Tag Archives: LAL-D

Phase 3 Trial of Sebelipase Alfa for Lysosomal Acid Lipase Deficiency

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A recent report (BK Burton et al. NEJM 2015; 373: 1010-20, editorial 1071-1) provides preliminary evidence of efficacy of Sebeliplase Alfa for lysosomal acid lipase deficiency.

In this multicenter, randomized, double-blind, placebo-controlled study of 66 patients, enzyme replacement therapy with Sebelipase alfa was examined (1 mg intravenously every other week).  After 20 weeks, all patients were treated by open-label. Of the 32 patients who had had liver biopsies, 10 (31%) were noted to have cirrhosis.

Findings:

  • Alanine aminotransferase normalized in 11 (36%) of treated patients compared with 2 (7%) of controls
  • Improvement in lipid levels and reduction in hepatic fat content were evident in treated patients (P<0.001 for all comparisons, except P-0.04 for triglycerides

The editorial provides a schematic explaining how sebelipase alfa targets the hepatocyte (Figure 1).  The authors note that “longer-term follow-up in a larger number of patients will be required for confirmation.”

Related blog post:

Lysosomal Acid Lipase Deficiency -Another Needle in a Haystack

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A recent article (Atherosclerosis 2014; 235: 21-30) reviews lysosomal acid lipase deficiency (LAL-D) and how this rare disease needs to be considered by pediatric hepatologists.

LAL-D is a rare lysosomal storage disease which encompasses a rapidly progressive disease in infants (previously referred to as Wolman disease) as well as a later-onset condition called cholesteryl ester storage disease (CESD).  Both of these diseases are caused by mutations in the LIPA gene and share the same pathophysiology related to deficiency of LAL. The disease prevalence estimates vary widely (1 in 40,000 to 1 in 300,000) and depend on ethnicity and location.  Jewish, Iraqi, and Iranian infants appear to be at highest risk.

According to the review algorithm, patients with three or more of the following should be considered for screening:

  • ALT >1.5 ULN
  • Hepatomegaly (may be mild)
  • HDL <50 mg/dL
  • Low BMI (in adults <30 kg/m2)
  • Liver biopsy with microvesicular steatosis; grossly the liver may appear orange

Thus, the potential target patients:

  1. Non-obese individuals with persistent increases in LFTs –usually with LDL >160 and low HDL <50
  2. Non-obese NAFLD/microvesicular steatosis

Given the potential for treatment with recombinant sebelipase alfa (Synageva Biopharma) and the widely available testing, looking for LAL-D makes sense in selected patients; though, even in highly selected patients, finding cases may truly be like finding the so-called ‘needle in a haystack’ given the huge numbers of individuals with elevated ALTs who do not have LAL-D.

Note: many of the review’s authors received research grants from Synageva.  (I do not have any financial conflicts to disclose.)