Olipudase Alfa – Description
- Olipudase alfa is an enzyme replacement therapy approved for adult and pediatric patients with acid sphingomyelinase deficiency (ASMD).
- Olipudase alfa is the first approved medication to treat symptoms that are not related to the central nervous system in patients with ASMD.
- ASMD is a rare genetic disease caused by the lack of an enzyme needed to break down a complex lipid, called sphingomyelin, that accumulates in the liver, spleen, lung, and brain.
- Olipudase alfa helps reduce sphingomyelin accumulation in the liver, spleen, and lung.
- The efficacy of olipudase alfa for the treatment of ASMD was demonstrated in a randomized, double-blind, placebo-controlled study of 31 adult patients and in a multicenter, open-label pediatric study (n = 8).
- Overall, treatment with olipudase alfa improved lung function and reduced liver and spleen size. Severe hypersensitivity and infusion-related reactions, including anaphylaxis and life-threatening reactions, have been reported during olipudase alfa administration.679166793767975
Indications & Dosage
- Acid sphingomyelinase deficiency
Maximum Dosage Limits:
•Adults
3 mg/kg/dose IV every 2 weeks.
•Geriatric
3 mg/kg/dose IV every 2 weeks.
•Adolescents
3 mg/kg/dose IV every 2 weeks.
•Children
3 mg/kg/dose IV every 2 weeks.
•Infants
3 mg/kg/dose IV every 2 weeks.
•Neonates
3 mg/kg/dose IV every 2 weeks.
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.
Precautions
- Breast-feeding
- Contraception requirements
- Pregnancy
- Pregnancy testing
- Reproductive risk
- Serious hypersensitivity reactions or anaphylaxis
Pregnancy
- There are no available data on olipudase alfa use in pregnant females to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
- However, based on findings from animal reproduction studies, olipudase alfa may cause embryo-fetal harm when administered during the first trimester of pregnancy. In an embryo-fetal toxicity study in pregnant mice, a rare malformation (exencephaly) was observed in offspring at an exposure less than the exposure at the maximum recommended human dose (MRHD) of olipudase alfa.
- Olipudase alfa dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite concentrations that may increase the risk of fetal malformations.
- Consider the need for olipudase alfa, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal acid sphingomyelinase deficiency (ASMD) disease when deciding whether to continue or discontinue olipudase alfa maintenance dosing in pregnancy.
- Advise the pregnant female of the potential risk to the fetus if olipudase alfa is administered during pregnancy.67916
Lactation
- There are no data on the presence of olipudase alfa in human milk, the effects on the breastfed infant, or the effects on milk production.
- Olipudase alfa is present in animal milk (1.3% of the estimated maximal maternal plasma concentration). When a drug is present in animal milk, it is likely that the drug will be present in human milk.
- Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for olipudase alfa and any potential adverse effects on the breastfed infant from olipudase alfa or from the underlying maternal condition.67916
Interactions
- There are no drug interactions associated with Olipudase Alfa products.
Adverse Reactions
- abdominal pain
- angioedema
- antibody formation
- arthralgia
- asthenia
- conjunctival hyperemia
- cough
- diarrhea
- dyspnea
- edema
- elevated hepatic enzymes
- erythema
- erythema nodosum
- fatigue
- fever
- headache
- hypotension
- infusion-related reactions
- injection site reaction
- myalgia
- nausea
- pruritus
- rash
- rhinitis
- serious hypersensitivity reactions or anaphylaxis
- sinus tachycardia
- throat irritation
- urticaria
- vomiting
Mechanism of Action
- Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease that results from reduced activity of the enzyme acid sphingomyelinase (ASM), caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 gene.
- ASM degrades sphingomyelin to ceramide and phosphocholine.
- The deficiency of ASM causes an intra-lysosomal accumulation of sphingomyelin (as well as cholesterol and other cell membrane lipids) in various tissues.
- Olipudase alfa provides an exogenous source of ASM. Olipudase alfa is not expected to cross the blood-brain barrier or modulate the CNS manifestations of ASMD.67916
Plasma ceramide concentrations
- Ceramide is elevated in the plasma of patients with ASMD.
- During clinical trials, plasma ceramide concentrations showed a transient increase after each administration (post infusion) of olipudase alfa. In the dose escalation phase, plasma ceramide concentrations were substantially increased compared to the baseline concentration.
- Plasma ceramide concentrations gradually decreased after repeated administration of olipudase alfa and the pre-infusion concentrations were generally lower than the baseline concentration during the maintenance phase of treatment.67916
Plasma lyosphingomyelin concentrations
Lysosphingomyelin is substantially elevated in the plasma of patients with ASMD. Plasma lysosphingomyelin concentrations decreased after repeated administration of olipudase alfa.67916
Liver sphingomyelin content
In adult patients, the liver sphingomyelin content, as assessed by histopathology, decreased from baseline to Week 52 in the olipudase alfa treatment group compared to an increase in the placebo group.67916
Pharmacokinetics
- Olipudase alfa is administered intravenously. The mean Vd of olipudase alfa was 13 L in adult patients with acid sphingomyelinase deficiency (ASMD). The metabolic pathway of olipudase alfa has not been determined.
- Olipudase alfa is expected to be metabolized into small peptides and amino acids via catabolic pathways. The mean clearance and half-life of olipudase alfa were 0.33 L/hour and 32 to 38 hours, respectively, in adult patients with ASMD.67916
Affected cytochrome P450 isoenzymes and transporters: none
•Route-Specific Pharmacokinetics
Intravenous Route
- In adult patients with ASMD, the mean Cmax and AUC of olipudase alfa at steady state were 30 mcg/mL and 607 mcg x hour/mL, respectively, at the recommended maintenance dose of 3 mg/kg/dose IV every 2 weeks.
- The Cmax and AUC of olipudase alfa increased proportionally over a dose range of 0.1 to 3 mg/kg (0.03 to 1 times the approved recommended maintenance dose).67916
•Special Populations
Pediatrics
- In pediatric patients (1 to 17 years of age) with ASMD, the mean Cmax and AUC of olipudase alfa were 24.3 mcg/mL and 449 mcg x hour/mL, respectively, at the recommended maintenance dose of 3 mg/kg/dose IV every 2 weeks.67916
Monitoring Parameters
- LFTs
- Pregnancy testing
Classifications
- Alimentary Tract and Metabolism
- Metabolic Disorder Agents
- Lysosomal Storage Disorder Agents
- Acid Sphingomyelinase Deficiency (ASMD) Agents
- Lysosomal Storage Disorder Agents
- Metabolic Disorder Agents
References
67916.Xenpozyme (olipudase alfa-rpcp) for injection package insert. Cambridge, MA: Genzyme Corporation; 2024 Sept.
67937.National Organization for Rare Disorders (NORD). Niemann Pick Disease Type C. Accessed Sept 25, 2024. Available on the World Wide Web at https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/.
67975.FDA News Release. FDA approves first treatment for acid sphingomyelinase deficiency, a rare genetic disease. Accessed August 31, 2022. Available on the World Wide Web at https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-acid-sphingomyelinase-deficiency-rare-genetic-disease?utm_medium=email&utm_source=govdelivery
