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Kanuma improves liver markers in patients with lysosomal acid lipase deficiency
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BOSTON — Kanuma improved various liver markers, as well as reduced liver fibrosis and cirrhosis, in children and adults with lysosomal acid lipase deficiency, according to long-term results of the phase 3 ARISE clinical trial presented at The Liver Meeting.
“The drug is very effective in both reducing inflammation in the liver and improving dyslipidemia which we expect to be translated to reduced cardiovascular risk. These improvements persisted over a period of 76 weeks so there are lasting effects,” Barbara K. Burton, MD, professor of pediatrics, Northwestern University Feinberg School of Medicine, and attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, told Healio.com/Hepatology.
In the trial, 66 patients with lysosomal acid lipase deficiency (LAL-D) — a rare genetic disorder where fat accumulates in the liver — received either a 1 mg/kg IV infusion of Kanuma (sebelipase alfa, Alexion Pharmaceuticals; n = 36) or placebo (n = 30) every other week for up to 130 weeks. Of these patients, 47 were children and 16 adults. Patients were dosed with sebelipase alfa or placebo for 20 weeks then entered an open-label extension period. Sixty-five of the 66 patients completed the double blind period and continued through the extension period.
“Lysosomal acid lipase deficiency is a rare genetic disorder in which there is a deficiency in the lysosome within the cells of the enzyme responsible for breaking down cholesterol esters and triglycerides,” Burton said. “The disorder comes in two forms: one is a rapidly progressing form in which patients accumulate huge amounts of cholesterol in the liver cells and intestines and a second, which is more common, in which children and adults also accumulate fat in the liver that leads to liver disease often progressing to fibrosis or cirrhosis, as well as severe dyslipidemia.”
Burton said LAL-D is often confused with nonalcoholic fatty liver disease because of the fat accumulation in the liver and believes it is also underdiagnosed.
“I think it is underdiagnosed in children and adults. LAL-D in infants is more obvious and more likely to be diagnosed, but children and adults are much more subtle,” Burton said. “They look and feel normal and fine. Similarly, with dyslipidemia, there is increased risk for heart attack or stroke but until a cardiovascular event occurs, a patient feels fine. LAL-D is a silent killer in a lot of ways.”
After 52 weeks of Kanuma treatment, six patients achieved a greater than two-stage reduction in liver fibrosis from baseline, with two patients achieving a one-stage reduction; one patient had cirrhosis and five had stage 3 fibrosis at baseline. Three other patients showed no change in fibrosis stage and one patient had an increase.
The patients who achieved a two-stage reduction in liver fibrosis also showed mean reductions of 61% in alanine aminotransferase, 40% in LDL-C and 32% in liver fat content following 52 weeks of treatment.
After 30 weeks of treatment with sebelipase alfa, four patients had a one-stage reduction in fibrosis, three had no change and one had an increase.
“One of the more striking things in these data was that there were patients who had reductions in fibrosis scores,” Burton said. “We’ve always hoped we could stabilize or prevent liver disease but it was unclear whether you could see reversal of fibrosis. The fact that several patients did have improvement in fibrosis score is extremely encouraging.”
Adverse events were similar between the two groups and mild in nature. The most common adverse events were rash, cough and cold unrelated to the drug; however, infusion reactions were common and drug-related.
“The most common adverse event related to the drug was infusion-related reaction which is similar to what we see with all other enzyme replacement products,” Burton said. “We do have patients who have infusion reactions, which are usually mild and easily treatable … this is true of other protein therapeutics as well,” adding that patients should begin therapy in an infusion center or hospital setting and should be treated for several months before transitioned to home therapy.
The FDA approved sebelipase alfa for the treatment of adult and pediatric patients diagnosed with lysosomal acid lipase deficiency in December 2015.
Disclosures: Burton reports receiving honoraria, consulting fees or speakers’ fees from Alexion, Armagen, Biomarin, Genzyme-Sanofi, ReGenX Bio and Shire; and receiving research funding for the conduct of clinical trials from Alexion, Armagen, Biomarin, Genzyme-Sanofi, Shire and Ultragenyx.