Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study

Abstract

BackgroundInfants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age.ResultsNine patients were enrolled; median age at baseline was 3.0 months (range 1.1–5.8 months). Sixty-seven percent (exact 95% CI 30%–93%) of sebelipase alfa–treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%–16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious.ConclusionSebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiencyTrial registrationClinicaltrials.gov NCT01371825. Registered 9 June 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0587-3) contains supplementary material, which is available to authorized users.

Early diagnosis of infantile-onset lysosomal acid lipase deficiency in the advent of available enzyme replacement therapy

“…Patient 2 initially received 3 mg/kg/dose and then was increased to 5 mg/kg/dose because of persistently abnormal laboratory results. Based on the clinical trial conducted in infant patients [9], in which two patients were increased to a dose of 5 mg/kg, which is also reported on the package insert for Kanuma®, both patients reported here were similarly increased to the highest reported dosage, 5 mg/ kg, to achieve optimal clinical improvement. Only Table 1 Clinical information for two patients with infantile-onset lysosomal acid lipase deficiency treated with enzyme replacement therapy (ERT) based on MRI, c based on ultrasound Patient 1 in our cohort was tested for the presence of drug antibodies at the time of this manuscript, and was found to be negative for antibodies after 18 months of weekly ERT.…”

“…The product label also states that for patients without optimal clinical response, the dosage should be increased to 3 mg/kg weekly. Lastly, the manufacturers note that in the 9-patient infant clinical trial with rapidly progressive LAL-D, a patient was increased to 5 mg/kg weekly at week 88 of treatment [9].…”

“…Infants treated with ERT enjoy improved hepatic function, somatic growth, and amelioration of gastrointestinal and hematologic complications [9]. As patients now survive beyond infancy, it is necessary to consider additional manifestations of disease and to respond with appropriate interventions.…”

“…As patients now survive beyond infancy, it is necessary to consider additional manifestations of disease and to respond with appropriate interventions. For instance, prior studies have reported a low-fat diet as a supportive and/or complementary treatment [9]. Other data underscore a need to be attentive to adrenal complications that may occur in utero [10,11].…”

LIPA Variants in Genome-Wide Association Studies of Coronary Artery Diseases

“…13, 14 First, what is the directionality of CAD causal variant(s) at the LIPA GWAS locus – are they LOF as might be anticipated based on the effects of rare Mendelian variants that cause CESD and atherosclerosis, or are these unexpectedly gain of function (GOF) variants that increase LIPA expression and function in monocytes/macrophages, as suggested by the eQTL studies? If GOF or LOF variants in monocytes/macrophages contribute to CAD in the general population, what is the underlying biological mechanism?…”