progressive familial intrahepatic cholestasisAlbireo Pharma announced that the first patient has been enrolled, a Phase 3 clinical trial (called PEDFIC-1) for patients with progressive familial intrahepatic cholestasis (PFIC), a rare and progressive liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals.

PFIC is estimated to affect between one in every 50,000 to 100,000 children born worldwide and causes progressive, life-threatening liver disease. Moderate to severe pruritus is a common and problematic clinical presentation of PFIC that can severely diminish quality of life. In many cases, PFIC leads to cirrhosis and liver failure within the first 10 years of life, and nearly all patients with PFIC require treatment before age 30. There are currently no approved pharmacological treatment options for PFIC.

“A PFIC diagnosis for our children was shocking and devastating, and we quickly found out that current treatment options are inadequate,” said Kristen and Michael Busby of New York, parents of two children with PFIC. “We applaud all research in this area, and it is great news to see a clinical trial as an option for children with PFIC.”

“We are very excited to have the first patient enrolled into the PEDFIC-1 pivotal study to determine the potential of A4250, with the goal of providing new options to patients with this debilitating disease,” said Professor Richard Thompson, King’s College London and principal investigator of the study. “The results of the Phase 2 trial, where A4250 reduced serum bile acids and decreased pruritus in most patients, while showing a favourable overall tolerability profile, gives us optimism and confidence that A4250 could be an excellent medical treatment option.”

The Phase 3 program includes a single randomized, double-blind, placebo-controlled clinical trial designed to evaluate A4250 in 60 patients, ages 6 months to 18 years, with PFIC (subtype 1 or 2), elevated serum bile acid (sBA) levels and pruritus, and an open-label extension study to assess long-term safety and durability of response. Patients in the double-blind trial will receive a 40 or 120 μg/kg oral dose of A4250 or placebo once daily for 24 weeks. The primary endpoint for the US Food and Drug Administration (FDA) evaluation will be an assessment of change in pruritus, and the primary endpoint for the European Medicines Agency (EMA) evaluation will be sBA responder rate.

A4250 has received orphan drug designation for PFIC in the United States and European Union, and has been granted access to the EMA’s PRIority MEdicines (PRIME) program for the treatment of PFIC.

Signs and Symptoms of PFIC

Signs and symptoms of PFIC typically begin in infancy and are related to bile buildup and liver disease. Specifically, affected individuals experience severe itching, yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly). There are three known types of PFIC: PFIC1, PFIC2, and PFIC3. The types are also sometimes described as shortages of particular proteins needed for normal liver function. Each type has a different genetic cause.

In addition to signs and symptoms related to liver disease, people with PFIC1 may have short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. Affected individuals typically develop liver failure before adulthood. The signs and symptoms of PFIC2 are typically related to liver disease only; however, these signs and symptoms tend to be more severe than those experienced by people with PFIC1. People with PFIC2 often develop liver failure within the first few years of life. Additionally, affected individuals are at increased risk of developing a type of liver cancer called hepatocellular carcinoma.

Most people with PFIC3 have signs and symptoms related to liver disease only. Signs and symptoms of PFIC3 usually do not appear until later in infancy or early childhood; rarely, people are diagnosed in early adulthood. Liver failure can occur in childhood or adulthood in people with PFIC3.

About A4250

A4250 has been granted orphan drug designation for PFIC in the United States and European Union. The European Medicines Agency (EMA) has also granted A4250 access to the PRIority MEdicines (PRIME) program for the treatment of PFIC, and its Paediatric Committee has agreed to Albireo’s A4250 Pediatric Investigation Plan. A4250 is currently being evaluated in a Phase 3 clinical program in patients with PFIC (subtype 1 or 2).