Children with progressive familial intrahepatic cholestasis will be able to take part in a Phase 3 clinical trial of A4250’s ability to combat the rare genetic disorder, according to its maker, Albireo.
The company will begin enrolling patients with the life-threatening genetic condition in the second half of 2017.
Albireo decided to start the trial after consultations with the U.S. Food and Drug Administration and the European Medicines Agency.
“We are pleased with the collaborative and constructive dialogue we have had for A4250 with regulatory authorities in the U.S. and Europe, which has guided us as we work to develop our investigational drug for children” with the condition, Ron Cooper, Albireo’s president and chief executive officer, said in a press release. “A4250 is a potent IBAT inhibitor that, with Phase 3 success and regulatory approval, could potentially transform the treatment paradigm for what is a life-altering disease. We look forward to initiating our Phase 3 program.”
Cholestatis occurs when the digestion-facilitating bile that the liver produces is unable to reach a section of the small intestine known as the duodenum. The disrupted flow leads to bile piling up in the liver. This accumulation not only causes cholestatis but also a skin disease caused pruritus.
Ninety-five percent of the bile acids that reach the small intestine are usually recirculated. This means that reducing the amount of bile returning to the liver could be a way to treat cholestatic liver diseases, the researchers said.
A4250 is a selective inhibitor of the ileal bile acid transporter, an enzyme that plays a key role in sending bile from the small intestine back to the liver. It acts in the gut, reducing the risk of side effects elsewhere.
Albireo plans to enroll 60 youngsters ranging from 6 months to 18 years old in the randomized, double-blind, placebo-controlled, multicenter Phase 3 trial. It will take part in the United States, Western Europe, Canada, Australia, and the Middle East.
Patients will receive one of two daily doses of A4250 or a placebo for sixth months. One dose will be three times higher than the other. Children taking medication for their pruritus will be able to keep using it during the trial.
The primary objectives of the trial will differ in the U.S. and European arms. U.S. regulators wanted the primary objective to be A4250’s ability to improve patients’ pruritus. European regulators wanted it to be the therapy’s ability to decrease bile acid levels in blood serum. High levels of serum bile acids have been linked to the development of progressive familial intrahepatic cholestasis.
The secondary objective in the U.S. arm will be whether A4250 can lower serum bile acid levels, and the secondary objective in the European arm whether it can improve pruritus.
Other yardsticks in the two arms will be changes in makers of the disease’s progression, changes in liver biochemistry variables, and the amount of the time it takes for the disease to progress to the point of needing surgery.
Albireo is also planning an open-label, long-term Phase 3 extension study. It will assess patients’ duration of response to A4250 and the therapy’s long-term safety. Youngsters enrolled in the Phase 3 trial will be able to participate in the extension study.
The company expects the results of the trials to support its bid for U.S. and European approval of A4250.
Albireo is also supporting an independent study on whether reducing serum bile acid levels is a good way to treat progressive familial intrahepatic cholestasis.