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An emerging drug class is proving viable for burdensome symptoms, as well as liver failure, in pediatric patients with the rare inherited disease.
Alagille syndrome is currently estimated to affect 1 in approximately 30,000 - 45,000 people. Though a particularly rare, inherited condition, its multisystemic effect particularly on children is burdensome and ill-met by available treatments.
That fortune may soon change, though.
In an interview with HCPLive, Nadia Ovchinsky, MD, director of the division of pediatric gastroenterology and hepatology in the department of pediatrics at NYU Grossman School of Medicine, discussed the pathophysiology and clinical presentation of Alagille syndrome, and the development of the promising ileal bile acid transporter (IBAT) inhibitor drug class for younger patients.
“Each child has a different phenotype, even the ones with the same genetic mutation,” Ovchinsky said. “It’s a multisystemic disorder, with numerous systems that can be involved: cardiovascular, skeletal, other vascular issues.”
But the clearest target for care remains the impact of disease on the liver, where a “paucity of small intrahepatic bile ducts” may drive the progression of cholestasis in patients.
“Although patients have different manifestations, some of the common ones that we see are ongoing cholestasis, resulting in malabsorption, pruritus—which can be debilitating to these patients—disfiguring cytomas, and over time, progressional liver disease,” Ovchinsky explained.
Though disease can present mildly in children, most patients who present with Alagille syndrome during infancy will experience continued issues with cholestasis, Ovchinsky said. As such, the supportive care strategy entails sufficient nutrition and caloric intake to ensure the children can grow, and a symptomatic focus on managing their pruritus.
“Up until (IBAT inhibitors) were developed, we only had a few options that were available,” Ovchinsky said. “The options were used as anti-pruritic agents, but these are all off-label use. (They) may make some difference to these patients, but in those with significant pruritus, we really don’t see significant symptomatic relief.”
Many patients eventually require liver transplants due to the progression of liver disease, but even more experience a burden on their quality of life due to severe pruritus.
“IBAT inhibitors are a new class of drugs that target a very specific receptor in the intestine—an important protein that allows our intestines to be cleaned,” Ovchinsky said. “What IBAT inhibitors do are act as potent and pretty selective inhibitors of this receptor; they interrupt intrahepatic circulation and prevent accumulation of these bile acids in the liver that can also spill over into the systemic circulation.”
With the development of potential agents like odevixibat for Alagille syndrome, Ovchinsky and colleagues may help mitigate the most severe components of this rare disease for pediatric patients.
“The main point that we can see with this drug class is a decrease in pruritus,” she said. “Eventually, the goal of using this drug is to try and slow down or prevent progression of liver disease over time.”