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Sebelipase Alfa Improves Survival to 3 Years in Infants with Rapidly Progressive Lysosomal Acid Lipase Deficiency

February 18, 2017—San Diego, California—Sebelipase alfa has been associated with a substantial survival benefit compared with historical controls, a favourable safety profile, and sustained improvements in disease manifestations in infants with lysosomal acid lipase deficiency (Wolman disease).

This preliminary outcome of an ongoing phase II/III study was reported at the 13th Annual WORLDSymposium, from February 13–18.

Catherine Breen, MD, of the Hôpital Couple-Enfants CHU Grenoble, France, explained that the infantile-onset form of lysosomal acid lipase deficiency, also known as Wolman disease, is a rare lysosomal disorder characterised by rapidly progressive disease, growth failure, hepatic failure, and death before 12 months if untreated.

Depending on ethnicity and geography, prevalence has been estimated to be between 1 in 40,000 and 1 in 300,000; based on these estimates the disease may be underdiagnosed. Jewish infants of Iraqi or Iranian origin appear to be most at risk based on a study of a community in Los Angeles in which a prevalence of one in 4200 was reported.

Lysosomal acid lipase deficiency is an autosomal-recessive genetic disease. It is an inborn error of metabolism that causes a lysosomal storage disease. The condition is caused by a mutation of the lipase A, lysosomal acid type (LIPA) gene, which codes for the lysosomal lipase protein (also called lysosomal acid lipase), which results in a loss of the protein's normal function.

The lack of the lysosomal acid lipase enzyme can lead to a build-up of fatty material in a number of organs including the liver, spleen, gut, vessel walls, and other important organs.

Lysosomal acid lipase deficiency typically affects infants in the first year of life. The accumulation of fat in the walls of the gut in early-onset disease leads to serious digestive problems including malabsorption. Affected infants usually fail to thrive. As the disease progresses, it can cause life-threatening liver dysfunction or liver failure.

Deficiency of lysosomal acid lipase results in the intracellular accumulation of cholesteryl esters. Oxysterols are oxidised derivatives of cholesterol, almost always produced by non-enzymatic processes.

Preliminary data from an ongoing phase II/III study of sebelipase alfa in infants with lysosomal acid lipase deficiency show improved survival of patients treated with sebelipase alfa vs a historical cohort whose median age at death was 3.7 months.

Other outcomes assessed included changes in markers of liver injury, haematological effects, weight centiles, and functional development. Nine infants with confirmed lysosomal acid lipase deficiency were enrolled.

All suffered from significant liver dysfunction at baseline. Median age at treatment initiation was 3.0 (1.1–5.8) months. As of 2016, five patients had survived to 3 years of age or older. Assessments of the five patients enrolled from 2016 showed improvement, with median percentage change for

  • Serum alanine aminotransferase, −36.0% (−67.1% to −6.3%)
  • Aspartate aminotransferase, −47.9% (−67.2% to –34.0%)
  • Haemoglobin, +6.5% (−7.5% to 76.4%)
  • Albumin, +8.5% (−5.0% to 63.2%)
  • Platelet levels +61.1% (−25.4% to 164.2%)

Median weight percentile changed from 3.6% at baseline to 35.1%. Gastrointestinal symptoms improved and hepatosplenomegaly was reduced. Denver II Developmental Screening Test assessments (at weeks 72–216), showed four of five ongoing patients scored as normal, one patient “suspect.”

One patient experienced treatment-related serious adverse events (tachycardia, pallor, chills, and pyrexia) that resolved with treatment. None discontinued treatment because of tolerability or infusion reactions. Of seven patients tested for antidrug antibodies, four exhibited detectable titres, two who developed neutralising antibodies. All four continued treatment.

Dr. Breen concluded that sebelipase alfa has been associated with a substantial survival benefit compared with historical controls, a favourable safety profile, and sustained improvements in disease manifestations in infants with lysosomal acid lipase deficiency. All patients exhibited normal development.

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Molecular Genetics and Metabolism is a contribution to the understanding of the metabolic basis of disease. The journal publishes articles describing investigations that use the tools of biochemistry and molecular biology for studies of normal and diseased states. In addition to original research articles, occasional minireviews reporting timely advances as well as brief communications and letters to the editor are considered.


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