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General Information

Kanuma (sebelipase alfa) is a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme.

Kanuma is specifically indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency.

Kanuma is supplied as a solution for intravenous infusion. The recommended dose is as follows:

Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life: The recommended starting dosage is 1 mg/kg administered once weekly as an intravenous infusion. For patients who do not achieve an optimal clinical response, increase to 3 mg/kg once weekly.

Pediatric and Adult Patients with LAL Deficiency: The recommended dosage is 1 mg/kg administered once every other week as an intravenous infusion.

Clinical Results

FDA Approval

The FDA approval of Kanuma was based on the following studies:

Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life:

A multicenter, open-label, single-arm clinical study of Kanuma was conducted in 9 infants with LAL deficiency who had growth failure or other evidence of rapidly progressive disease prior to 6 months of age. The age range at entry was 1 to 6 months. Patients received Kanuma at 0.35 mg/kg once weekly for the first 2 weeks and then 1 mg/kg once weekly. Due to suboptimal clinical response, doses in all 6 surviving patients were escalated to 3 mg/kg once weekly, between 4 and 88 weeks (median 11 weeks) after starting treatment at 1 mg/kg. In one patient, the dose was escalated to 5 mg/kg once weekly at Week 88 due to decreased growth velocity in a setting of positive neutralizing anti-drug antibodies to Kanuma. The recommended dosage for these patients is 1 mg/kg to 3 mg/kg once weekly. Efficacy of Kanuma was assessed by comparing the survival of 9 Kanuma-treated patients at 12 months of age with an untreated historical cohort of 21 patients with a similar age at disease presentation and clinical characteristics. Of the 9 Kanuma-treated infants, 6 patients survived beyond 12 months of age, compared to 0 of 21 patients in the historical cohort, all of whom died by 8 months of age. The median age of the 6 surviving Kanuma-treated patients was 18.1 months (range 12 to 42.2 months). Following initiation of treatment with Kanuma 1 mg/kg once weekly, weight-for-age z-scores improved in 3 of 5 surviving patients with growth failure, and all 6 surviving patients demonstrated improvements in weight-for-age z-scores following dose escalation to 3 mg/kg once weekly.

Pediatric and Adult Patients with LAL Deficiency:

The safety and efficacy of Kanuma were assessed in 66 pediatric and adult patients with LAL deficiency, aged 4 to 58 years (71% were less than 18 years old), in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to receive Kanuma at a dosage of 1 mg/kg (n=36) or placebo (n=30) once every other week for 20 weeks in the double-blind period. Sixty-two of the 66 (94%) patients had LDL-c of 130 mg/dL or greater at study entry. The majority of patients (58%) had LDL-c above 190 mg/dL at study entry, and 24% of patients with LDL-c above 190 mg/dL remained on lipid lowering medications. At the completion of the 20-week double-blind period of the trial, a statistically significant improvement in percent change from baseline in LDL-c was observed in the Kanuma-treated group as compared to the placebo group (p<0.0001). LDL-c of less than 130 mg/dL was achieved in 13 of 32 Kanuma-treated patients and in only 2 of 30 placebo-treated patients with baseline LDL-c of 130 mg/dL or greater. A statistically significant improvement in percent change from baseline at 20 weeks was also observed in the Kanuma-treated group compared to the placebo group for other parameters related to LAL deficiency, including decreases in non-HDL-c (p<0.0001) and triglycerides (p=0.0375), and increases in HDL-c (p<0.0001). The effect of Kanuma on cardiovascular morbidity and mortality has not been established.

Side Effects

Adverse effects associated with the use of Kanuma may include, but are not limited to, the following:

Patients with Rapidly Progressive Disease Presenting within the First 6 Months of Life (≥30%):

diarrhea
vomiting
fever
rhinitis
anemia
cough
nasopharyngitis
urticaria

Pediatric and Adult Patients (≥8%):

headache
fever
oropharyngeal pain
nasopharyngitis
asthenia
constipation
nausea

Mechanism of Action

Kanuma (sebelipase alfa) is a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme. LAL deficiency is an autosomal recessive lysosomal storage disorder characterized by a genetic defect resulting in a marked decrease or loss in activity of the lysosomal acid lipase (LAL) enzyme. The primary site of action of the LAL enzyme is the lysosome, where the enzyme normally causes the breakdown of lipid particles including LDL-c. Deficient LAL enzyme activity results in progressive complications due to the lysosomal accumulation of cholesteryl esters and triglycerides in multiple organs, including the liver, spleen, intestine, and the walls of blood vessels. The resulting lipid accumulation in the liver may lead to increased liver fat content and progression of liver disease, including fibrosis and cirrhosis. Lipid accumulation in the intestinal wall leads to malabsorption and growth failure. In parallel, dyslipidemia due to impaired degradation of lysosomal lipid is common with elevated LDL-c and triglycerides and low HDL-cholesterol (HDL-c). Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and is subsequently internalized into lysosomes. Sebelipase alfa catalyzes the lysosomal hydrolysis of cholesteryl esters and triglycerides to free cholesterol, glycerol and free fatty acids.