Rare Disease Report

Sebelipase Alfa Continues to be Effective in LAL Deficiency Open-Label Extension Study

NOVEMBER 10, 2014
James Radke

At the 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) being held in Boston this week, new data from Synageva’s phase 3, global, double-blind, placebo-controlled trial evaluating sebelipase alfa in children and adults with lysosomal acid lipase deficiency (LAL deficiency) were presented. The new data includes 16 weeks open-label extension following the 20 week phase 3 study. 
LAL deficiency is an autosomal recessive lysosomal storage disorder caused by decreased activity of the LAL enzyme. The end result is an accumulation of lipid substrates in various tissues and cell types, primarily in the hepatic, gastrointestinal, and cardiovascular systems. Disease progression is highly variable with a broad range of abnormalities, including dyslipidemia, enlargement of the liver and spleen, liver dysfunction, liver fibrosis, cirrhosis, and, ultimately, hepatic failure as well as severe malabsorption. Currently, there are no approved drugs for the treatment of LAL deficiency. Sebelipase alfa was granted orphan drug designation and  fast track designation by the FDA. The drug has also received breakthrough therapy designation by the FDA for LAL Deficiency presenting in infants.
In June, the data from the 20 week phase 3 clinical trial was announced showing the efficacy and safety of sebelipase alfa in children and adults with LAL Deficiency.

20-Week Phase 3 Trial

Children and adults with LAL Deficiency (n=66; median age 13 yrs, range 4-58) were randomized to receive biweekly infusions of sebelipase alfa (1 mg/kg) or placebo for 20 weeks.  LAL Deficiency patients enrolled in the trial presented with multiple clinically important abnormalities at baseline.  Fibrosis and/or cirrhosis was documented in 100% (32/32) of patients who had baseline biopsies.  Dyslipidemia was also common at baseline, with median LDL cholesterol levels of 204 mg/dL and median HDL cholesterol levels of 32.5 mg/dL.

Following 20 weeks of treatment, the trial met the primary endpoint with 31% (11/36) of sebelipase alfa patients reaching normalization of ALT (defined as 34-43 U/L, depending on age and gender) compared with 7% (2/30) of placebo patients (p=0.027).  All sebelipase alfa patients showed a decrease in ALT with mean changes in ALT of -57.9 U/L, compared to -6.7 U/L in the placebo group.  In addition, treatment with sebelipase alfa showed significant improvements in multiple disease-related parameters of dyslipidemia and liver injury.

The adverse events were generally minor. Most common adverse events in the sebelipase alfa  group compared to the placebo group were headache (28% versus 20%), pyrexia or increased body temperature (25% versus 23%), oropharyngeal pain (17% versus 3%), nasopharyngitis (11% versus 10%), abdominal pain (8% versus 3%), constipation (8% versus 3%), nausea (8% versus 7%) and asthenia (8% versus 3%).  Serious adverse events were reported in two sebelipase alfa-treated patients and one placebo patient.  One patient experienced a serious adverse event described as an atypical infusion related reaction following treatment with sebelipase alfa and discontinued from the double-blind portion of the clinical trial.  The other sebelipase-alfa treated patient experienced gastritis, which was moderate in severity and unrelated to sebelipase alfa.

36 Week Extension Study

Preliminary results from the open-label extension period was presented at AASLD.  Sixty-five of the 66 patients enrolled in the 20-week phase 3 study entered into a long-term, open-label extension study in which all patients were given sebelipase alfa.  Details of the data were not available at press time, but according to Synageva, the patients previously in the placebo patients who switched to sebelipase alfa during the open label extension showed reductions in ALT and LDL cholesterol while those who began on sebelipase alfa and continue taking the drug, experienced sustained reductions in ALT and further reductions in LDL cholesterol at week 36.  The safety profile in the open-label period was consistent with that observed during the double-blind period. 

Manisha Balwani, M.D., M.S., Assistant Professor of Genetics and Genomic Sciences and Assistant Professor of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, and principal investigator in the study said:

"The results from this Phase 3 trial demonstrated that sebelipase alfa, relative to placebo, improved key parameters associated with LAL Deficiency including markers of liver injury, dyslipidemia, and liver fat content.  Importantly, sustained reductions in markers of liver injury and further improvements in LDL cholesterol were observed with sebelipase alfa during the early part of the open-label extension period."


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