The Rare
Diseases

That Need
Our Attention

Cholestasis

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
  • Primary sclerosing cholangitis (PSC)4
  • Primary biliary cholangitis (PBC)4

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

Addressing Cholestasis Through IBAT Inhibition

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

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 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 Europe2,5
  • Approximately 2,000 to 2,500 pediatric ALGS patients in the United States6
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)7
Itchy skin
(pruritus)7
Stunted growth7
Disfiguring cholesterol deposits under the skin (xanthomas)7

The unrelenting itch, or pruritus, experienced by patients with ALGS is often so severe that it can result in bleeding and scarring.8-10

Current treatments

There are approved options for patients with cholestatic 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.11

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.12 PFIC is classified into 7 subtypes.13

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.12

Prevalence
  • PFIC1-PFIC7 affect 1 in every 50,000 to 100,000 births in the United States and Europe14
  • Fewer than 1,000 pediatric patients in either the United States or Europe6
Symptoms

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

Severe itch
(pruritus)12
Stunted growth12
Vitamin
deficiency12
Progressive
liver damage12
Liver failure12
Yellow skin
or eyes (jaundice)12
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.12,15

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.16

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.4

Onset

The median age at diagnosis is approximately 35 years, and approximately 70% of PSC patients have inflammatory bowel disease, principally ulcerative colitis.17,18

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.17 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.19 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.18

Prevalence

Estimated to affect:

  • 29,000 people in the United States6

  • 50,000 people in Europe6
Symptoms

Earliest symptoms include:

Extreme fatigue20
Itchy skin
(pruritus)
without a rash20
Abdominal discomfort
often called right
upper-quadrant pain20
Chills and fever
(typically associated
with cholangitis)6

As the condition worsens, patients may develop:

Yellow skin
or eyes (jaundice)20
Enlarged
spleen20

Up to 70% of patients suffer from pruritus during the course of the disease.6

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%.6,19

While certain drugs can be used as off label treatments, there are no FDA approved treatments for PSC.4

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.21

Prevalence
  • Primarily affects women, but more men are now being diagnosed22
  • Typically becomes apparent during middle age, initially affecting most individuals between the ages of 45 to 65 years22
  • Estimated to affect 1 in 1,000 women over the age of 4022
  • Prevalence is increasing in the United States and Europe6
Symptoms

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

Fatigue23
Severe itch
(pruritus)23
Abdominal pain23

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

Darkening of the skin
(hyperpigmentation)23
Enlargement of the
liver and spleen
(hepatosplenomegaly)23
Yellowing of the skin
(jaundice) in advanced
disease23
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.23

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. 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
  5. 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
  6. Data on File. Mirum Pharmaceuticals.
  7. Alagille syndrome. Johns Hopkins Medicine. Accessed April 29, 2021. https://www.hopkinsmedicine.org/health/conditions-and-diseases/alagille-syndrome
  8. 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
  9. 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
  10. 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
  11. Alagille syndrome. SSM Health. Accessed April 29, 2021. https://www.ssmhealth.com/cardinal-glennon/pediatric-transplant/pediatric-liver-transplant/alagille-syndrome
  12. Progressive familial intrahepatic cholestasis (PFIC). Cincinnati Children’s Hospital Medical Center. Accessed April 29, 2021. https://www.cincinnatichildrens.org/health/p/pfic
  13. 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/
  14. Progressive familial intrahepatic cholestasis. Medline Plus. Accessed April 29, 2021. https://medlineplus.gov/genetics/condition/progressive-familial-intrahepatic-cholestasis/
  15. 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
  16. Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis: a comprehensive review. J Hepatol. 2017;67:1298-1323.
  17. 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
  18. 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
  19. 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
  20. 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/
  21. 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/
  22. Primary biliary cholangitis. NORD (National Organization for Rare Disorders). Accessed June 1, 2021. https://rarediseases.org/rare-diseases/primary-biliary-cholangitis/
  23. 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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