acid lipase replacement investigating safety and efficacy (arise) in participants with lysosomal acid lipase deficiency

Conditions: Lysosomal Acid Lipase Deficiency

Summary: this phase 3 study evaluated the efficacy and safety of 1 milligram/kilogram (mg/kg) intravenous (iv) infusions of sbc-102 (sebelipase alfa) administered every other week (qow) in participants with late onset lysosomal acid lipase deficiency (lal-d) (cholesteryl ester storage disease \[cesd\]). late-onset lal-d is an underappreciated cause of cirrhosis, liver failure and dyslipidemia. there is currently no standard treatment for lal-d other than supportive care. enzyme replacement therapy may be a potential new treatment option for lal-d participants.

lysosomal acid lipase deficiency (lal-d) is a genetic disease characterized by abnormal lipid accumulation in many parts of the body due to a marked decrease in activity of the enzyme lysosomal acid lipase (lal). the lal-d disease spectrum ranges from a presentation in infants that is rapidly progressive to a presentation that occurs in childhood, adolescence, or less frequently, in adulthood in which the rate of disease progression is more variable. irrespective of where a patient is on the disease spectrum, lal-d is associated with significant burden of disease and a shortened life expectancy in some patients. the non-infantile onset form of the disease, also known as cesd, occurs in both children and adults and is an under-appreciated cause of fatty liver with prominent microvesicular steatosis, fibrosis, and cirrhosis. although the natural history of the disease has not been well studied, serious complications are frequently described, including early death, liver transplantation, or cardiovascular accidents. other complications include premature atherosclerosis (hardening of arteries) associated with high levels of total cholesterol and low-density lipoprotein (ldl) cholesterol, often called the "bad" cholesterol. the levels of triglycerides can also be high and the levels of high-density lipoprotein (hdl) cholesterol (the "good" cholesterol) are typically low. in the past, treatments mainly focused on control of the lipid abnormalities through diet and the use of lipid-lowering medications, which only address some aspects of the disease, while progression to fibrosis and cirrhosis may still occur. in preclinical studies and clinical studies in participants with lal-d, treatment with sbc-102 (sebelipase alfa, kanuma®) has been shown to produce improvements in markers of liver damage and in the lipid abnormalities. the purpose of this study was to examine the effects of using sbc-102 to treat lal-d through a placebo-controlled, randomized, double-blinded study in children and adults. this multicenter, randomized, double-blind, placebo-controlled study involving 66 participants evaluated the safety and efficacy of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg/kg of body weight qow). the study included a 20-week placebo-controlled period followed by open-label treatment periods for all participants. the primary end-point was normalization of the alanine aminotransferase level. secondary end-points included additional disease-related efficacy and safety assessments. final study results have not been published in a peer-reviewed journal.

Eligibility criteria:
inclusion criteria: * participant and/or participant's parent or legal guardian provided informed consent. * participant was ≥ 4 years of age on the date of informed consent. * deficiency of lal enzyme activity confirmed by dried blood spot testing at screening. * alanine aminotransferase ≥ 1.5x upper limit of normal on 2 consecutive screening measurements obtained at least 1 week apart. * female participants of childbearing potential must not have been pregnant or breastfeeding and must have agreed to use a medically acceptable method of preventing contraception from screening until 4 weeks after the last dose of study drug. * participant receiving lipid-lowering therapies must have been on a stable dose of the medication for at least 6 weeks prior to randomization and was willing to remain on a stable dose for at least the first 32 weeks of treatment in the study. * participant receiving medications for the treatment of nonalcoholic fatty liver disease must have been on a stable dose for at least 16 weeks prior to randomization and was willing to remain on a stable dose for at least the first 32 weeks of treatment in the study. exclusion criteria: * severe hepatic dysfunction (child-pugh class c). * other medical conditions or comorbidities, which, in the opinion of the investigator, would have interfered with study compliance or data interpretation. * previous hematopoietic or liver transplant procedure. * received treatment with high-dose corticosteroids (acute or chronic) within 26 weeks. (note: participants receiving maintenance therapy with low-dose oral, intranasal, topical, or inhaled corticosteroids were considered eligible for the study). * known hypersensitivity to eggs. * participated in a study employing an investigational medicinal product within 4 weeks prior to randomization.

Keywords: enzyme replacement therapy (ert) lysosomal storage disease late-onset lysosomal acid lipase deficiency (lal-d) acid cholesteryl ester hydrolase deficiency, type 2 acid lipase disease cholesterol ester hydrolase deficiency lal-d lipa deficiency wolman disease cholesterol ester storage disease (cesd)