BOSTON – Lysosomal acid lipase deficiency (LAL-D), a rare genetic cause of marked dyslipidemia that causes early multisystem organ damage, was effectively treated by a human recombinant enzyme to replace deficient lysosomal acid lipase, and the replacement enzyme was well tolerated over a 76-week trial.

LAL-D, when it begins in infancy, is usually fatal within the first year.

When LAL-D occurs later in life, it’s believed to be an “underappreciated cause of fibrosis, cirrhosis, severe dyslipidemia, and early-onset atherosclerosis,” according to Katryn Furuya, MD, and the coauthors of a poster presentation given at the annual meeting of the American Association for the Study of Liver Diseases.

Supplying the human recombinant lysosomal acid lipase, termed sebelipase alfa (SA), to children and adults with LAL-D over a 76-week period resulted in a reduction in alanine aminotransferase (ALT) for 98% of participants, normalization of ALT for 51% of participants, and normalization of aspartate aminotransferase (AST) levels for 65% of patients. Patients on SA also experienced reductions in serum triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and liver fat and total liver volume. “We’re basically replacing what they’re missing,” senior author Barbara Burton, MD, said in an interview.

“The target tissues that we want to get to are the liver, primarily, but also the spleen and the endothelial cells,” said Dr. Burton, professor of gastroenterology at Northwestern University, Chicago. “So the enzyme gets in and then it clears the accumulated fat, and that leads to a reduction in inflammation in the liver, because you don’t have these enlarged lysosomes that are irritating to the cells.”

The effects were seen in LAL-D patients participating in an open-label extension of a double-blind placebo-controlled trial of SA. Patients in the placebo arm who began receiving SA “experienced marked and sustained improvements in liver and lipid parameters, mirroring those observed in the SA group during the double-blind period,” wrote Dr. Furuya and her coauthors. Dr. Furuya, currently a pediatric gastroenterologist at the Mayo Clinic in Rochester, Minn., was a fellow at the Alfred I. duPont Hospital for Children, Wilmington, Del., at the time of the study.

The ARISE (Acid Lipase Replacement Investigating Safety and Efficacy) study included patients aged 4 years and older with a confirmed LAL-D diagnosis. They had to have a baseline ALT at least 1.5 times the upper limit of normal, and if taking lipid-lowering medications, they had to have been on a stable dose for at least 6 weeks before starting the study, and remain on the stable dose for at least the first 32 weeks of the study.

Patients with a history of hematopoietic or liver transplantation were excluded, as were those with severe liver dysfunction, indicated by a Child-Pugh score falling into class C.

The study began with 66 patients entering a randomized, double-blind, placebo-controlled study in which patients received an every-other-week intravenous infusion of SA 1 mg/kg (n = 36), or placebo (n = 30). Median age of participants was 13 years (range, 4-58 years).

After 22 weeks, this was followed by an open-label extension period, during which patients in both arms were unblinded and received SA 1 mg/kg for the duration of the study period; 65/66 patients entered this phase. This means that patients who were initially given SA during the blinded phase of the trial received a total of 76 weeks of SA, while patients who first received placebo before entering the open-label extension did not have their data analyzed until they had been on SA for a total of 78 weeks. The extra 2 weeks accounted for a crossover period for the placebo arm to enter the open-label phase.

The protocol allowed dose increases up to 3 mg/kg if patients’ AST, ALT, LDL-C, or TG levels remained elevated, or if patients under the age of 18 continued to have low weight-for-age z scores. For patients who had problems tolerating SA, the dose could be reduced to 0.35 kg/mg.

Efficacy outcome measures included the proportion of patients who achieved AST and ALT normalization, and those whose ALT values were reduced (but not necessarily normalized). Other measures included changes in LDL-C, HDL-C, non-HDL-C, and TG; reductions in hepatic fat content and total liver volume were also tracked.

After 76 weeks, LDL-C levels were reduced by a mean 27.5%, from 199 to 142 mg/dL, and non-HDL-C dropped by a mean 26.6%, from 230 to 166 mg/dL.

Liver volume and fat content was assessed by multiecho gradient echo magnetic resonance imaging (MEGE-MRI) performed at baseline, at week 20, and at study week 52, representing 52 weeks of SA treatment for the intervention arm and 30 weeks for the placebo arm of the initial trial.

After 52 weeks of SA exposure, the mean hepatic fat reduction was 20.5%, with 88% of patients having reduced liver fat. Of those with 30 weeks of SA exposure, 88% also had reduced liver fat, with a mean fat reduction of 28%.

Liver volume also dropped, by a mean of 13.2% for those with 52 weeks of SA exposure, with 90% of patients experiencing reduced liver volume. Patients with 30 weeks of SA treatment saw a mean 11.2% reduction in liver volume; 96% of this patient group saw some decrease in liver volume.

Safety outcomes included tracking treatment-emergent adverse events (TEAEs), as well as monitoring participants for anti-drug antibodies and for the development of neutralizing antibodies to SA. The safety outcome measures were assessed for patients with longer SA exposure, ranging from 86 to 152 weeks.

There were no patient discontinuations because of TEAEs, and most events were mild or moderate; the only serious adverse event considered related to treatment was an infusion-associated reaction. This patient was able to restart SA therapy after desensitization.

Anti-drug antibodies showed up in 11% of patients (n = 7), and two of these patients had neutralizing antibodies. The safety profile was not different for the group of patients testing positive for anti-drug antibodies, wrote Dr. Furuya and her coauthors.

Replacing LAL-D has promise for a population whose disease may go long undetected. “The patients are not obvious. They are difficult to diagnose,” said Dr. Burton. “They look normal, and they feel normal in many cases, until they have life-threatening disease,” such as end-stage liver disease or cardiovascular complications, she said. Even if elevated transaminases are found in routine screening, physicians are much more likely to think of the more-common nonalcoholic fatty liver disease (NAFLD) than LAL-D, said Dr. Burton, noting that an MRI won’t clarify the diagnosis, though a liver biopsy will show microvesicular rather than macrovesicular fat distribution in LAL-D.

When the clinical picture doesn’t fit with NAFLD, though, LAL-D should be in the differential, she said, adding that she suspects the actual incidence of LAL-D may be higher than has been reported in the literature.

Dr. Burton reported receiving research support, consulting fees, and honoraria from Alexion Pharmaceuticals – the study sponsor and manufacturer of sebelipase alfa. Dr. Furuya reported no disclosures.

koakes@frontlinemedcom.com

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Lysosomal acid lipase replacement corrects rare genetic cause of liver failure, atherosclerosis