Sebelipase alfa is an intravenous therapy that provides a recombinant form of human lysosomal acid lipase (rhLAL) protein in patients with lysosomal acid lipase (LAL) deficiency. LAL deficiency, also known as Wolman disease and cholesteryl ester storage disease (CESD), is an autosomal recessive lysosomal storage disorder that results in a marked decrease or loss in activity of the lysosomal acid lipase (LAL) enzyme. Wolman disease often presents around 2 to 4 months of age and is a rapidly progressive disease affecting 1 to 2 infants per million births. CESD is a milder, later-onset form of LAL deficiency and presents in early childhood or later affecting 25 individuals per million births. The life expectancy of patients with CESD depends on the disease severity and associated complications. Deficient LAL enzyme activity results in progressive complications in multiple organs. Lipid accumulation in the liver may lead to increased liver fat content and progression of liver disease, including fibrosis and cirrhosis. Additionally, lipid accumulation in the intestinal wall leads to malabsorption and growth failure. Early and progressive hepatic dysfunction associated with dyslipidemia can often lead to liver failure and transplantation. Accumulation in the blood vessels may result in premature cardiovascular disease. There can be a long duration between initial disease and diagnosis in some patients since symptoms may be consistent with other metabolic diseases. Hepatomegaly, elevated liver enzymes, and/or fatty liver and dyslipidemia, may be confused with more common disorders such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, and/or familial hypercholesterolemia. Sebelipase alfa is produced from genetically engineered chickens' eggs. The rhLAL functions in place of the missing or partially active LAL protein in patients with lysosomal acid lipase (LAL) deficiency. In an open-label, historically controlled trial in 9 infants with rapidly progressive Wolman disease, 6 of 9 infants (67%) treated with sebelipase alfa were alive compared to 0 of the 21 infants in the historical control group. The median age of the 6 surviving sebelipase alfa-treated patients was 18.1 months (range 12 to 42.2 months). Additionally, an improvement in weight-for-age z-scores was noted. In a multicenter, double-blind, placebo-controlled trial of pediatric and adult patients with LAL deficiency, there was a statistically significant improvement in LDL-cholesterol levels and other disease-related parameters in patients treated with sebelipase alfa vs. placebo after 20 weeks. Sebelipase alfa was approved by the FDA in December 2015.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-The solution should be a clear to slightly opalescent, colorless to slightly colored solution. Thin, translucent particles or fibers may be present in the vials or diluted solution. Do not use if the solution is cloudy or if other particulate matter is observed.
Intravenous Administration
Dilution
-Determine the number of vials needed based on the calculated dose.
-Remove vials from the refrigerator and allow them to reach room temperature before withdrawing the dose.
-Dilute sebelipase alfa with an appropriate amount of 0.9% NaCl injection to achieve the recommended final volume for infusion (final concentration should be between 0.1 mg/mL and 1.5 mg/mL). The total infusion volume is based on the prescribed dose and patient weight:-For a 1 mg/kg dose the total infusion volumes (mL) are as follows:-Patient weight 1 to 2.9 kg: 4 mL final infusion volume
-Patient weight 3 to 5.9 kg: 6 mL final infusion volume
-Patient weight 6 to 10.9 kg: 10 mL final infusion volume
-Patient weight 11 to 24.9 kg: 25 mL final infusion volume
-Patient weight 25 to 49.9 kg: 50 mL final infusion volume
-Patient weight 50 to 99.9 kg: 100 mL final infusion volume
-Patient weight 100 to 120.9 kg: 250 mL final infusion volume
-For a 3 mg/kg dose the total infusion volumes (mL) are as follows:
--Patient weight 1 to 2.9 kg: 8 mL final infusion volume
-Patient weight 3 to 5.9 kg: 12 mL final infusion volume
-Patient weight 6 to 10.9 kg: 25 mL final infusion volume
-Patient weight 11 to 24.9 kg: 50 mL final infusion volume
-Patient weight 25 to 49.9 kg: 100 mL final infusion volume
-Patient weight 50 to 99.9 kg: 250 mL final infusion volume
-Patient weight 100 to 120.9 kg: 500 mL final infusion volume
-For a 5 mg/kg dose the total infusion volumes (mL) are as follows:-Patient weight 1 to 2.9 kg: 12 mL final infusion volume
-Patient weight 3 to 5.9 kg: 20 mL final infusion volume
-Patient weight 6 to 10.9 kg: 50 mL final infusion volume
-Patient weight 11 to 24.9 kg: 150 mL final infusion volume
-Patient weight 25 to 49.9 kg: 250 mL final infusion volume
-Patient weight 50 to 99.9 kg: 500 mL final infusion volume
-Patient weight 100 to 120.9 kg: 600 mL final infusion volume
-Mix gently by inversion. Do NOT shake the vials or the prepared infusion.
-Vials are for single-use only. Discard any unused product. Do not freeze.
-Storage: Use immediately after dilution; vial does not contain preservatives. If immediate use is not possible, diluted product may be stored for up to 24 hours in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). Do not freeze or shake. Protect from light.
Intermittent IV Infusion
-Administer the diluted solution using a low-protein binding infusion set equipped with a low-protein binding 0.2 micron in-line filter.
-Infuse over at least 2 hours. Consider further prolonging the infusion time for patients receiving doses greater than 1 mg/kg or those who have experienced hypersensitivity reactions.
-A 1-hour infusion may be considered for those patients receiving the 1 mg/kg dose who tolerate the infusion.
Adverse event data are available from 75 patients who received sebelipase alfa for LAL deficiency during pre-marketing clinical trials. A total of 9 infants (age range at entry was 1 to 6 months) who had growth failure or other evidence of rapidly progressive LAL deficiency presenting within the first 6 months of life received sebelipase alfa at escalating doses ranging between 0.35 mg/kg/dose and 5 mg/kg/dose once weekly for up to 165 weeks (median 60 weeks). Sixty-six pediatric and adult patients with LAL deficiency (aged 4 to 58 years) received sebelipase alfa 1 mg/kg every other week up to 36 weeks.
In clinical trials, gastrointestinal disturbances were reported in patients receiving sebelipase alfa. Diarrhea (67%), vomiting (67%), and retching were reported in infants receiving sebelipase alfa for rapidly progressive LAL deficiency. Constipation (8%) and nausea (8%) occurred in pediatric patients and adults receiving sebelipase alfa for LAL deficiency. Diarrhea and abdominal pain were reported in 8% or more of pediatric and adult patients who received sebelipase alfa since the time of marketing authorization, including patients who received an escalated weekly dose of 3 mg/kg.
Respiratory adverse reactions that have been reported in infants receiving sebelipase alfa for rapidly progressive LAL deficiency include rhinitis (56%), cough (33%), naso-pharyngitis (33%), decreased oxygen saturation, and sneezing. Oropharyngeal pain (17%) and naso-pharyngitis (11%) were reported in pediatric patients and adults with LAL deficiency.
General adverse reactions reported in infants with rapidly progressive LAL deficiency receiving treatment with sebelipase alfa include fever (56%), anemia (44%), urticaria (33%), hypotonia, and tachycardia. Headache (28%), fever (25%), asthenia (8%), anxiety, and chest discomfort were reported in pediatric patients and adults with LAL deficiency receiving sebelipase alfa.
In clinical trials, 21 of 106 (20%) sebelipase-treated patients, including 9 of 14 (64%) infants and 12 of 92 (13%) pediatric patients and adults experienced signs and symptoms consistent with hypersensitivity reactions. In addition, 3 of 106 (3%) infant patients experienced signs and symptoms consistent with anaphylaxis, including chest pain (unspecified), conjunctival injection, dyspnea, generalized and itchy rash, hyperemia, swelling of eyelids, rhinorrhea, severe respiratory distress, tachycardia, tachypnea, and urticaria. Hypersensitivity, respiratory distress, and tachycardia were reported in 30% or more of infants who received sebelipase alfa since the time of marketing authorization, including patients who received an escalated weekly dose of 5 mg/kg. Hypersensitivity and dizziness were reported in 8% or more of pediatric and adult patients who received sebelipase alfa since the time of marketing authorization, including patients who received an escalated weekly dose of 3 mg/kg. Observe patients closely during and after infusion. Anaphylaxis occurred as early as the 6th infusion and as late as 1 year after treatment initiation. Signs and symptoms of hypersensitivity reactions (non-anaphylactic), occurring in 2 or more patients, included abdominal pain, agitation, fever, chills, diarrhea, eczema, edema, hypertension, irritability, laryngeal edema, nausea, pallor, pruritus, rash, and vomiting. Most reactions occurred during or within 4 hours of the completion of the infusion. Patients were not routinely pre-medicated prior to sebelipase alfa infusion in clinical trials. Because of the risk for anaphylactic shock, ensure appropriate medical support is readily available when sebelipase alfa is administered. If an anaphylactic or severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Inform patients of the signs and symptoms of anaphylaxis. Manage hypersensitivity reactions based on the severity of the reaction which may include interruption of the infusion, lowering the infusion rate, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. If interrupted, the infusion may be resumed at a slower rate with increases as tolerated. Pre-treatment with antipyretics and/or antihistamines may prevent subsequent reactions in those cases where symptomatic treatment was required. Consider the risks and benefits of re-administering sebelipase alfa to patients with a severe reaction.
Hyperlipidemia reported with sebelipase alfa includes elevated LDL-cholesterol and triglycerides. Increases in circulating LDL-cholesterol (LDL-c) and triglycerides above pre-treatment values were observed in 29 of 36 (81%) and 21 of 36 (58%) patients, respectively, at 2 and 4 weeks after initiation of sebelipase alfa. The maximum mean percentage increase was 18% for LDL-c at Week 2 and 5% for triglycerides at Week 4.
As with all therapeutic proteins, there is a potential for immunogenicity (antibody formation) with sebelipase alfa use. Across clinical trials, 9 out of 106 (8%) pediatric and adult patients with LAL deficiency developed anti-drug antibody (ADA) to sebelipase alfa after treatment. Two of the 9 patients were positive for neutralizing antibodies (NAb). Approximately 10 out of 19 (53%) infants with rapidly progressive LAL deficiency developed ADA after sebelipase alfa treatment. Nine of the 10 patients were positive for NAb. In 1 clinical trial, 4 out of 7 (57%) infants with rapidly progressive disease tested positive for ADA formation during sebelipase alfa treatment. All 4 ADA-positive patients were determined to be positive for NAb that inhibit in vitro enzyme activity and cellular uptake of the enzyme. Persistent ADA was observed in all 4 patients. Hypersensitivity reactions occurred in all 4 of the ADA-positive patients, but none of the patients discontinued treatment. One patient experienced decreased growth velocity in the setting of NAb. In the double-blind portion of another clinical trial, 5 of 35 (14%) pediatric patients and adults with LAL deficiency developed ADA. Two patients developed in vitro NAb and 3 patients with measurable ADA titers decreased to undetectable concentrations during continued treatment. There is no clear association between the development of ADA and decreased efficacy in pediatric and adult patients treated with sebelipase alfa.
At the time of FDA approval, the product labeling reported no contraindications for the use of sebelipase alfa in patients with Lysosomal Acid Lipase (LAL) deficiency.
Due to the risk of serious hypersensitivity reactions or anaphylaxis, the administration of sebelipase alfa requires a specialized care setting and readily available medical support. Anaphylaxis has occurred as early as the sixth infusion and as late as 1 year after treatment initiation. If anaphylaxis or other severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Consider the risks and benefits of administering future doses of sebelipase after a severe reaction. If a less severe reaction occurs, management depends on the severity and may include temporarily interrupting the infusion, slowing the infusion rate, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. If interrupted, the infusion may be resumed at a slower rate with increases as tolerated. Pre-treatment with antipyretics and/or antihistamines may prevent subsequent reactions.
Sebelipase alfa is produced in the egg whites of genetically engineered chickens. Patients with a known egg hypersensitivity were excluded from clinical trials. Consider the risks and benefits of treatment with sebelipase alfa in patients with known systemic hypersensitivity reactions to eggs or egg products.
Available data regarding sebelipase alfa use during human pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal data (rats and rabbits) did not reveal evidence of impaired fertility or harm to the fetus when sebelipase alfa was administered during the period of organogenesis at doses resulting in exposures up to 164 and 526 times the exposure at the recommended human dosage of 1 mg/kg every other week.
There are no data on the presence of sebelipase alfa in animal or human milk, the effects on breast-feeding infants, or the effects on milk production.
For the treatment of patients with lysosomal acid lipase (LAL) deficiency (Wolman disease):
-for rapidly progressive LAL deficiency presenting within the first 6 months of life:
Intravenous dosage:
Infants and Children: 1 mg/kg/dose IV infusion administered once weekly. For patients not achieving an optimal clinical response, increase dose to 3 mg/kg/dose IV once weekly then to 5 mg/kg/dose IV once weekly if clinical response continues to be suboptimal. A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers, or persistent or worsening organomegaly.
-for patients with LAL deficiency (non-rapidly progressive form):
Intravenous dosage:
Adults: 1 mg/kg/dose IV infusion administered once every other week. For patients not achieving an optimal clinical response, increase dose to 3 mg/kg/dose IV once every other week. A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)), and/or parameters of lipid metabolism (e.g., low-density lipoprotein cholesterol (LDL-c), triglycerides (TG)).
Infants, Children, and Adolescents: 1 mg/kg/dose IV infusion administered once every other week. For patients not achieving an optimal clinical response, increase dose to 3 mg/kg/dose IV once every other week. A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)), and/or parameters of lipid metabolism (e.g., low-density lipoprotein cholesterol (LDL-c), triglycerides (TG)).
Maximum Dosage Limits:
-Adults
3 mg/kg/dose IV once every other week.
-Geriatric
3 mg/kg/dose IV once every other week.
-Adolescents
3 mg/kg/dose IV once every other week.
-Children
5 mg/kg/dose IV weekly for patients with rapidly progressive LAL deficiency; 3 mg/kg/dose IV once every other week for all other patients.
-Infants
5 mg/kg/dose IV weekly for patients with rapidly progressive LAL deficiency; 3 mg/kg/dose IV once every other week for all other patients.
-Neonates
Although neonates were not included in clinical trials, if the drug is used in this population, do not exceed the maximum recommended dose for infants: 5 mg/kg/dose IV weekly for patients with rapidly progressive LAL deficiency; 3 mg/kg/dose IV once every other week for all other patients.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Sebelipase alfa products.
Lysosomal acid lipase (LAL) deficiency is an autosomal recessive genetic lysosomal storage disorder that results in a marked decrease or loss in activity of the LAL enzyme, which normally breaks down lipid particles including LDL-c. Deficient LAL enzyme activity results in an accumulation of fats within the cells and progressive complications in multiple organs, including the liver, spleen, intestine, and the walls of blood vessels. Lipid accumulation in the liver can lead to increased liver fat content and progression of liver disease, including fibrosis and cirrhosis, accumulation in the intestinal wall leads to malabsorption and growth failure, and accumulation in blood vessels can lead to premature cardiovascular disease. Sebelipase alfa is a recombinant human lysosomal acid lipase (rhLAL) that functions in place of the missing or inactive LAL protein. The drug binds to cell surface receptors via glycans expressed on the protein and is internalized into lysosomes. Sebelipase alfa catalyzes the lysosomal hydrolysis of cholesteryl esters and triglycerides to fee cholesterol, glycerol and free fatty acids.
Sebelipase alfa is administered as an intravenous infusion. Its pharmacokinetics were nonlinear with a greater than dose-proportional increase in exposure between 1 and 3 mg/kg based on non-compartmental analysis of data from 26 adults. No accumulation was observed after once weekly or once every other week dosing.
Using a population pharmacokinetic model, pharmacokinetic parameters were estimated for 65 patients, including 18 adults, who received sebelipase alfa 1 mg/kg/dose IV once every other week. At week 22, the pharmacokinetic profiles were similar between adolescents and adults. The Tmax (1.1 to 1.3 hours) and t1/2 (5.4 to 6.6 minutes) were similar across all age groups. The following mean PK parameters were calculated for adults: Cmax = 957 +/- 303 ng/mL, AUC = 1,861 +/- 599 h x ng/mL, clearance = 38.2 +/- 12.5 L/h, central volume of distribution = 6.6 +/- 3.7 L.
In clinical trials, LDL-c and triglycerides increased within the first 2 to 4 weeks after initiation of treatment with sebelipase alfa. In general, after increases in LDL-c and triglycerides, these parameters decreased to below pre-treatment values within 8 weeks of treatment. Reductions in ALT values were observed, generally within 2 weeks after initiation of treatment. Treatment interruption resulted in increases in LDL-c and ALT values and decrease in HDL-c.
-Special Populations
Pediatrics
Estimated mean parameters at week 22 based a population pharmacokinetic model using data from patients receiving sebelipase alfa 1 mg/kg/dose IV once every other week :
Adolescents 12 to 17 years (n = 23)
Tmax (hours) = 1.1 +/- 0.3
Cmax (ng/mL) = 784 +/- 480
AUC (hour x ng/mL) = 1,454 +/- 699
Vd (L) = 5.4 +/- 2.4
CL (L/hour) = 37.4 +/- 12.4
t1/2 (min) = 6.6 +/-3.7
Children 4 to 11 years ( n = 24)
Tmax (hours) = 1.3 +/- 0.6
Cmax (ng/mL) = 490 +/- 205
AUC (hour x ng/mL) = 942 +/- 388
Vd (L) = 3.6 +/- 3
CL (L/hour) = 31.1 +/- 7.1
t1/2 (min) = 5.4 +/- 4.3