Sebelipase alfa

Sebelipase alfa is a recombinant human lysosomal acid lipase (rhLAL).

Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and is subsequently internalised into lysosomes. Sebelipase alfa catalyses the lysosomal hydrolysis of cholesteryl esters and triglycerides to free cholesterol, glycerol and free fatty acids. Replacement of LAL enzyme activity leads to reductions in liver fat content and transaminases, and enables metabolism of cholesteryl esters and triglycerides in the lysosome, leading to reductions in low-density lipoprotein (LDL) cholesterol and nonhigh-density lipoprotein (HDL) cholesterol, triglycerides, and increases in HDL cholesterol. Improvement in growth occurs as a result of substrate reduction in the intestine.

Lysosomal acid lipase (LAL) deficiency

LAL deficiency is a rare disease associated with significant morbidity and mortality, which affects individuals from infancy through adulthood. LAL deficiency presenting in infants is a medical emergency with rapid disease progression over a period of weeks that is typically fatal within the first 6 months of life. LAL deficiency is an autosomal recessive lysosomal storage disorder characterised by a genetic defect resulting in a marked decrease or loss in activity of the lysosomal acid lipase (LAL) enzyme.

Deficient LAL enzyme activity results in the lysosomal accumulation of cholesteryl esters and triglycerides. In the liver, this accumulation leads to hepatomegaly, increased hepatic fat content, transaminase elevation signaling chronic liver injury, and progression to fibrosis, cirrhosis, and complications of end stage liver disease. In the spleen, LAL deficiency results in splenomegaly, anemia, and thrombocytopenia. Lipid accumulation in the intestinal wall leads to malabsorption and growth failure. Dyslipidemia is common with elevated LDL and triglycerides and low HDL, associated with increase liver fat content and transaminase elevations. In addition to liver disease, patients with LAL deficiency experience increased risk for cardiovascular disease and accelerated atherosclerosis.

Children and adults

The pharmacokinetics of sebelipase alfa in children and adults were determined using a population pharmacokinetic analysis of 65 patients with LAL deficiency who received intravenous infusions of sebelipase alfa at 1 mg/kg once every other week in LAL-CL02. Twenty-four patients were aged 4-11 years, 23 were aged 12-17 years, and 18 were aged ≥18 years (Table). Based on a noncompartmental analysis of data from adults (LAL-CL01/LAL-CL-04), the pharmacokinetics of sebelipase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure observed between the 1 and 3 mg/kg doses. No accumulation was seen at 1 mg/kg (once weekly or once every other week) or 3 mg/kg once weekly.

Mean Population Pharmacokinetic Parameters:

* Week 22 for placebo patients reset to Week 0, i.e. first week of active treatment.
AUC_ss = Area under the plasma concentration time curve at steady-state
C_max = Maximum concentration
T_max = Time to maximum concentration
CL = Clearance
V_c = Central volume of distribution
T_1/2 = Half-life

Infants (<6 months of age)

In LAL-CL03, sebelipase alfa was eliminated from the systemic circulation with a median T_1/2 of 0.1 hr (range: 0.1-0.2) at the 3 mg/kg once weekly dose (n=4). The difference in exposures to sebelipase alfa between the once weekly 0.35 mg/kg and 3 mg/kg groups was more than dose proportional, with a 8.6-fold increase in dose resulting in a 9.6-fold increase in exposure for AUC and a 10.0-fold increase for C_max.

Linearity/non-linearity

Based on these data, the pharmacokinetics of sebelipase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure observed between the 1 and 3 mg/kg dose.

Special populations

During the covariate analysis of the population pharmacokinetics model for sebelipase alfa, age, body weight, and sex were not found to have a significant influence on CL and V_c of sebelipase alfa. Sebelipase alfa has not been investigated in patients 2 to 4 years of age or patients aged 65 years or older.

There is limited information of sebelipase alfa pharmacokinetics in non-Caucasian ethnic groups.

Sebelipase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of sebelipase alfa. There is a lack of data in patients with severe hepatic impairment.

Renal elimination of sebelipase alfa is considered a minor pathway for clearance. There is a lack of data in patients with renal impairment. There is limited information on the impact of ADA on sebelipase alfa pharmacokinetics.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity in rats and monkeys, or fertility, embryo-foetal and peri- and postnatal development in rats and rabbits. Chronic toxicity studies in juvenile cynomolgous monkeys showed no toxicity at doses up to 3 times the recommended dose in infants and 10 times the recommended dose in adults/children. No adverse findings were observed in rat and rabbit embryofoetal development studies at doses up to at least 10 times the adult/children recommended dose and in rat fertility and peri-postnatal development studies at doses up to 10 times the adult/children recommended dose.

Studies to evaluate the mutagenic and carcinogenic potential of sebelipase alfa have not been performed.