The Rare Liver
Diseases

That Need
Our Attention

Our passion for science and our desire to serve people is what motivates and inspires us. That’s why we are developing potentially life-changing medicines for people with rare liver disease. Our research is driven by meaningful scientific evidence. Our mission is to deliver effective treatment options that empower patients to take back what rare liver disease often takes away.

IBAT inhibition: our scientific focus

We are developing two selective inhibitors of the ileal bile acid transporter (also known as IBAT). To better understand how IBAT therapies can help those living with cholestatic liver disease, let’s take a look at how a functioning IBAT system operates.

In a fully functioning system, the body circulates bile acids to help digest food (among other important roles) in the small intestine and then recycles—or transports—them back to the liver.

But for various reasons only partially understood, those who have liver disease experience what we call “cholestasis.”1,2

What is cholestasis?

Cholestasis happens when the flow of bile from the liver is reduced or blocked. Toxic levels of this bile buildup can lead to rare cholestatic liver diseases, including (but not limited to):

  • Alagille syndrome (ALGS)2
  • Progressive familial intrahepatic cholestasis (PFIC)3
  • Biliary atresia (BA)4
  • Primary sclerosing cholangitis (PSC)5
  • Intrahepatic cholestasis of pregnancy (ICP)6
  • Primary biliary cholangitis (PBC)5

Patients with cholestatic liver disease typically experience debilitating itching (pruritus) that can lead to scarring, sleep disruption, and significant fatigue, all of which take a significant toll on psychological and social well-being and dramatically impact the quality of life of patients and families. In severe cases, cholestatic liver disease can lead to liver failure and the need for a liver transplant.1

How IBAT inhibition can help

Our science seeks to help redirect bile acids so that more are excreted in the feces, leading to lower circulating levels and reduced bile buildup in the liver that can lead to damage.

IBAT holds great therapeutic potential

Aiming to turn rare liver diseases
into livable conditions

There is a void of effective therapies for rare cholestatic liver diseases. We believe IBAT therapies can help fill the void, delivering potentially life-changing medicine.

Alagille syndrome (ALGS)

What it is

Alagille syndrome (ALGS) is a rare genetic disorder caused by abnormalities in bile ducts that can lead to progressive liver disease. Bile ducts carry bile (which helps to digest fats) from the liver to the gallbladder and small intestine. Malformed bile ducts cause the accumulation of bile acids in the liver (cholestasis), which leads to inflammation and injury and prevents the liver from working properly.2 ALGS affects several organs and systems in the body, including (but not limited to) the liver, heart, kidneys, and central nervous system.

Prevalence
  • Estimated incidence – 1 in every 30,000 births in the United States and Europe2,7
  • Approximately 2,000 to 2,500 pediatric ALGS patients in the United States8
Symptoms

Signs and symptoms of ALGS typically begin during infancy. Patients often experience numerous symptoms as a result of the disease. Those symptoms attributed to cholestasis include:

Yellow skin
or eyes (jaundice)9
Itchy skin
(pruritus)9
Stunted growth9
Disfiguring cholesterol deposits under the skin (xanthomas)9

The unrelenting itch, or pruritus, experienced by patients with ALGS is often so severe that it can result in bleeding and scarring.10-12

Current treatments

There is now an FDA-approved treatment for pruritus associated with ALGS Until now, the only treatment options for cholestatic pruritus in ALGS included off label antipruritic medications. Both refractory pruritus and disease progression are indications for liver transplant. Additional management can include nutritional support.13

Progressive familial intrahepatic cholestasis (PFIC)

What it is

Progressive familial intrahepatic cholestasis (PFIC) is a rare genetic (inherited) disorder caused by defects in genes that produce proteins needed to form bile and transport it out of the liver.14 PFIC is classified into 7 subtypes.15

Bile, which helps digest fats, is transported through ducts from the liver to the gallbladder and small intestine. A blockage means that toxins remain in the body. This damages liver cells and causes a harmful buildup of waste in the blood stream, preventing the body from absorbing fats and vitamins.14

Prevalence
  • PFIC1-PFIC7 affect 1 in every 50,000 to 100,000 births in the United States and Europe16
  • Fewer than 1,000 pediatric patients in either the United States or Europe8
Symptoms

Signs of the disease begin during infancy and can result in:

Severe itch
(pruritus)14
Stunted growth14
Vitamin
deficiency14
Progressive
liver damage14
Liver failure14
Yellow skin
or eyes (jaundice)14
Current treatments

Options for pruritus and symptom management include an ileal bile acid transport (IBAT) inhibitor in addition to off label and unproven treatments. Supportive treatments include nutritional management. Most options for addressing symptoms and disease progression eventually include liver transplantation or biliary diversion surgery.14,17

Biliary atresia (BA)

What it is

Biliary atresia (BA) is a rare liver disorder in which there is a blockage or absence of large bile ducts that leads to bile accumulation in the liver and ultimately results in progressive cholestasis and liver damage.18 BA is the most common reason for liver transplants in children.19

What causes BA

The underlying causes of BA are not completely understood. For some patients, BA may occur because the bile ducts did not form properly during fetal development, and in others, inflammation around the time of birth leads to destruction of bile ducts. As a result of BA, bile acids are not able to adequately drain from the liver. The rapid progression of BA necessitates surgical intervention within the first months of life.20

Prevalence
  • Occurs in infants18
  • Estimated to affect 1 in every 10,000 to 15,000 live births in the United States8
Symptoms

Signs and symptoms show up shortly after birth. They can include:

Yellow skin
or eyes (jaundice)18
Dark urine18
Enlarged liver18
Current treatments

There remains a substantial unmet medical need for therapeutic interventions, as invasive surgery is often unsuccessful. The standard of care for BA is the Kasai procedure, a surgery in which a segment of the small intestine is used to attach the small intestine directly to the liver where bile is expected to drain, and is most successful if conducted in the first 8 weeks of life.18 The success rate of the Kasai procedure is about 30% to 40%.21 The remaining patients are at risk of progressive liver disease requiring liver transplantation.18

Intrahepatic cholestasis of pregnancy (ICP)

What it is

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that occurs in pregnant women, often during the second or third trimester, and impairs the normal release of bile from liver cells and can lead to impaired liver function and complications for the baby.6

What causes ICP

The underlying cause of ICP is not completely understood, but it is thought that a combination of genetic factors and increases in pregnancy hormones typically during the second and third trimesters contribute to the impaired liver function and bile flow characteristic of ICP.6 Also, some women have a genetic profile similar to that seen in PFIC.22

Prevalence
  • Approximately 1% of pregnancies and up to almost 5% in specific populations23
  • Yearly estimate—40,000 cases in the United States and 100,000 cases in Europe8
Symptoms and complications

ICP can lead to serious complications for both the mother and the unborn child, including:

Severe itch
(pruritus)6
Fatigue6
Preterm birth24
Meconium-stained
amniotic fluid6
Neonatal asphyxia24
Stillbirth6
Current treatments

There are currently no approved, effective therapies that adequately address maternal symptoms and fetal complications of ICP. So there remains high unmet medical need for a safe and effective treatment option for ICP.8 Some patients are treated with an off-label medication, although clinical studies suggest that it may provide minimal improvement for most patients.24

Because the rates of these childbirth complications rise with increasing levels of maternal serum bile acid and increasing gestational age, elective early delivery (ie, prior to full term) is often recommended as an option for high-risk pregnancies but bears the risk of long-term consequences for the child.22

LEARN MORE ABOUT ICP FROM 2 LEADING EXPERTS, DR. KATHERINE KOHARI AND DR. CATHERINE WILLIAMSON

Primary sclerosing cholangitis (PSC)

What it is

Primary sclerosing cholangitis (PSC) is a rare, serious idiopathic chronic cholestatic liver disease characterized by progressive inflammation and destruction of bile ducts, which may lead to fibrosis, cirrhosis, portal hypertension, cancer, and ultimately liver failure.25

What causes PSC

The cause of PSC is not completely understood but it is thought to stem from genetic as well as environmental factors. There is evidence that variations in certain genes involved in bile acid synthesis/transport increase the risk for developing PSC.5

Onset

The median age at diagnosis is approximately 35 years, and approximately 70% of PSC patients have inflammatory bowel disease, principally ulcerative colitis.26,27

Progression

Eventually, the buildup of bile damages liver cells and contributes to progression of the disease from chronic liver disease to subsequent liver failure. Median transplant-free survival for PSC patients is estimated to be 9 to 18 years from diagnosis in symptomatic patients depending upon the stage of the disease at the time of diagnosis.26 Complications involving the biliary tree are common and include cholangitis as well as ductal strictures and gallstones that may require frequent endoscopic or surgical interventions.28 Primary sclerosing cholangitis increases the risk of development of malignancies, with cholangiocarcinoma, a group of cancers that begin in the bile ducts, being the most common.27

Prevalence

Estimated to affect:

  • 29,000 people in the United States8

  • 50,000 people in Europe8
Symptoms

Earliest symptoms include:

Extreme fatigue29
Itchy skin
(pruritus)
without a rash29
Abdominal discomfort
often called right
upper-quadrant pain29
Chills and fever
(typically associated
with cholangitis)8

As the condition worsens, patients may develop:

Yellow skin
or eyes (jaundice)29
Enlarged
spleen29

Up to 70% of patients suffer from pruritus during the course of the disease.8

Current treatments

There is a serious need for an effective therapy for PSC as liver transplantation is currently the only known treatment shown to improve clinical outcomes. However, it requires long-term administration of immunosuppressants, only a portion of the patients who require a liver transplant are able to match with a suitable donor organ, and there is a posttransplant recurrence rate as high as 25%.8,28

While certain drugs can be used as off label treatments, there are no FDA approved treatments for PSC.5

Primary biliary cholangitis (PBC)

What it is

Primary biliary cholangitis (PBC) is a chronic cholestatic disease in which the body’s immune system mistakenly attacks healthy cells and tissue (also known as an autoimmune disease). This results in the progressive destruction of the small bile ducts in the liver. Bile is a fluid made in the liver that aids with digestion and helps the body remove cholesterol, toxins, and worn-out red blood cells. When the ducts are destroyed, bile builds up in the liver to toxic levels, leading to inflammation, liver cell necrosis, and scarring (fibrosis). As scar tissue replaces healthy liver tissue, the liver becomes increasingly impaired. This may eventually result in cirrhosis and liver failure.30

Prevalence
  • Primarily affects women, but more men are now being diagnosed31
  • Typically becomes apparent during middle age, initially affecting most individuals between the ages of 45 to 65 years31
  • Estimated to affect 1 in 1,000 women over the age of 4031
  • Prevalence is increasing in the United States and Europe8
Symptoms

In early stages, people may not experience any symptoms; however, patients with more advanced disease generally have symptoms including:

Fatigue32
Severe itch
(pruritus)32
Abdominal pain32

On physical examination, patients may also exhibit findings such as:

Darkening of the skin
(hyperpigmentation)32
Enlargement of the
liver and spleen
(hepatosplenomegaly)32
Yellowing of the skin
(jaundice) in advanced
disease32
Current treatments

There is no cure, but medications such as ursodiol and Ocaliva® may help manage the disease and slow the progression of liver damage. Other medications are typically prescribed to help manage a person’s symptoms, including itching and fatigue. When medications do not help, liver transplantation may be necessary.32

References

  1. Hilscher MB, Kamath PS, Eaton JE. Cholestatic liver diseases: a primer for generalists and subspecialists. Mayo Clin Proc. 2020;95(10):2263-2279. doi:10.1016/j.mayocp.2020.01.015
  2. Definition & Facts for Alagille Syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed June 4, 2021. https://www.niddk.nih.gov/health-information/liver-disease/alagille-syndrome/definition-facts
  3. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol. 2014;4(1):25-36. doi:10.1016/j.jceh.2013.10.005
  4. Ghallab A. Pharmacological inhibition of the ideal apical sodium-dependent bile acid transporter ASBT ameliorates cholestatic liver disease in mice. Arch Toxicol. 2019;93(10):3039-3040. doi:10.1007/s00204-019-02583-7
  5. Hegade VS, Jones DEJ, Hisrchfield GM. Apical sodium-dependent transporter inhibitors in primary biliary cholangitis and primary sclerosing cholangitis. Dig Dis. 2017;35(3):267-274. doi:10.1159/000450988
  6. Lee RH, Greenberg M, Metz TD, Pettker CM. Society for Maternal-Fetal Medicine Consult Series #53: Intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol. 2021;224(2):B2-B9. doi:10.1016/j.ajog.2020.11.002
  7. Fawaz R, Baumann U, Ekong U, et al. Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2017;64(1):154-168. doi:10.1097/MPG.0000000000001334
  8. Data on File. Mirum Pharmaceuticals.
  9. Alagille syndrome. Johns Hopkins Medicine. Accessed April 29, 2021. https://www.hopkinsmedicine.org/health/conditions-and-diseases/alagille-syndrome
  10. 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
  11. Kronsten V, Fitzpatrick E, Baker A. Management of cholestatic pruritus in pediatric patients with Alagille syndrome: the King’s College Hospital experience. J Pediatr Gastroenterol Nutr. 2013;57(2):149-154. doi:10.1097/MPG.0b013e318297e384
  12. Elisofon SA, Emerick KM, Sinacore JM, Alonso EM. Health status of patients with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;51(6):759-765. doi:10.1097/MPG.0b013e3181ef3771
  13. Alagille syndrome. SSM Health. Accessed April 29, 2021. https://www.ssmhealth.com/cardinal-glennon/pediatric-transplant/pediatric-liver-transplant/alagille-syndrome
  14. Progressive familial intrahepatic cholestasis (PFIC). Cincinnati Children’s Hospital Medical Center. Accessed April 29, 2021. https://www.cincinnatichildrens.org/health/p/pfic
  15. Types and subtypes of progressive familial intrahepatic cholestasis (PFIC). Progressive Familial Intrahepatic Cholestasis Advocacy and Resource Network. Accessed June 3, 2021. https://www.pfic.org/types-and-subtypes-of-pfic/
  16. Progressive familial interhepatic cholestasis. Medline Plus. Accessed April 29, 2021. https://medlineplus.gov/genetics/condition/progressive-familial-intrahepatic-cholestasis/
  17. Krajnik M, Zylicz Z. Understanding pruritus in systemic disease. J Pain Symptom Manage. 2001;21(2):151-168. doi:10.1016/S0885-3924(00)00256-6
  18. Biliary atresia: symptoms and treatment like the Kasai procedure. American Liver Foundation. Accessed June 3, 2021. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/biliary-atresia/
  19. Yoon PW, Bresee JS, Olney RS, James LM, Khoury MJ. Epidemiology of biliary atresia: a population-based study. Pediatrics. 1997;99(3):376-382. doi:10.1542/peds.99.3.376
  20. Biliary atresia: symptoms and treatment. Cincinnati Children’s Hospital Medical Center. Accessed June 3, 2021. https://www.cincinnatichildrens.org/health/b/biliary
  21. Lang T, Kappler M, Dietz H, Harms HK, Bertele-Harms R. Biliary atresia: which factors predict the success of a Kasai operation? an analysis of 36 patients. Eur J Med Res. 2000;5(3):110-114.
  22. Dixon PH, Williamson C. The molecular genetics of intrahepatic cholestasis of pregnancy. Obstet Med. 2008;1(2):65-71. doi:10.1258/om.2008.080010
  23. Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis. 2007;2:26. doi:10.1186/1750-1172-2-26
  24. Ovadia C, Seed PT, Sklavounos A, et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet. 2019;393(10174):899-909. doi:10.1016/S0140-6736(18)31877-4
  25. Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis: a comprehensive review. J Hepatol. 2017;67:1298-1323.
  26. Rupp C, Rössler A, Zhou T, et al. Impact of age at diagnosis on disease progression in patients with primary sclerosing cholangitis. United Eur Gastroenterol J. 2018;6(2):255-262. doi:10.1177/2050640617717156
  27. Palmela C, Peerani F, Castaneda D, Torres J, Itzkowitz SH. Inflammatory bowel disease and primary sclerosing cholangitis: a review of the phenotype and associated specific features. Gut Liver. 2018;12(1):17-29. doi:10.5009/gnl16510
  28. Bjøro K, Schrumpf E. Liver transplantation for primary sclerosing cholangitis. J Hepatol. 2004;40(4):570-577. doi:10.1016/j.jhep.2004.01.021
  29. Primary sclerosing cholangitis: symptoms, causes, and treatment. American Liver Foundation. Accessed June 3, 2021. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/primary-sclerosing-cholangitis/
  30. Primary biliary cholangitis: symptoms, causes, and treatment. American Liver Foundation. Accessed June 1, 2021. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/primary-biliary-cholangitis/
  31. Primary biliary cholangitis. NORD (National Organization for Rare Disorders). Accessed June 1, 2021. https://rarediseases.org/rare-diseases/primary-biliary-cholangitis/
  32. Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. Published online November 6, 2018:hep.30145. doi:10.1002/hep.30145

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