Synageva BioPharma, a biopharmaceutical company developing therapeutic products for rare disorders, has announced results of sebelipase alfa for LAL Deficiency in two different trials.
LAL Deficiency is a serious, underdiagnosed disease that manifests with significant morbidity and early mortality. LAL Deficiency causes progressive and multisystemic organ damage including hepatic cirrhosis and accelerated atherosclerosis that can lead to sudden and unpredictable clinical complications. LAL Deficiency often manifests in childhood but can be diagnosed at all ages with a simple blood test. LAL Deficiency is caused by genetic mutations that result in decreased LAL enzyme activity in the lysosomes across multiple body tissues, leading to the buildup of fatty material in the liver, blood vessel walls and other tissues.
Nine adults with LAL Deficiency enrolled in the phase I/II trial with sebelipase alfa. After completing the initial four-week portion of the trial, patients were allowed to continue treatment with sebelipase alfa as part of a long-term, open-label extension study. Eight of nine patients enrolled in the extension study and continue treatment with sebelipase alfa. The ninth patient delayed entering the extension study and, after 10 months without treatment, experienced progression of liver disease requiring an urgent liver transplant.
As previously reported, with six of the eight patients enrolled in the ongoing phase I/II extension study completing two years of treatment, sebelipase alfa continued to demonstrate sustained reductions in the biomarkers of liver damage (both ALT and AST), frequently into the normal range, from the pre-treatment baseline to two years of the extension study. Sebelipase alfa also maintained improvements in dyslipidemia associated with LAL Deficiency, with decreases in LDL and triglycerides and increases in HDL from the pre-treatment baseline to two years of the extension study.
Most adverse events through the two years of the extension study were mild and unrelated to sebelipase alfa. Infusion associated reactions were uncommon, generally mild and gastrointestinal in nature (diarrhea, abdominal cramping). Two serious adverse events (cholecystitis/cholelithiasis) considered unlikely related to sebelipase alfa occurred in one patient and this patient continues treatment with sebelipase alfa in the study.
Updated data from this ongoing phase I/II trial presented at the NASPGHAN meeting include pre-treatment and post-sebelipase alfa treatment liver biopsies obtained from two patients. Compared to historical pre-treatment biopsies, biopsies obtained after more than 18 months of treatment with sebelipase alfa showed less steatosis and fibrosis based on assessments performed by local pathologists.
One patient had a pre-treatment biopsy at 17 years of age with notable steatosis assessed visually and extensive fibrosis with numerous fibrous bridges and initial nodulations. A subsequent liver biopsy conducted one and a half years after treatment with sebelipase alfa at 22 years of age showed substantial decreases in steatosis with less fibrosis localized to periportal areas associated with some septa.
A second patient had a pre-treatment liver biopsy at 37 years of age revealing significant steatosis and fibrosis. A subsequent liver biopsy conducted two years after treatment with sebelipase alfa at 44 years of age showed mild steatosis with no significant fibrosis.
The ongoing phase II/III trial is an open-label, multicenter study of sebelipase alfa in infants with LAL Deficiency. Infants with growth failure before six months of age were eligible to enroll and receive weekly infusions with sebelipase alfa (1-3mg/kg). The primary endpoint of the trial is survival at 12 months of age.
In a natural history study, failure to thrive, liver complications and mortality were confirmed in infants with LAL Deficiency. The median age (range) for infants at symptom onset, diagnosis and death was 1 month (0-6.0), 2.6 months (1.0-17.7) and 3.7 months (1.4-46.3), respectively. Growth failure and aggressive liver disease contributed to early mortality. Transaminase levels (ALT and/or AST), abnormal at diagnosis, markedly increased with disease progression.
Hematopoietic stem cell transplants were performed in 10 infants; seven of these 10 infants died before nine months of age and three infants died between 26.9-46.3 months of age.
The median age of infants at first infusion with sebelipase alfa was 3 months. The median baseline liver function tests (ALT and AST of 145 IU/L and 125 IU/L, respectively) revealed underlying liver dysfunction and high baseline ferritin levels (median 586ug/L) indicated macrophage activation. Diarrhea and vomiting, hepatomegaly, splenomegaly and adrenal calcification were also common.
Six infants met the primary endpoint of survival at 12 months of age and five infants continue on treatment with sebelipase alfa. In addition to improved survival relative to the historical cohort, all infants demonstrated improved weight gain, improvement of gastrointestinal symptoms and reductions in hepatosplenomegaly. In addition to these clinical effects, rapid improvements in biochemical and hematological markers including ALT, AST, hemoglobin and bilirubin were also observed.
Four infants died during the study. Three infants died shortly after the start of the study, unrelated to sebelipase alfa, and one infant who met the primary endpoint of survival at 12 months of age subsequently died at 15 months of age, and this was considered unlikely related to treatment with sebelipase alfa.
Adverse events with sebelipase alfa were mostly mild to moderate. Serious adverse events were mainly related to central line infections or hospitalizations for treatment with antibiotics. One patient experienced three related serious adverse events that included fever, malaise and tachycardia developed during the infusion of sebelipase alfa. Four infants previously were described as having developed anti-drug antibodies and only one infant remains anti-drug antibody positive at the last data cut. All four infants continue on infusions with sebelipase alfa.
Sebelipase alfa is a recombinant form of the human LAL enzyme being developed by Synageva as an enzyme replacement therapy for LAL Deficiency. Sebelipase alfa has been granted Orphan designation by the FDA, the EMA and the Japanese Ministry of Health, Labor and Welfare. Additionally, sebelipase alfa received Fast Track designation by the FDA, and Breakthrough Therapy designation by the FDA for LAL Deficiency presenting in infants.