The Rare
Diseases

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.

• Estimated incidence – 1 in every 30,000 births in the United States and Europe^2,5
• Approximately 2,000 to 2,500 pediatric ALGS patients in the United States⁶

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

There are approved options for patients with cholestatic pruritus associated with ALGS:

• United States
• Europe
• Canada

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) 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

• 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

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

IBAT inhibition has been approved to treat cholestatic pruritus in patients with PFIC.

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

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

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

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

Estimated to affect:

• 29,000 people in the United States⁶


• 50,000 people in Europe⁶

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

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) 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

• 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

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

There is no cure, but medications 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