Sebelipase alfa

{{DrugProjectFormSinglePage |authorTag=Martin Nino [1] |genericName=Sebelipase alfa |aOrAn=a |drugClass=hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme |indicationType=treatment |indication=patients with Lysosomal Acid Lipase (LAL) deficiency. |adverseReactions=diarrhea, vomiting, fever, rhinitis,anemia, cough, nasopharyngitis, and urticaria (≥30%) in patients with rapidly progressive disease presenting within the first 6 months of life and for pediatric and adult patients the most common adverse reactions include headache,fever, oropharyngeal pain, nasopharyngitis, asthenia, constipation, and nausea (≥8%)

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Indications

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

Dosage

• 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.

|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Sebelipase alfa in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Sebelipase alfa in adult patients. |fdaLIADPed=Safety and effectiveness of KANUMA have been established in pediatric patients aged 1 month and older (Same indications and dosage as adults). Clinical trials with KANUMA were conducted in 56 pediatric patients (range 1 month to <18 years old) |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Sebelipase alfa in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Sebelipase alfa in pediatric patients. |contraindications=None |warnings=

Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in KANUMA-treated patients. In clinical trials, 3 of 106 (3%) patients treated with KANUMA experienced signs and symptoms consistent with anaphylaxis. These patients experienced reactions during infusion with signs and symptoms including chest discomfort, conjunctival injection, dyspnea, generalized and itchy rash, hyperemia, swelling of eyelids, rhinorrhea, severe respiratory distress, tachycardia, tachypnea, and urticaria. Anaphylaxis has occurred as early as the sixth infusion and as late as 1 year after treatment initiation.

In clinical trials, 21 of 106 (20%) KANUMA-treated patients, including 9 of 14 (64%) infants and 12 of 92 (13%) pediatric patients, 4 years and older, and adults, experienced signs and symptoms either consistent with or that may be related to a hypersensitivity reaction. Signs and symptoms of hypersensitivity reactions, occurring in two or more patients, included abdominal pain, agitation, fever, chills, diarrhea, eczema,edema, hypertension, irritability, laryngeal edema,nausea, pallor,pruritus,rash, and vomiting. The majority of reactions occurred during or within 4 hours of the completion of the infusion. Patients were not routinely pre-medicated prior to infusion of KANUMA in these clinical trials.

Due to the potential for anaphylaxis, appropriate medical support should be readily available when KANUMA is administered. If anaphylaxis occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Observe patients closely during and after the infusion. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur.

The management of hypersensitivity reactions should be based on the severity of the reaction and may include temporarily interrupting 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. If a severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment.

Consider the risks and benefits of re-administering KANUMA following a severe reaction. Monitor patients, with appropriate resuscitation measures available, if the decision is made to re-administer the product.

Hypersensitivity to Eggs or Egg Products

KANUMA is produced in the egg whites of genetically engineered chickens. Patients with a known history of egg allergies were excluded from the clinical trials. Consider the risks and benefits of treatment with KANUMA in patients with known systemic hypersensitivity reactions to eggs or egg products.

|clinicalTrials= Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In clinical trials, a total of 106 patients received treatment with KANUMA. The data described below reflect exposure to KANUMA in 75 patients who received KANUMA at dosages up to 3 mg/kg once weekly in clinical trials:

• Nine patients (5 males, 4 females) who had growth failure or other evidence of rapidly progressive LAL deficiency presenting within the first 6 months of life received KANUMA for up to 165 weeks (median 60 weeks) at escalating doses ranging between 0.35 mg/kg and 5 mg/kg once weekly. The recommended initial dosage for these patients is 1 mg/kg escalating to 3 mg/kg once weekly.
• 66 pediatric and adult patients with LAL deficiency aged 4 to 58 years (33 males, 33 females) received KANUMA 1 mg/kg every other week up to 36 weeks.

Table 2 summarizes the most common adverse reactions occurring in >30% of patients with rapidly progressive LAL deficiency presenting within the first 6 months of life receiving KANUMA.

• Table 2: Most Common Adverse Reactions* in Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life

This image is provided by the National Library of Medicine.

KANUMA: Sebelipase alfa's Brand name

Other less common adverse reactions reported in patients with rapidly progressive disease presenting within the first 6 months of life who received KANUMA included hypotonia, decreased oxygen saturation, retching, sneezing, and tachycardia.

Table 3 summarizes the most common adverse reactions that occurred in ≥8% of pediatric and adult patients with LAL deficiency receiving KANUMA at a dosage of 1 mg/kg once every other week during the 20-week double-blind treatment period.

• Table 3: Most Common Adverse Reactions* in Pediatric and Adult Patients with LAL Deficiency

This image is provided by the National Library of Medicine.

KANUMA: Sebelipase alfa's Brand name

Other less common adverse reactions reported in pediatric and adult patients who received KANUMA included anxiety and chest discomfort.

• Hyperlipidemia

• 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 following initiation of KANUMA. The maximum mean percentage increase was 18% for LDL-c at Week 2 and 5% for triglycerides at Week 4.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Patients have developed anti-drug antibodies (ADA) to KANUMA. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to KANUMA with the incidence of antibodies to other products may be misleading.

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

• Seven of the 9 infants with rapidly progressive disease had at least one post-treatment ADA assessment, and 4 of these 7 (57%) patients developed ADA during treatment with KANUMA. Two of the 4 ADA-positive patients were determined to be positive for neutralizing antibodies that inhibit in vitro enzyme activity and cellular uptake of the enzyme. At the time of initial ADA positivity, 3 patients were receiving a dosage of 1 mg/kg once weekly and 1 patient was receiving a dosage of 3 mg/kg once weekly. Three of the 4 ADA-positive patients had ADA titers monitored from the initiation of treatment, and developed measureable ADA titers within the first 2 months of exposure. One of the 4 ADA-positive patients had persistent ADA titers. ADA titers decreased to undetectable levels in the remaining 3 patients while receiving continued treatment at a dosage of 3 mg/kg once weekly.

• Hypersensitivity reactions occurred in all 4 of the ADA-positive patients, whereas they occurred in only 1 of the 3 ADA-negative patients. None of the patients discontinued treatment. In 1 patient, decreased growth velocity in a setting of neutralizing antibodies to KANUMA was observed.

• Pediatric and Adult Patients with LAL Deficiency

• Five of 35 (14%) KANUMA-treated pediatric and adult patients who completed the 20-week double-blind period of study treatment developed ADA. All patients were receiving 1 mg/kg once every other week. All 5 ADA-positive patients first developed measurable ADA titers within the first 3 months of exposure. Two of the 5 ADA-positive patients had a measurable ADA titer at only one time point. In the 3 patients with measurable ADA titers at multiple time points, ADA titers decreased to undetectable levels during continued treatment. Two patients developed in vitro neutralizing antibodies during the open-label extension phase after 20 weeks and 52 weeks of treatment with KANUMA, respectively. There is no clear association between the development of ADA and decreased efficacy in pediatric and adult patients treated with KANUMA.

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• Risk Summary

• There are no available data on KANUMA in pregnant women to inform any drug-associated risk. Animal reproductive studies conducted with sebelipase alfa showed no evidence of embryolethality, fetotoxicity, teratogenicity, or abnormal early embryonic development at dosages up to 164 and 526 times the human dosage of 1 mg/kg every other week (based on AUC) in rats and rabbits, respectively.

• The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

• Animal Data

• Sebelipase alfa administered during the period of organogenesis to rats (on gestation days 6, 9, 12, 15 and 17) and rabbits (on gestation days 7, 10, 13, 16 and 19) at intravenous doses up to 60 and 50 mg/kg, respectively, (approximately 164 and 526 times the human AUC of 1387 ng.h/mL at 1 mg/kg dose administered once every other week, respectively) did not cause any adverse effects on embryofetal development. A pre- and postnatal development study in rats showed no evidence of adverse effects on pre- and postnatal development at intravenous doses (administered on gestation days 6, 9, 12, 15, 18, and 20 and days 4, 7, 10, 14, and 17 postpartum) of sebelipase alfa up to 60 mg/kg/day (approximately 164 times the human AUC of 1387 ng.h/mL at 1 mg/kg dose administered once every other week).

|useInNursing=There are no data on the presence of sebelipase alfa in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known if sebelipase alfa is present in animal milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KANUMA and any potential adverse effects on the breastfed infant from sebelipase alfa or from the underlying maternal condition. |useInPed=Safety and effectiveness of KANUMA have been established in pediatric patients aged 1 month and older. Clinical trials with KANUMA were conducted in 56 pediatric patients (range 1 month to <18 years old). |useInGeri=Clinical trials of KANUMA did not include any patients aged 65 years old and older. It is not known whether they respond differently than younger patients.

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• Preparation Instructions

KANUMA is for intravenous infusion only. Prepare KANUMA using the following steps.

1. Determine the number of vials needed based on the patient's weight and the recommended dose of 1 mg/kg or 3 mg/kg, using the following calculations (a-b):

a. Total dose (mg) = Patient's weight (kg) × Recommended dose (mg/kg)

b. Total number of vials = Total dose (mg) divided by 20 mg/vial

2. Round to the next whole vial and remove the required number of vials from the refrigerator to allow them to reach room temperature.

a. Volume (mL) of calculated total dose = Total dose (mg) divided by the 2 mg/mL concentration

b. Volume (mL) of 0.9% Sodium Chloride for dilution = Total infusion volume (mL) for patient's weight (see TABLE 1) – Volume (mL) of calculated total dose

• Table 1: Total Infusion Volumes*

This image is provided by the National Library of Medicine.

KANUMA: Sebelipase alfa's Brand name

3. Mix gently by inversion. Do not shake the vials or the prepared infusion.

4. The solution should be inspected visually for particulate matter and discoloration prior to administration. 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.

5. Vials are for single-use only. Discard any unused product. Do not freeze.

• Administration Instructions

• Administer the diluted solution as an intravenous infusion using a low-protein binding infusion set with an in-line, low-protein binding 0.2 micron filter.

• Infuse over at least 2 hours. Consider further prolonging the infusion time for patients receiving the 3 mg/kg dose 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.

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Sebelipase alfa
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