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UNDERSTANDING PFIC

Bile Acid Buildup May Fuel Cholestatic Pruritus* Now and Impact the Liver Later1,2

Mechanism of Disease

Progressive Familial Intrahepatic Cholestasis (PFIC) Is a Group of Rare, Autosomal Recessive Disorders3

PFIC is classified into 3 main subtypes, with PFIC2 (bile salt export pump [BSEP] deficiency) being the most aggressive subtype and accounting for approximately half of cases.3-5 Across all PFIC subtypes, there is an inhibition of bile flow between the liver and small intestine, resulting in a persistent state of cholestasis.6,7

PFIC1, PFIC2, PFIC3

    Mutations in hepatocellular transport genes cause functional deficiencies that disrupt the ability for bile acids to be transported out of hepatocytes. This results in increased serum bile acid (sBA) levels systemically.3,8-10

  • The 3 most common subtypes of PFIC (ie, PFIC1, PFIC2, and PFIC3) present with elevated sBA—nearly 10- to 20-fold elevations—with extremely elevated levels in PFIC211-13

Consequences of Cholestasis

Cholestasis leads to bile acid buildup in the liver and is the main driver of 1,7,14,15:

Inflammation

Progressive liver injury

Fibrosis

In PFIC1 and PFIC2, it has been reported that approximately

50%

of patients are alive and have their native liver at 10 years old.16

  • In PFIC2, specifically, only 32% of patients are alive and have their native liver by 18 years old4
section-background section-background

The Potential for Surgical Intervention and Liver Transplant

Many patients with PFIC with uncontrolled cholestatic pruritus continue to opt for surgical biliary diversion and/or liver transplant.4,7,17

Among 38 pediatric patients with PFIC who underwent surgical biliary diversion, the most common indication was cholestatic pruritus (92%).18

End-stage liver disease (80%) was the most common indication for liver transplant in patients with PFIC, followed by refractory cholestatic pruritus (20%).19

80%

End-stage
liver disease

20%

Refractory cholestatic pruritus

For patients with PFIC, there is a need for effective treatment options that reduce bile acid buildup and promptly relieve cholestatic pruritus.7

BSEP=bile salt export pump; FIC1=familial intrahepatic cholestasis 1; MDR3=multidrug resistance class 3.

*The pathophysiology of cholestatic pruritus in PFIC is not completely known.

References: 1. Cai S-Y, Li M, Boyer J. The role of bile acid-mediated inflammation in cholestatic liver injury. In: Arias IM, Alter HJ, Boyer JR, et al, eds. The Liver: Biology and Pathobiology. 6th ed. Wiley; 2020:728-736. doi:10.1002/9781119436812.ch56 2. Jesina D. Alagille syndrome: an overview. Neonatal Netw. 2017;36(6):343-347. doi:10.1891/0730-0832.36.6.343 3. Jacquemin E. Progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2012;36(suppl 1):S26-S35. doi:10.1016/S2210-7401(12)70018-9 4. van Wessel DBE, Thompson RJ, Gonzalez E, et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol. 2020;73(1):84-93. doi:10.1016/j.jhep.2020.02.007 5. Orphanet. The portal for rare diseases and orphan drugs. Progressive familial intrahepatic cholestasis type 2. Updated May 2011. Accessed May 31, 2024. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=79304&lng=EN 6. Felzen A, Verkade HJ. The spectrum of progressive familial intrahepatic cholestasis diseases: update on pathophysiology and emerging treatments. Eur J Med Genet. 2021;64(11):104317. doi:10.1016/j.ejmg.2021.104317 7. Kamath BM, Stein P, Houwen RHJ, Verkade HJ. 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.1455 8. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol. 2014;4(1):25-36. doi:10.1016/j.jceh.2013.10.005 9. Amer S, Hajira A. A comprehensive review of progressive familial intrahepatic cholestasis (PFIC): genetic disorders of hepatocanalicular transporters. Gastroenterol Res. 2014;7(2):39-43. doi:10.14740/gr609e 10. Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol. 2019;11(5):450-463. doi:10.4254/wjh.v11.i5.450 11. Gunaydin M, Bozkurter Cil AT. Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment. Hepat Med. 2018;10:95-104. doi:10.2147/HMER.S137209 12. Jericho HS, Kaurs E, Boverhof R, et al. Bile acid pool dynamics in progressive familial intrahepatic cholestasis with partial external bile diversion. J Pediatr Gastroenterol Nutr. 2015;60(3):368-374. doi:10.1097/MPG.0000000000000630 13. Wehrman AJ. Progressive familial intrahepatic cholestasis. Medscape. Updated October 4, 2021. Accessed May 31, 2024. https://emedicine.medscape.com/article/932794-print 14. Karpen SJ, Kelly D, Mack C, Stein P. Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol Int. 2020;14(5):677-689. doi:10.1007/s12072-020-10070-w 15. Li T, Chiang J. Bile acid-induced liver injury in cholestasis. In: Ding WX, Yin XM, eds. Li T, Chiang J. Bile acid-induced liver injury in cholestasis. In: Ding WX, Yin XM, eds. Cellular Injury in Liver Diseases. Springer; 2017:143-172. Cell Death in Biology and Diseases. Springer; 2017:143-172. doi:10.1007/978-3-319-53774-0_7 16. van Wessel D, Thompson R, Grammatikopoulos T, et al. The natural course of FIC1 deficiency and BSEP deficiency: initial results from the NAPPED-consortium (Natural course and Prognosis of PFIC and Effect of biliary Diversion). Poster presented at: International Liver Congress; April 11-15, 2018; Paris, France. 17. Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67(2):148-156. doi:10.1097/MPG.0000000000001958 18. 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 19. Vasudevan AK, Shanmugam N, Rammohan A, et al. Outcomes of pediatric liver transplantation for progressive familial intrahepatic cholestasis. Pediatr Transplant. 2023;(8):e14600. doi:10.1111/petr.14600

INDICATION

LIVMARLI is indicated for the treatment of cholestatic pruritus in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC).

Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in nonfunctional or complete absence of bile salt export pump (BSEP) protein.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events (eg, variceal hemorrhage, ascites, or hepatic encephalopathy).

WARNINGS AND PRECAUTIONS

Hepatotoxicity: LIVMARLI treatment is associated with a potential for drug-induced liver injury (DILI).

In the PFIC trial, treatment-emergent hepatic decompensation events and elevations of liver tests or worsening of liver tests occurred. Two patients experienced DILI attributable to LIVMARLI. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these 4 patients, 1 patient required liver transplant and another patient died.

Obtain baseline liver tests and monitor during treatment. Liver-related adverse reactions and physical signs of hepatic decompensation should also be monitored. Dose reduction or treatment interruption may be considered if abnormalities occur in the absence of other causes. Permanently discontinue LIVMARLI if a patient experiences the following: persistent or recurrent liver test abnormalities, clinical hepatitis upon rechallenge, or a hepatic decompensation event.

Gastrointestinal (GI) Adverse Reactions: Diarrhea and abdominal pain were reported as the most common adverse reactions. Monitor for dehydration and treat promptly. Consider reducing the dosage or interrupting LIVMARLI dosing if a patient experiences persistent diarrhea or diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever.

Fat-Soluble Vitamin (FSV) Deficiency: Patients can have FSV deficiency (vitamins A, D, E, and K) at baseline, and LIVMARLI may adversely affect absorption of FSVs. Treatment-emergent bone fracture events have been observed more frequently with patients treated with LIVMARLI compared with patients treated with placebo. If bone fractures or bleeding occur, consider interrupting LIVMARLI and supplement with FSVs. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.

Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age): Total daily intake of propylene glycol should be considered for managing the risk of propylene glycol toxicity. Monitor patients for signs of propylene glycol toxicity. Discontinue LIVMARLI if toxicity is suspected.

ADVERSE REACTIONS

The most common adverse reactions are diarrhea, FSV deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures.

DRUG INTERACTIONS

Administer bile acid binding resins at least 4 hours before or 4 hours after administration of LIVMARLI.
A decrease in the absorption of OATP2B1 substrates (eg, statins) due to OATP2B1 inhibition by LIVMARLI in the GI tract cannot be ruled out. Consider monitoring the drug effects of OATP2B1 substrates as needed.

DOSING INFORMATION

LIVMARLI should be taken twice daily 30 minutes before a meal. The provided oral dosing dispenser must be used to accurately measure the dose. Any remaining LIVMARLI should be discarded 100 days after first opening the bottle.

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References: 1. Cai S-Y, Li M, Boyer J. The role of bile acid-mediated inflammation in cholestatic liver injury. In: Arias IM, Alter HJ, Boyer JR, et al, eds. The Liver: Biology and Pathobiology. 6th ed. Wiley; 2020:728-736. doi:10.1002/9781119436812.ch56 2. Jesina D. Alagille syndrome: an overview. Neonatal Netw. 2017;36(6):343-347. doi:10.1891/0730-0832.36.6.343 3. Jacquemin E. Progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2012;36(suppl 1):S26-S35. doi:10.1016/S2210-7401(12)70018-9 4. van Wessel DBE, Thompson RJ, Gonzalez E, et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol. 2020;73(1):84-93. doi:10.1016/j.jhep.2020.02.007 5. Orphanet. The portal for rare diseases and orphan drugs. Progressive familial intrahepatic cholestasis type 2. Updated May 2011. Accessed May 31, 2024. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=79304&lng=EN 6. Felzen A, Verkade HJ. The spectrum of progressive familial intrahepatic cholestasis diseases: update on pathophysiology and emerging treatments. Eur J Med Genet. 2021;64(11):104317. doi:10.1016/j.ejmg.2021.104317 7. Kamath BM, Stein P, Houwen RHJ, Verkade HJ. 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.1455 8. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol. 2014;4(1):25-36. doi:10.1016/j.jceh.2013.10.005 9. Amer S, Hajira A. A comprehensive review of progressive familial intrahepatic cholestasis (PFIC): genetic disorders of hepatocanalicular transporters. Gastroenterol Res. 2014;7(2):39-43. doi:10.14740/gr609e 10. Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol. 2019;11(5):450-463. doi:10.4254/wjh.v11.i5.450 11. Gunaydin M, Bozkurter Cil AT. Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment. Hepat Med. 2018;10:95-104. doi:10.2147/HMER.S137209 12. Jericho HS, Kaurs E, Boverhof R, et al. Bile acid pool dynamics in progressive familial intrahepatic cholestasis with partial external bile diversion. J Pediatr Gastroenterol Nutr. 2015;60(3):368-374. doi:10.1097/MPG.0000000000000630 13. Wehrman AJ. Progressive familial intrahepatic cholestasis. Medscape. Updated October 4, 2021. Accessed May 31, 2024. https://emedicine.medscape.com/article/932794-print 14. Karpen SJ, Kelly D, Mack C, Stein P. Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol Int. 2020;14(5):677-689. doi:10.1007/s12072-020-10070-w 15. Li T, Chiang J. Bile acid-induced liver injury in cholestasis. In: Ding WX, Yin XM, eds. Li T, Chiang J. Bile acid-induced liver injury in cholestasis. In: Ding WX, Yin XM, eds. Cellular Injury in Liver Diseases. Springer; 2017:143-172. Cell Death in Biology and Diseases. Springer; 2017:143-172. doi:10.1007/978-3-319-53774-0_7 16. van Wessel D, Thompson R, Grammatikopoulos T, et al. The natural course of FIC1 deficiency and BSEP deficiency: initial results from the NAPPED-consortium (Natural course and Prognosis of PFIC and Effect of biliary Diversion). Poster presented at: International Liver Congress; April 11-15, 2018; Paris, France. 17. Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67(2):148-156. doi:10.1097/MPG.0000000000001958 18. 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 19. Vasudevan AK, Shanmugam N, Rammohan A, et al. Outcomes of pediatric liver transplantation for progressive familial intrahepatic cholestasis. Pediatr Transplant. 2023;(8):e14600. doi:10.1111/petr.14600

INDICATION

LIVMARLI is indicated for the treatment of cholestatic pruritus in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC).

Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in nonfunctional or complete absence of bile salt export pump (BSEP) protein.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events (eg, variceal hemorrhage, ascites, or hepatic encephalopathy).

WARNINGS AND PRECAUTIONS

Hepatotoxicity: LIVMARLI treatment is associated with a potential for drug-induced liver injury (DILI).

In the PFIC trial, treatment-emergent hepatic decompensation events and elevations of liver tests or worsening of liver tests occurred. Two patients experienced DILI attributable to LIVMARLI. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these 4 patients, 1 patient required liver transplant and another patient died.

Obtain baseline liver tests and monitor during treatment. Liver-related adverse reactions and physical signs of hepatic decompensation should also be monitored. Dose reduction or treatment interruption may be considered if abnormalities occur in the absence of other causes. Permanently discontinue LIVMARLI if a patient experiences the following: persistent or recurrent liver test abnormalities, clinical hepatitis upon rechallenge, or a hepatic decompensation event.

Gastrointestinal (GI) Adverse Reactions: Diarrhea and abdominal pain were reported as the most common adverse reactions. Monitor for dehydration and treat promptly. Consider reducing the dosage or interrupting LIVMARLI dosing if a patient experiences persistent diarrhea or diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever.

Fat-Soluble Vitamin (FSV) Deficiency: Patients can have FSV deficiency (vitamins A, D, E, and K) at baseline, and LIVMARLI may adversely affect absorption of FSVs. Treatment-emergent bone fracture events have been observed more frequently with patients treated with LIVMARLI compared with patients treated with placebo. If bone fractures or bleeding occur, consider interrupting LIVMARLI and supplement with FSVs. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.

Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age): Total daily intake of propylene glycol should be considered for managing the risk of propylene glycol toxicity. Monitor patients for signs of propylene glycol toxicity. Discontinue LIVMARLI if toxicity is suspected.

ADVERSE REACTIONS

The most common adverse reactions are diarrhea, FSV deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures.

DRUG INTERACTIONS

Administer bile acid binding resins at least 4 hours before or 4 hours after administration of LIVMARLI.
A decrease in the absorption of OATP2B1 substrates (eg, statins) due to OATP2B1 inhibition by LIVMARLI in the GI tract cannot be ruled out. Consider monitoring the drug effects of OATP2B1 substrates as needed.

DOSING INFORMATION

LIVMARLI should be taken twice daily 30 minutes before a meal. The provided oral dosing dispenser must be used to accurately measure the dose. Any remaining LIVMARLI should be discarded 100 days after first opening the bottle.