and bile acid sequestrants. Intern Emerg Med. 2013;8(3):205–210. doi: 10.1007/s11739-011-0653-0
  • Li T, Chiang JYL. Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription. Am J Physiol Gastrointest Liver Physiol. 2005;288(1 51–1):74–84.
  • Beuers U, Wolters F, Oude Elferink RPJ. Mechanisms of pruritus in cholestasis: understanding and treating the itch. Nat Rev Gastroenterol Hepatol. 2023;20(1):26–36. doi: 10.1038/s41575-022-00687-7
  • Wietholtz H, Marschall HU, Jan S, et al. Stimulation of bile acid 6α-hydroxylation by rifampin. J Hepatol. 1996;24(6):713–718. doi: 10.1016/S0168-8278(96)80268-6
  • Marschall H, Wagner M, Zollner G, et al.. Complementary Stimulation of Hepatobiliary Transport and Detoxification Systems by Rifampicin and Ursodeoxycholic Acid in Humans. Gastroenterology. 2005;129(2):476–485. doi: 10.1016/j.gastro.2005.05.009
  • Murray-Brown FL. Naltrexone for cholestatic itch: A systematic review. BMJ Support Palliat Care. 2021;11(2):217–225. doi: 10.1136/bmjspcare-2020-002801
  • Yang CH, Perumpail BJ, Yoo ER, et al. Nutritional needs and support for children with chronic liver disease. Nutrients. 2017;9(10):1–16. doi: 10.3390/nu9101127
  • Agarwal S, Lal BB, Rawat D, et al. Progressive familial Intrahepatic Cholestasis (PFIC) in Indian children: clinical spectrum and outcome. J Clin Exp Hepatol. 2016;6(3):203–208. doi: 10.1016/j.jceh.2016.05.003
  • Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. 1988;95(1):130–136. doi: 10.1016/0016-5085(88)90301-0
  • Gunaydin M, Tander B, Demirel D, et al. Different techniques for biliary diversion in progressive familial intrahepatic cholestasis. J Pediatr Surg. 2016;51(3):386–389. doi: 10.1016/j.jpedsurg.2015.08.011
  • Van Vaisberg V, Tannuri ACA, Lima FR, et al. Ileal exclusion for pruritus treatment in children with progressive familial intrahepatic cholestasis and other cholestatic diseases. J Pediatr Surg. 2020;55(7):1385–1391. doi: 10.1016/j.jpedsurg.2019.09.018
  • Usui M, Isaji S, Das BC, et al. Liver retransplantation with external biliary diversion for progressive familial intrahepatic cholestasis type 1: a case report. Pediatr Transplant. 2009;13(5):611–614. doi: 10.1111/j.1399-3046.2008.00878.x
  • Wang KS, Tiao G, Bass LM, et al. Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology. 2017;65(5):1645–1654. doi: 10.1002/hep.29019
  • Hüpper MN, Pichler J, Huber WD, et al.. Surgical versus Medical Management of Progressive Familial Intrahepatic Cholestasis—Case Compilation and Review of the Literature. Children. 2023;10(6):949. doi: 10.3390/children10060949
  • Van Der Woerd WL, Houwen RHJ, Van De Graaf SFJ. Current and future therapies for inherited cholestatic liver diseases. World J Gastroenterol. 2017;23(5):763–75.
  • Pfister ED, Jaeger VK, Karch A, et al. Native liver survival in bile salt export pump deficiency: results of a retrospective cohort study. Hepatol Commun. 2023;7(4). 10.1097/HC9.0000000000000092
  • Bull LN, Pawlikowska L, Strautnieks S, et al. Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies. Hepatol Commun. 2018;2(5):515–528. doi: 10.1002/hep4.1168
  • Kaliciński PJ, Ismail H, Jankowska I, et al. Surgical Treatment of Progressive Familial Intrahepatic Cholestasis: Comparison of Partial External Biliary Diversion and Ileal Bypass. Eur J Pediatr Surg. 2003;13(5):307–11.
  • Bjornland K, Hukkinen M, Gatzinsky V, et al. Partial biliary diversion may promote long-term relief of pruritus and native liver survival in children with cholestatic liver diseases. Eur J Pediatr Surg. 2021;31(4):341–346. doi: 10.1055/s-0040-1714657
  • Miyagawa-Hayashino A, Egawa H, Yorifuji T, et al. Allograft Steatohepatitis in Progressive Familial Intrahepatic Cholestasis Type 1 After Living Donor Liver Transplantation. Liver Transplant. 2007;13(5):767–8.
  • Aydogdu S, Cakir M, Arikan C, et al. Liver transplantation for progressive familial intrahepatic cholestasis: clinical and histopathological findings, outcome and impact on growth. Pediatr Transplant. 2007;11(6):634–640. doi: 10.1111/j.1399-3046.2007.00722.x
  • Nicastro E, Stephenne X, Smets F, et al. Recovery of graft steatosis and protein-losing enteropathy after biliary diversion in a PFIC 1 liver transplanted child. Pediatr Transplant. 2012;16(5):177–182. doi: 10.1111/j.1399-3046.2011.01514.x
  • Mali VP, Fukuda A, Shigeta T, et al. Total internal biliary diversion during liver transplantation for type 1 progressive familial intrahepatic cholestasis: a novel approach. Pediatr Transplant. 2016;20(7):981–986. doi: 10.1111/petr.12782
  • Knisely AS, Strautnieks SS, Meier Y, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology. 2006;44(2):478–486. doi: 10.1002/hep.21287
  • Dröge C, Bonus M, Baumann U, et al. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. J Hepatol. 2017;67(6):1253–1264. doi: 10.1016/j.jhep.2017.07.004
  • Jara P, Hierro L, Martínez-Fernández P, et al. Recurrence of bile salt export pump deficiency after liver transplantation. N Engl J Med. 2009;361(14):1359–1367. doi: 10.1056/NEJMoa0901075
  • Keitel V, Burdelski M, Vojnisek Z, et al. De Novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology. 2009;50(2):510–517. doi: 10.1002/hep.23083
  • Stindt J, Kluge S, Dröge C, et al. Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency. Hepatology. 2016;63(2):524–537. doi: 10.1002/hep.28311
  • Siebold L, Dick AAS, Thompson R, et al. Recurrent low gamma-glutamyl transpeptidase cholestasis following liver transplantation for bile salt export pump (BSEP) disease (Posttransplant recurrent BSEP disease). Liver Transplant. 2010;16(7):856–863. doi: 10.1002/lt.22074
  • Grammatikopoulos T, Knisely AS, Dhawan A, et al. Anti-CD20 monoclonal antibody therapy in functional bile salt export pump deficiency after liver transplantation. J Pediatr Gastroenterol Nutr. 2015;60(6):e50–3. doi: 10.1097/MPG.0000000000000238
  • Jadlowiec CC, Taner T. Liver transplantation: Current status and challenges. World J Gastroenterol. 2016;22(18):4438–45.
  • Graffner H, Gillberg PG, Rikner L, et al. The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation. Aliment Pharmacol Ther. 2016;43(2):303–310. doi: 10.1111/apt.13457
  • European Medicines Agency. Bylvay (odevixibat) Medicine Overview [Internet]. 2021 [cited 2023 Oct 24]. Available from: https://www.ema.europa.eu/en/documents/overview/mylotarg-epar-summary-public_en.pdf
  • Albireo Pharma. Bylvay Prescribing Information [Internet]. 2023 [cited 2023 Oct 24]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215498s000lbl.pdf
  • European Medicines Agency. Bylvay Summary of Product Characteristics [Internet]. 2021 [cited 2023 Oct 24]. Available from: https://www.ema.europa.eu/en/documents/product-information/bylvay-epar-product-information_en.pdf
  • Thompson RJ, Arnell H, Artan R, et al. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2022;7(9):830–842. doi: 10.1016/S2468-1253(22)00093-0.
  • Ellinger P, Stindt J, Dröge C, et al. Partial external biliary diversion in bile salt export pump deficiency: association between outcome and mutation. World J Gastroenterol. 2017;23(29):5295–5303. doi: 10.3748/wjg.v23.i29.5295
  • Thompson RJ, Artan R, Baumann U, et al. Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis. JHEP Rep. 2023;5(8):100782. doi: 10.1016/j.jhepr.2023.100782
  • Gonzales E, Hardikar W, Stormon M, et al. Efficacy and safety of maralixibat treatment in patients with alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet. 2021;398(10311):1581–1592. doi: 10.1016/S0140-6736(21)01256-3
  • Kunst RF, de Waart DR, Wolters F, et al. Systemic ASBT inactivation protects against liver damage in obstructive cholestasis in mice. JHEP Rep. 2022;4(11):100573. doi: 10.1016/j.jhepr.2022.100573.
  • Food & Drug Administration. Orphan Drug Designations and Approvals [Internet]. 2021. Available from: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=370912
  • European Medicines Agency. Orphan Maintenance Assessment report Bylvay (Odevixibat) [Internet]. 2021. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/evrysdi
  • Ipsen. The acquisition of Albireo [Internet]. 2023. Available from: https://www.ipsen.com/websites/ipsen_com_v2/wp-content/uploads/2023/01/23204433/The-acquistion-of-Albireo.pdf
  • Committee for Medicinal Products for Human Use. Assessment report - Bylvay (Odevixibat). EMA/319560/2021. 2021.
  • Albireo Pharma. Current Report exhibit 99.2 [Internet]. 2020. Available from: https://www.sec.gov/Archives/edgar/data/1322505/000110465920008111/tm205897d2_ex99-2.htm
  • Felzen A, van Wessel DBE, Gonzales E, et al. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. JHEP Rep. 2023;5(2):100626. doi: 10.1016/j.jhepr.2022.100626
  • Albireo Pharma. Albireo Reports Q3 2022 Financial Results and Business Update. 2022.
  • Ipsen. Ipsen delivers solid sales growth in the first nine months of 2023 and confirms its full-year guidance. YTD 2023 - sales announcement. 2023.
  • Ipsen. U.S. FDA approves Bylvay® for patients living with cholestatic pruritus due to Alagille syndrome. 2023.
  • Tandvårds- och läkemedelsförmånsverket (TLV). TLV Decision Bylvay. 2023.
  • Zorginstituut Nederland. GVS advice odevixibat (Bylvay®). 2023.
  • Van de Peppel IP, Verkade HJ, Jonker JW. Metabolic consequences of ileal interruption of the enterohepatic circulation of bile acids. Am J Physiol Gastrointest Liver Physiol. 2020;319(5):G619–25.
  • Mareux E, Lapalus M, Ben Saad A, et al. In vitro rescue of the bile acid transport function of ABCB11 variants by CFTR potentiators. Int J Mol Sci. 2022;23(18):10758. doi: 10.3390/ijms231810758
  • Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol. 2013;368(1–2):17–29. doi: 10.1016/j.mce.2012.05.004
  • Floreani A, Gabbia D, De Martin S. Update on the Pharmacological Treatment of Primary Biliary Cholangitis. Biomedicines. 2022;10(8):1–17. doi: 10.3390/biomedicines10082033
  • Gonzales E, Jacquemin E. Mutation specific drug therapy for progressive familial or benign recurrent intrahepatic cholestasis: a new tool in a near future? J Hepatol. 2010;53(2):385–387. doi: 10.1016/j.jhep.2010.03.012
  • Garrison P, Bangs JD. p97 Inhibitor CB-5083 Blocks ERAD in Trypanosoma brucei. Mol Biochem Parasitol. 2020;239(Sep):111313.
  • Hayashi H, Sugiyama Y. 4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps. Hepatology. 2007;45(6):1506–1516. doi: 10.1002/hep.21630
  • Mareux E, Lapalus M, Amzal R, et al. Functional rescue of an ABCB11 mutant by ivacaftor: a new targeted pharmacotherapy approach in bile salt export pump deficiency. Liver Int. 2020;40(8):1917–1925. doi: 10.1111/liv.14518
  • European Medicines Agency. Livmarli Summary of Product Characteristics [Internet]. 2022 [cited 2023 Oct 26]. Available from: https://www.ema.europa.eu/en/documents/product-information/livmarli-epar-product-information_en.pdf
  • Food & Drug Administration. Livmarli Prescribing Information [Internet]. 2024 [cited 2023 Oct 19]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214662s000lbl.pdf
  • European Medicines Agency. Livmarli Medicine Overview [Internet]. 2022 [cited 2023 Oct 19]. Available from: https://www.ema.europa.eu/en/documents/overview/livmarli-epar-medicine-overview_en.pdf
  • Mirum Pharma. Mirum Submits for European Approval of LIVMARLI in Progressive Familial Intrahepatic Cholestasis [Internet]. Available from: https://ir.mirumpharma.com/news-events/News/news-details/2023/Mirum-Submits-for-European-Approval-of-LIVMARLI-in-Progressive-Familial-Intrahepatic-Cholestasis/default.aspx
  • Mirum Pharma. Mirum Pharmaceuticals Announces Data from EMBARK Phase 2b Study for Biliary Atresia. Available from: https://ir.mirumpharma.com/news-events/News/news-details/2023/Mirum-Pharmaceuticals-Announces-Data-from-EMBARK-Phase-2b-Study-for-Biliary-Atresia/default.aspx
  • Loomes KM, Squires RH, Kelly D, et al. Maralixibat for the treatment of PFIC: long-term, IBAT inhibition in an open-label, phase 2 study. Hepatol Commun. 2022;6(9):2379–2390. doi: 10.1002/hep4.1980.
  • Miethke A, Moukarzel A, Porta G, et al. Efficacy and Safety of Maralixibat in Patients with Progressive Familial Intrahepatic Cholestasis (MARCH-PFIC): A Randomized Placebo-Controlled Phase 3 Study. In: Journal of pediatric gastroenterology and nutrition. 2023. p. 709‐710.
  • A Study to Evaluate the Efficacy and Safety of Maralixibat in Subjects With Progressive Familial Intrahepatic Cholestasis (MARCH-PFIC) NCT03905330 [Internet]. 2023 [cited 2023 Dec 8]. Available from: https://clinicaltrials.gov/study/NCT03905330
  • Miethke A, Moukarzel A, Porta G, et al. Analysis of safety in maralixibat-treated participants with progressive familial intrahepatic cholestasis: data from MARCH-PFIC. J Hepatol. 2023;78:S387–8. 10.1016/S0168-8278(23)01039-5
  • Thompson R, Mogul D, Nunes T, et al. Maralixibat leads to significant reductions in pruritus and improvements in sleep for children with progressive familial intrahepatic cholestasis: data from MARCH-PFIC. J Hepatol. 2023;78:S370. 10.1016/S0168-8278(23)01010-3
  • D’Antiga L, Miethke A, Mogul D, et al. Maralixibat leads to significant reductions in bilirubin for patients with progressive familial intrahepatic cholestasis: data from MARCH-PFIC. J Hepatol. 2023;78:S61. 10.1016/S0168-8278(23)00526-3
  • Miethke AG, Moukarzel A, Porta G, et al. Long-Term Maintenance of Response and Improved Liver Health With Maralixibat in Patients With Progressive Familial Intrahepatic Cholestasis (PFIC): 2-Year Data From the MARCH-ON Study. In: American Association for the Study of Liver Diseases (AASLD) The Liver Meeting [Internet]. 2023. p. P5048C. Available from: https://mirumpharma.com/wp-content/uploads/2023/11/Thompson-RJ-AASLD-2023-Longterm-maintenance-of-response-and-improved-liver-health-with-MRX-in-PFIC.pdf
  • Nakano S, Osaka S, Sabu Y, et al. Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis. Sci Rep. 2019;9(1):1–12. doi: 10.1038/s41598-019-53628-x
  • Lam P, Pearson CL, Soroka CJ, et al. Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. Am J Physiol - Cell Physiol. 2007;293(5):1709–16.
  • Hayashi H, Inamura K, Aida K, et al. AP2 adaptor complex mediates bile salt export pump internalization and modulates its hepatocanalicular expression and transport function. Hepatology. 2012;55(6):1889–1900. doi: 10.1002/hep.25591
  • Gonzales E, Grosse B, Cassio D, et al. Successful mutation-specific chaperone therapy with 4-phenylbutyrate in a child with progressive familial intrahepatic cholestasis type 2. J Hepatol. 2012;57(3):695–698. doi: 10.1016/j.jhep.2012.04.017
  • Gonzales E, Grosse B, Schuller B, et al. Targeted pharmacotherapy in progressive familial intrahepatic cholestasis type 2: evidence for improvement of cholestasis with 4-phenylbutyrate. Hepatology. 2015;62(2):558–566. doi: 10.1002/hep.27767
  • Naoi S, Hayashi H, Inoue T, et al. Improved liver function and relieved pruritus after 4-phenylbutyrate therapy in a patient with progressive familial intrahepatic cholestasis type 2. J Pediatr. 2014;164(5):1219–1227.e3. doi: 10.1016/j.jpeds.2013.12.032
  • Mareux E, Lapalus M, Ben-Saad A, et al. In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis. 2021;16(1):1–4. doi: 10.1186/s13023-021-02125-4
  • Caballero-Camino FJ, Rodrigues PM, Wångsell F, et al. A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans. Hepatology. 2023;78(3):709–726. doi: 10.1097/HEP.0000000000000376.
  • Trauner M, Gulamhusein A, Hameed B, et al. The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of Cholestasis and liver injury in patients with primary sclerosing cholangitis. Hepatology. 2019;70(3):788–801. doi: 10.1002/hep.30509
  • Kowdley K V., Vuppalanchi R, Levy C, et al. A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis. J Hepatol. 2020;73(1):94–101.
  • Mayo MJ, Wigg AJ, Leggett BA, et al. NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Commun. 2018;2(9):1037–1050. doi: 10.1002/hep4.1209
  • Food & Drug Administration. OCALIVA® (obeticholic acid) Prescribing Information [Internet]. 2016. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207999s008lbl.pdf
  • European Medicines Agency. Ocaliva Summary of Product Characteristics [Internet]. 2022. Available from: https://www.ema.europa.eu/en/documents/product-information/ocaliva-epar-product-information_en.pdf
  • Pellicciari R, Fiorucci S, Camaioni E, et al. 6r-Ethyl-Chenodeoxycholic Acid (6-ECDCA), a Potent and Selective FXR Agonist Endowed with Anticholestatic Activity. Society. 2002;45(17):15–8.
  • Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631–643. doi: 10.1056/NEJMoa1509840
  • Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–965. doi: 10.1016/S0140-6736(14)61933-4
  • Kunst RF, Bolt I, van Dasselaar RDJ, et al. Combined inhibition of bile salt synthesis and intestinal uptake reduces cholestatic liver damage and colonic bile salts in mice. JHEP rep. 2023;6(1):100917.
  • Soroka CJ, Boyer JL Biosynthesis and trafficking of the bile salt export pump, BSEP: Therapeutic implications of BSEP mutations. Mol Aspects Med. 2014;37:3–14. 10.1016/j.mam.2013.05.001
  • Jacquemin E, Hermans D, Myara A, et al. Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis. Hepatology. 1997;25(3):519–523. doi: 10.1002/hep.510250303
  • Pepe A, Colucci A, Carucci M, et al. Case report: add-on treatment with odevixibat in a new subtype of progressive familial intrahepatic cholestasis broadens the therapeutic horizon of genetic cholestasis. Front Pediatr. 2023;11(February):1–5. doi: 10.3389/fped.2023.1061535
  • Di Giorgio A, Sciveres M, Fuoti M, et al. Treatment with an ileal bile acid transporter inhibitor in patients with TJP2 deficiency. Clin Res Hepatol Gastroenterol. 2023;47(8):102185. doi: 10.1016/j.clinre.2023.102185
  • Misawa T, Hayashi H, Sugiyama Y, et al. Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2. Bioorganic Med Chem. 2012;20(9):2940–2949. doi: 10.1016/j.bmc.2012.03.016
  • Luo J, Ko B, Elliott M, et al. Liver disease: a nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med. 2014;6(247):1–12. doi: 10.1126/scitranslmed.3009098
  • Halilbasic E, Steinacher D, Trauner M. Nor-Ursodeoxycholic Acid as a novel therapeutic approach for cholestatic and metabolic liver diseases. Dig Dis. 2017;35(3):288–292. doi: 10.1159/000454904
  • Kuipers F, Bloks VW, Groen AK. Beyond intestinal soap - Bile acids in metabolic control. Nat Rev Endocrinol. 2014;10(8):488–98.
  • Ghallab A, González D, Strängberg E, et al. Inhibition of the Renal Apical Sodium Dependent Bile Acid Transporter Prevents Cholemic Nephropathy in Mice with Obstructive Cholestasis. J Hepatol. 2023;
  • Almes M, Jobert A, Lapalus M, et al. Glycerol phenylbutyrate therapy in progressive familial intrahepatic cholestasis type 2. J Pediatr Gastroenterol Nutr. 2020;70(6):E139. doi: 10.1097/MPG.0000000000002713
  • Hinderer C, Katz N, Buza EL, et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an Adeno-Associated Virus Vector Expressing Human SMN. Hum Gene Ther. 2018;29(3):285–298. doi: 10.1089/hum.2018.015
  • Aronson SJ, Bakker RS, Shi X, et al. Liver-directed gene therapy results in long-term correction of progressive familial intrahepatic cholestasis type 3 in mice. J Hepatol. 2019;71(1):153–162. doi: 10.1016/j.jhep.2019.03.021
  • De Vree JML, Ottenhoff R, Bosma PJ, et al.. Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis. Gastroenterology. 2000;119(6):1720–1730. doi: 10.1053/gast.2000.20222
  • Daya S, Berns KI. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev. 2008;21(4):583–593. doi: 10.1128/CMR.00008-08
  • Cunningham SC, Spinoulas A, Carpenter KH, et al. AAV2/8-mediated correction of OTC deficiency is robust in adult but not neonatal Spfash mice. Mol Ther. 2009;17(8):1340–1346. doi: 10.1038/mt.2009.88
  • Johns Hopkins University. Online Mendelian Inheritance in Man PFIC [Internet]. 2023. Available from: https://www.omim.org/search?index=entry&start=1&limit=10&sort=score+desc%2C+prefix_sort+desc&search=pfic
  • Gudbjartsson DF, Helgason H, Gudjonsson SA, et al. Large-scale whole-genome sequencing of the Icelandic population. Nat Genet. 2015;47(5):435–444. doi: 10.1038/ng.3247
  • Tougeron D, Fotsing G, Barbu V, et al. ABCB4/MDR3 gene mutations and cholangiocarcinomas. J Hepatol. 2012;57(2):467–468. doi: 10.1016/j.jhep.2012.01.025
  • Jacquemin E, DeVree JML, Cresteil D, et al. The wide spectrum of multidrug resistance 3 deficiency: From neonatal cholestasis to cirrhosis of adulthood. Gastroenterology. 2001;120(6):1448–58.
  • Kamarajah S, Patten D, Wadkin J, et al. Reduced expression of TJP-2 is associated with chronic liver disease and hepatic malignancy. Gut. 2016;65(1):A159.
  • Sambrotta M, Thompson RJ. Mutations in TJP2, encoding zona occludens 2, and liver disease. Tissue Barriers. 2015;3(3):1–5. doi: 10.1080/21688370.2015.1026537
  • Amirneni S, Haep N, Gad MA, et al. Molecular overview of progressive familial intrahepatic cholestasis. World J Gastroenterol. 2020;26(47):7470–7484. doi: 10.3748/wjg.v26.i47.7470
  • Gissen P, Arias IM. Structural and functional hepatocyte polarity and liver disease. J Hepatol. 2015;63(4):1023–1037. doi: 10.1016/j.jhep.2015.06.015
  • Gonzales E, Taylor SA, Davit-Spraul A, et al. MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease. Hepatology. 2017;65(1):164–173. doi: 10.1002/hep.28779
  • Bull LN, Ellmers R, Foskett P, et al. Cholestasis Due to USP53 deficiency. J Pediatr Gastroenterol Nutr. 2021;72(5):667–673. doi: 10.1097/MPG.0000000000002926
  • Samanta A, Parveen N, Sen Sarma M, et al. Cholestatic liver disease due to novel USP53 mutations: a case series of three Indian children. J Clin Exp Hepatol. 2024;14(2):101290. doi: 10.1016/j.jceh.2023.10.001
  • Nakagawa T, Tanaka Y, Matsuoka E, et al. Identification and classification of 16 new kinesin superfamily (KIF) proteins in mouse genome. Proc Natl Acad Sci U S A. 1997;94(18):9654–9659. doi: 10.1073/pnas.94.18.9654
  • Stalke A, Sgodda M, Cantz T, et al. KIF12 Variants and Disturbed Hepatocyte Polarity in Children with a Phenotypic Spectrum of Cholestatic Liver Disease. J Pediatr. 2022;240:284–91.
  • Luan W, Hao CZ, Li JQ, et al. Biallelic loss-of-function ZFYVE19 mutations are associated with congenital hepatic fibrosis, sclerosing cholangiopathy and high-GGT cholestasis. J Med Genet. 2021;58(8):514–525. doi: 10.1136/jmedgenet-2019-106706
  • Mandato C, Siano MA, Nazzaro L, et al. A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant. Orphanet J Rare Dis. 2021;16(1):1–9. doi: 10.1186/s13023-021-01775-8
  • Wu SH, Chang MH, Chen YH, et al. The ESCRT-III molecules regulate the apical targeting of bile salt export pump. J Biomed Sci. 2021;28(1):1–18. doi: 10.1186/s12929-020-00706-2
  • Satomura Y, Bessho K, Nawa N, et al. Novel gene mutations in three Japanese patients with ARC syndrome associated mild phenotypes: a case series. J Med Case Rep. 2022;16(1):1–6. doi: 10.1186/s13256-022-03279-w
  • Fu K li, Chen P, Zhou Y ying, et al. Hepatic Vps33b deficiency aggravates cholic acid-induced cholestatic liver injury in male mice. Acta Pharmacol Sin. 2022;43(4):933–40.

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