Lipid Disorder Symptoms Improved with Enzyme Replacement

Promising results for those with lysosomal acid lipase deficiency in phase III trial

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• by Crystal Phend
  Senior Staff Writer, MedPage Today

• This article is a collaboration between MedPage Today® and:
  

Patients with lysosomal acid lipase deficiency who took enzyme replacement with sebelipase alfa (Kanuma) experienced reduced reduced serum aminotransferase levels, disease-related lipid abnormalities, and hepatic fat in a phase III trial.
After 20 weeks, the treatment normalized serum aminotransferase levels in 31% of patients, compared to only 7% of placebo (P=0.03), according to author Barbara K. Burton, MD, of Northwestern University in Chicago, and colleagues.
That liver injury marker dropped by 58 U per liter with the recombinant human enzyme on average compared with 7 U per liter on placebo (P<0.001), the researchers reported in the New England Journal of Medicine.
Other benefits of the enzyme replacement therapy over placebo on prespecified secondary endpoints included:

• Reduction in hepatic fat content: mean -32.0 versus -4.2 percentage points (P<0.001)
• Normalization of the aspartate aminotransferase level: 42% versus 3% (P<0.001)
• LDL cholesterol lowering: 22.2 percentage point difference (P<0.001)
• Triglyceride lowering: 14.4 percentage point difference (P=0.04)
• Increase in HDL cholesterol: 19.9 percentage point difference (P<0.001)
• Reduction in serum apolipoprotein B level: 23.1 percentage point difference (P<0.001)
• Increase of serum apolipoprotein A1 level: 11.7 percentage point difference (P<0.001)

"Because lysosomal cholesteryl esters, triglycerides, or both appear to be potent inducers of liver fibrosis (100% of the patients who underwent biopsy in the current study had evidence of fibrosis, and cirrhosis appeared within months after birth in the most severely affected patients)," the researchers wrote, "the marked reductions in aminotransferase levels and other markers of hepatic disease and in hepatic fat content seen in this study suggest that sebelipase alfa may have potential value in reducing the risk of fibrosis and progression to cirrhosis among patients with lysosomal acid lipase deficiency."
While that's likely to be the case and cardiovascular risk may be reduced as well, longer-term follow-up in a larger number of patients will be required for confirmation, Daniel J. Rader, MD, of the University of Pennsylvania in Philadelphia, noted in an accompanying editorial.
Enzyme replacement therapy has transformed treatment of some lysosomal storage diseases but is currently approved and commercially available for only seven of the more than 50 such diseases, he pointed out.
Sebelipase alfa is under accelerated review by the FDA but the date for an answer on approval was recently pushed back from Sept. 8 to Dec. 8, after the agency received additional information on manufacturing. The enzyme was approved Sept. 1 by European regulators for people of any age with lysosomal acid lipase deficiency.
Once enzyme replacement therapy for the condition becomes available, under-recognition and misdiagnosis as familial hypercholesterolemia or nonalcoholic fatty liver disease will need to be addressed.
Rader wrote that "physicians will need to, as early as possible, consider and diagnose this disorder and initiate therapy for it."
"Lysosomal acid lipase deficiency should be suspected in patients with substantial hypercholesterolemia without a clear family history, especially if it is accompanied by a low HDL cholesterol level, elevated aminotransferase level, or fatty liver, and it should also be suspected in any patient with a diagnosis of micronodular cirrhosis on liver biopsy," he added. "A simple blood-based enzymatic assay is clinically available for patients in whom the diagnosis is suspected."
The trial included 66 adults and children with lysosomal acid lipase deficiency randomized to IV sebelipase alfa (1 mg/kg body weight every other week) or placebo for 20 weeks, then treated open-label with the enzyme replacement therapy.

Adverse event rates were similar between groups, with most events being mild.
One serious adverse event occurred that was considered related to sebelipase alfa, a case of infusion-associated reaction 8.5 hours after infusion that resolved rapidly after a single dose of oral diphenhydramine.
"A total of five of 35 patients in the sebelipase alfa group had one or more positive anti-drug antibody tests during the 20-week study period," Burton's group noted. "Titers were generally low and unsustained, and the development of anti-drug antibody did not have any effect on safety or efficacy variables."
Stuyy limitations included lack of long-term follow-up and inability to sort out potential synergy of combination treatment with LDL-lowering medications, they added, "although the study design controlled for the confounding effects of lipid-lowering medications and confirmed that sebelipase alfa reduced LDL cholesterol levels regardless of baseline status with regard to the use of lipid-lowering medication."

The study was supported by Synageva BioPharma (now part of Alexion Pharmaceuticals). The study at Mount Sinai was supported by a grant from the National Center for Research Resources; and the study at Boston Children's Hospital, by a National Center for Advancing Translational Sciences grant from the Harvard Catalyst Clinical and Translational Science Center.
Burton disclosed no relevant relationships with industry. Co-authors disclosed being current and former employees of Synageva BioPharma, as well as holder of a patent related to use of sebelipase alfa held by the company.
Rader disclosed relevant relationships with Synageva, Pfizer, Novartis, Eli Lilly, Alnylam, Aegerion, and CSL Behring.

last updated 09.10.2015

• Primary Source

  New England Journal of Medicine

  Source Reference: Burton BK, et al "A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency" N Engl J Med 2015; 373: 1010-1020.

• Secondary Source

  New England Journal of Medicine

  Source Reference: Rader DJ "Lysosomal Acid Lipase Deficiency -- A New Therapy for a Genetic Lipid Disease" N Engl J Med 2015; 373: 1071-1073.