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Sebelipase Alfa Improved Parameters of Liver Injury and Lipid Abnormalities Over 76 Weeks in Children, Adults with Lysosomal Acid Lipase Deficiency
February 18, 2017—San Diego, California—Long-term treatment with sebelipase alfa has produced early, rapid, and sustained improvements in markers of liver injury and lipid abnormalities in children and adults with lysosomal acid lipase deficiency.
This outcome of the phase III Acid lipase Replacement Investigating Safety and Efficacy (ARISE) study was reported at the 13th Annual WORLDSymposium, from February 13–18.
Barbara K. Burton, MD, of Northwestern University, Feinberg School of Medicine, Chicago, Illinois, explained that lysosomal acid lipase deficiency is a progressive multisystem disease that causes cirrhosis, severe dyslipidaemia, and early-onset atherosclerosis.
The accumulation of fat in the walls of the gut in early-onset lysosomal acid lipase deficiency leads to serious digestive problems including malabsorption, which leads to failure to thrive. As the disease progresses, it can cause life-threatening liver dysfunction or liver failure.
Until 2015 very few infants with lysosomal acid lipase deficiency survived beyond the first year of life. Infants with lysosomal acid lipase deficiencies typically showed signs of disease in the first weeks of life and if untreated, died within 6–12 months due to multi-organ failure. Older children or adults with lysosomal acid lipase deficiency who remain undiagnosed or are misdiagnosed die early from a heart attack or stroke or suddenly of liver failure.
In 2015, the enzyme replacement therapy sebelipase alfa was approved in the US and EU. Prior to 2015, statins were used. They helped control cholesterol but did not appear to slow liver damage; liver transplantation was necessary in most patients.
In ARISE, alanine transaminase levels and multiple secondary outcome measures improved significantly after 20 weeks of sebelipase alfa treatment in patients with lysosomal acid lipase deficiency.
“We undertook this study,” Dr. Burton said, “to demonstrate that the improvements in markers of hepatic injury and in dyslipidaemia, previously demonstrated in the phase III study, persist on long-term therapy.”
Sixty-six patients (median age 13, range 4–58 years) were randomised to placebo or sebelipase alfa, 1 mg per kilogram of body weight, every other week, for 20 weeks. Sixty-five patients entered an ongoing, open-label extension phase in which all receive sebelipase alfa.
Dr. Burton reported efficacy data after 76 weeks of treatment and safety results from the open-label period after 86–152 weeks of treatment. Alanine transaminase and aspartate transaminase normalisation were achieved by 52% (32/61) and 65% (37/57) of patients, respectively.
Placebo recipients who crossed over to sebelipase alfa exhibited marked and sustained improvements in alanine transaminase and aspartate transaminase that mirrored improvements in the sebelipase alfa group during the double-blind phase. Patients who continued receiving sebelipase alfa in the open-label period sustained the improvements they had achieved in the double-blind period.
Mean baseline low-density-lipoprotein cholesterol (199.2 mg/dL [5.16 mmol/L]), non-high-density-lipoprotein cholesterol (230.0 mg/dL [5.96 mmol/L]), and triglycerides (153.9 mg/dL [1.74 mmol/L]) decreased by −28%, −27%, and −17%, respectively, after 76 weeks of sebelipase alfa exposure. Mean high-density-lipoprotein cholesterol (baseline 32.5 mg/dL [0.84 mmol/L]) increased by 23%.
Most adverse events in the open-label period were mild to moderate in severity. The most common were headache, nasopharyngitis, cough, and pyrexia. Four patients experienced serious adverse events (one treatment-related, an infusion-associated reaction). Twelve patients (19%) experienced infusion-associated reactions (mild or moderate in all except one patient). No patient discontinued due to an adverse event.
Six (9%) patients tested positive for antidrug antibody in at least one sample. Two developed neutralising antibodies. Sebelipase alfa was well tolerated. The long-term safety profile was similar to that seen during the double-blind portion.
Dr. Burton concluded that long-term treatment with sebelipase alfa produced early, rapid, and sustained improvements in markers of liver injury and lipid abnormalities in this cohort of children and adults with lysosomal acid lipase deficiency.
“I find the results striking,” Dr. Burton said. “And I suggest that treatment with sebelipase alfa should reduce the risk of both cirrhosis and cardiovascular disease in patients with lysosomal acid lipase deficiency.”
She added, “Future research will focus on long-term clinical outcomes in patients receiving treatment with sebelipase alfa.”