Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Alexion Europe SAS, 103-105 rue Anatole France, 92300, Levallois-Perret, France
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Enzymes
ATC code: A16AB14
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.
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.
LAL-CL03 was a multicentre, open-label, single-arm study of sebelipase alfa in 9 patients with LAL deficiency with growth failure or other evidence of rapidly progressive disease prior to 6 months of age. Patients also had rapidly progressive liver disease and severe hepatosplenomegaly. The age range at study entry was 1-6 months. Patients received sebelipase alfa at 0.35 mg/kg once weekly for the first 2 weeks and then 1 mg/kg once weekly. Based on clinical response, dose escalation to 3 mg/kg once weekly occurred as early as 1 month and up to 20 months after starting treatment at 1 mg/kg. A further dose escalation to 5 mg/kg once weekly was allowed.
Efficacy was assessed by comparing the survival experience of sebelipase alfa-treated patients who survived past 12 months of age in LAL-CL03 with a historical cohort of untreated infants presenting with LAL deficiency with similar clinical characteristics. In LAL-CL03, 6 of 9 sebelipase alfa-treated infants survived beyond 12 months (67% 12-month survival, 95% CI: 30% to 93%). With continued treatment beyond 12 months of age, 1 additional patient died at age 15 months. In the historical cohort, 0 of 21 patients survived beyond 8 months of age (0% 12-month survival, 95% CI: 0% to 16%).
Sebelipase alfa at doses up to 1 mg/kg once weekly resulted in improvements in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and weight gain within the first several weeks of treatment. From baseline to week 48, the mean reductions for ALT and AST were -34.0 U/l and -44.5 U/l, respectively. Dose escalation to 3 mg/kg once weekly was associated with additional improvements in weight gain, lymphadenopathy and serum albumin. From baseline to week 48, mean weight-for-age percentile improved from 12.74% to 29.83% and mean serum albumin levels increased from 26.7 g/l to 38.7 g/l.
One infant was treated with 5 mg/kg once weekly in LAL-CL03; no new adverse reactions were reported at this dose. In the absence of more clinical data, this dose is not recommended.
LAL-CL02 was a multicentre, double-blind, placebo-controlled study in 66 children and adults with LAL deficiency. Patients were randomised to receive sebelipase alfa at a dose of 1 mg/kg (n=36) or placebo (n=30) once every other week for 20 weeks in the double-blind period. The age range at randomisation was 4-58 years old (71% were <18 years old). For study entry, patients were required to have ALT levels of ≥1.5 X upper limit of normal (ULN). The majority of patients (58%) had LDL-cholesterol >190 mg/dl at study entry, and 24% of patients with LDL-cholesterol >190 mg/dl were on lipid lowering medicinal products. Of the 32 patients who had a liver biopsy at study entry, 100% had fibrosis and 31% had cirrhosis. The age range of patients with biopsy evidence of cirrhosis was 4-21 years old.
The following endpoints were assessed: normalisation of ALT, decrease in LDL-cholesterol, decrease in non-HDL-cholesterol, normalisation of AST, decrease in triglycerides, increase in HDL-cholesterol, decrease in liver fat content assessed by multi-echo gradient echo magnetic resonance imaging (MEGEMRI), and improvement in hepatic steatosis measured by morphometry.
A statistically significant improvement in multiple endpoints was observed in the sebelipase alfa-treated group as compared to the placebo group at the completion of the 20-week double-blind period of the study, as shown in Table 3. The absolute reduction in mean ALT level was -57.9 U/l (-53%) in the sebelipase alfa-treated group and -6.7 U/l (-6%) in the placebo group.
Table 3. Primary and secondary efficacy endpoints in LAL-CL02:
| Endpoint | sebelipase alfa (n=36) | Placebo (n=30) | P-valued |
|---|---|---|---|
| Primary Endpoint | |||
| Normalisation of ALTa | 31% | 7% | 0.0271 |
| Secondary Endpoints | |||
| LDL-cholesterol, mean % change from baseline | -28% | -6% | <0.0001 |
| Non-HDL-cholesterol, mean % change from baseline | -28% | -7% | <0.0001 |
| Normalisation of ASTb | 42% | 3% | 0.0003 |
| Triglycerides, mean % change from baseline | -25% | -11% | 0.0375 |
| HDL-cholesterol, mean % change from baseline | 20% | -0,3% | <0.0001 |
| Liver fat contentc, mean % change from baseline | -32% | -4% | <0.0001 |
a Proportion of patients who achieved normalisation defined as 34 or 43 U/l, depending on age and gender.
b Proportion of patients who achieved normalisation defined as 34-59 U/l, depending on age and gender. Evaluated in patients with abnormal baseline values (n=36 for sebelipase alfa; n=29 for placebo).
c Evaluated in patients with MEGE-MRI assessments performed (n=32 for sebelipase alfa; n=25 for placebo).
d P-values are from Fisher’s exact test for normalisation endpoints and Wilcoxon rank-sum test for all other endpoints.
Paired liver biopsies at baseline and week 20 were available in a subset of patients (n=26). Of patients with paired liver biopsies, 63% (10/16) of sebelipase alfa-treated patients had improvement in hepatic steatosis (at least ≥5% reduction) as measured by morphometry compared to 40% (4/10) of placebo patients. This difference was not statistically significant.
Sixty-five of 66 patients entered the open-label period (up to 130 weeks) at a sebelipase alfa dose of 1 mg/kg once every other week. In patients who had received sebelipase alfa during the double-blind period, reductions in ALT levels during the first 20 weeks of treatment were maintained and further improvements were seen in lipid parameters including LDL-cholesterol and HDL-cholesterol levels. Four (4) of 65 patients in the open label period were dose escalated to 3 mg/kg once every other week based on clinical response.
Placebo patients had persistently elevated serum transaminase and abnormal serum lipid levels during the double-blind period. Consistent with what was observed in sebelipase alfa-treated patients during the double-blind period, initiation of treatment with sebelipase alfa during the open-label period produced rapid improvements in ALT levels and in lipid parameters including LDL-cholesterol and HDL-cholesterol levels.
In a separate open-label study (LAL-CL01/LAL-CL04) in adult patients with LAL deficiency, improvements in serum transaminase and lipid levels were sustained through the 104-week treatment period.
Fifty-six of 84 patients (67%) who received sebelipase alfa during clinical studies (LAL-CL01/LALCL04, LAL-CL02 and LAL-CL03) were in the paediatric and adolescent age range (1 month up to 18 years).
The European Medicines Agency has deferred the obligation to submit the results of studies with sebelipase alfa in one or more subsets of the paediatric population in LAL deficiency (see section 4.2 for information on paediatric use).
Medical or healthcare professionals are encouraged to participate and enrol all patients diagnosed with LAL deficiency in the LAL deficiency registry
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 4). 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.
Table 4. Mean Population Pharmacokinetic Parameters:
| Pharmacokinetic parameter | Study LAL-CL02 – – Children and Adults 1 mg/kg once every other week | |||||
|---|---|---|---|---|---|---|
| 4–11 years old n=24 | 12–17 years old n=23 | ≥18 years old n=18 | ||||
| Week 0 | Week 2 2* | Week 0 | Week 2 2* | Week 0 | Week 2 2* | |
| AUCss (ng∙hr/ml) | 1133.8 | 941.6 | 1436.4 | 1453.6 | 1989.3 | 1861.0 |
| Cmax (ng/ml) | 571.7 | 489.6 | 736.4 | 783.6 | 1076.9 | 957.0 |
| Tmax (hr) | 1.2 | 1.3 | 1.2 | 1.1 | 1.4 | 1.3 |
| CL (L/hr) | 28.8 | 31.1 | 35.1 | 37.4 | 36.4 | 38.2 |
| Vc (L) | 3.3 | 3.6 | 5.0 | 5.4 | 5.5 | 5.3 |
| T1/2 (hr) | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
* Week 22 for placebo patients reset to Week 0, i.e. first week of active treatment.
AUCss = Area under the plasma concentration time curve at steady-state
Cmax = Maximum concentration
Tmax = Time to maximum concentration
CL = Clearance
Vc = Central volume of distribution
T1/2 = Half-life
In LAL-CL03, sebelipase alfa was eliminated from the systemic circulation with a median T1/2 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 Cmax.
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.
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 Vc 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.
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