Rare Disease Report
Patients & Caregivers

Sebelipase Alfa May Reduce Cardiovascular Risk in Patients with LAL Deficiency

JUNE 13, 2015
Lorraine L. Janeczko, MPH

Patients with lysosomal acid lipase (LAL) deficiency appear to have higher 10-year Framingham cardiovascular (CV) risk than the general population. Sebelipase alfa (SA) treatment likely reduces that risk, based on an analysis of patients over age 30 years in a poster presented at the National Lipid Association Scientific Sessions, June 10-14, 2015, in Chicago, Illinois.
LAL is an enzyme responsible for the lysosomal hydrolysis of cholesteryl esters and triglycerides, and is essential for normal lipid metabolism. LAL deficiency is a rare, progressive, multisystemic disease that is inadequately recognized as a cause of cirrhosis, severe dyslipidemia, and early-onset atherosclerosis.
No effective therapies are currently available, and SA is the first enzyme replacement therapy being developed for LAL deficiency.
To estimate SA’s impact on reducing the risk of developing coronary heart disease in the next 10 years in the Framingham Heart Study (FHS)—the 10-year Framingham Risk Score (FRS)—in patients with LAL deficiency before and after treatment with SA, lead study author Digisha Shah, BPharm, PhD, and colleagues from Synageva BioPharma Corp in Lexington, Massachusetts, used data from a randomized phase 3 clinical trial involving 66 participants whose median age was 13 years.1 The study was designed to evaluate the safety and efficacy of SA in children and adults. Thirty-six patients were assigned to the SA treatment group and 30 patients received placebo.   
The FRS can be computed only for patients between the ages of 30 and 74 years, and 6 participants (9%) met the criteria for FRS. Delta FRS, a measure of incremental risk created by LAL deficiency, was considered to be the difference between the risk for a LAL-deficient patient and the risk for a normal patient, adjusted for age and risk factors at normal levels, according to the FHS equation.
Due to the small sample size, only descriptive statistics were calculated, and because the trial excluded patients with diabetes and no smokers were enrolled, the authors state that the risk is underestimated.
The mean baseline age for the 6 LAL-deficient patients for whom FRS could be calculated was 45, and 50% were male. The mean FRS was 7.1% and the delta was 2.5%, implying a mean increase in risk of 54% over the normal population.
At baseline, the 10-year FRS and delta scores for the 3 participants in the placebo group were 6.7% and 3.5%, respectively, compared with 6.4% and 3.0% at 20 weeks. This suggests a mean absolute reduction of 5% in the 10-year Framingham CV risk; 67% of placebo patients had reduced CV risk. Compared with the normal population, the incremental 10-year CV risk due to LAL deficiency decreased by 14% at 20 weeks.
Among the 3 patients who received SA, the FRS and delta scores at baseline were 7.5% and 1.5%, respectively. At 20 weeks, they dropped to 4.7% and -1.6%, respectively, suggesting a mean absolute reduction of 39% in the 10-year CV risk. Reduced CV risk was seen in all SA patients. Treatment with SA reduced the incremental 10-year CV risk due to LAL deficiency by 207% compared with the normal population.
The study authors recommend future studies with larger sample sizes to validate the effects of SA on reducing 10-year Framingham CV risk, and to examine whether FRS is an appropriate estimator, given the younger age of these patients.

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