Enzyme replacement helps children, adults with rare deficiency

Last Updated: 2015-09-09

By Gene Emery

NEW YORK (Reuters Health) - Treatment with the Alexion Pharmaceuticals drug Kanuma (sebelipase alfa) produced significant improvement in children and adults with a rare but often-fatal enzyme deficiency, a new paper reports.

People with the condition, known as lysosomal acid lipase deficiency, have trouble breaking down fatty material, causing it to build up in places such as the liver, spleen, intestines and the walls of blood vessels.

Also called cholesteryl ester storage disease, its estimated prevalence is as high as 1 in 40,000. It is "an underrecognized genetic cause of cirrhosis and severe dyslipidemia that can, according to reports, cause atherosclerotic cardiovascular disease early in life," said the research team, led by Dr. Barbara Burton of the Northwestern University Feinberg School of Medicine in Chicago.

"For patients who have this disease, this is going to spare them the progression to liver transplant and that's a fairly big deal," Dr. Burton told Reuters Health by phone.

A report of the Alexion-funded study was released online September 9 in The New England Journal of Medicine.

The trial involved 66 volunteers, age four and older. All received IV injections every other week, half involving placebo.

After 20 weeks, alanine aminotransferase levels returned to normal in 31% of the 36 who got the drug versus 7% of those given placebo (p=0.03).

At the start of the study, those levels had been at least 50% above the upper limit of the normal range.

Aspartate aminotransferase levels also normalized in 42% of the drug recipients compared to 3% getting placebo (p<0.001). Hepatic fat content, as assessed by MRI, declined by 32 percentage points with the drug. The decrease was 4.2 percentage points with placebo (p<0.001).

Treatment was also marked by significant decreases in triglyceride levels (p=0.04), LDL cholesterol and non-HDL cholesterol (p<0.001 for both).

HDL cholesterol levels rose by a mean of 19.6 percentage points while essentially staying flat in the placebo group (P<0.001).

Placebo recipients saw similar improvements in LDL, HDL and alanine aminotransferase when they were switched to the drug for 16 weeks. The patients who were already on the drug showed sustained benefits during that extended period.

"I've got patients in the trial who have been on it for several years now" with continued benefit, Dr. Burton said. "I haven't seen data going on beyond 52 weeks but it looks like there was continued benefit and some continued improvement in the lipid abnormalities over time. There's no evidence that the benefit ceases."

Patients would probably need to be treated for life, she said. Otherwise the lipids would reaccumulate.

The treatment produced no serious side effects regarded as related to the drug and "infusion-associated reactions were uncommon," the researchers said.

"There were a few infusion-related reactions that we see with any enzyme-replacement product, but they're minimal," Dr. Burton said.

The phase III study was known as ARISE.

European health regulators approved the drug for the condition on Sept. 1. A decision by the U.S. Food and Drug Administration has been delayed until December. The product has already been granted orphan drug status in the U.S. The company is also trying to market the drug in Japan.

"Although these findings suggest that this therapy is likely to reduce progression to end-stage fibrotic liver disease, longer-term follow-up in a larger number of patients will be required for confirmation," said Dr. Daniel Rader of the University of Pennsylvania in a Journal editorial.

A version of the condition found in infants usually kills within six months and is known as Wolman's disease. Its estimated incidence is 1 in 500,000 live births. A separate study is testing the drug in babies.

If approved, Dr. Rader wrote, the drug "may be transformational in the treatment of both infant-onset and later-onset lysosomal acid lipase deficiency and result in greater awareness and diagnosis of this underappreciated genetic lipid disorder."

SOURCE: http://bit.ly/1in4TAH

N Engl J Med 2015.