Olipudase alfa
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Identification
- Summary
Olipudase alfa is a recombinant human acid sphingomyelinase used to treat Acid Sphingomyelinase Deficiency (ASMD) in children and adults.
- Generic Name
- Olipudase alfa
- DrugBank Accession Number
- DB12835
- Background
Olipudase alfa is recombinant human acid sphingomyelinase.1 It is the first and only enzyme replacement therapy in the world for the treatment of Acid Sphingomyelinase Deficiency (ASMD), also known as Niemann–Pick disease.6 ASMD is a rare lysosomal storage disease caused by mutations in the SMPD1 gene, leading to a deficiency in acid sphingomyelinase and the abnormal accumulation of the primary ASM substrate, sphingomyelin.3 Olipudase alfa works to hydrolyze sphingomyelin accumulated in body tissues, such as the lungs, liver, spleen, kidneys, and bone marrow.1
Olipudase alfa gained its first global approval in Japan on March 28, 2022.1 It was later approved by the European Commission on June 28, 2022 6 and by the FDA on August 31, 2022.8
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Other protein based therapies - Protein Chemical Formula
- C2900H4373N783O791S24
- Protein Average Weight
- 63590.933 Da (exact)
- Sequences
>Olipudase alfa sequence HPLSPQGHPARLHRIVPRLRDVFGWGNLTCPICKGLFTAINLGLKKEPNVARVGSVAIKL CNLLKIAPPAVCQSIVHLFEDDMVEVWRRSVLSPSEACGLLLGSTCGHWDIFSSWNISLP TVPKPPPKPPSPPAPGAPVSRILFLTDLHWDHDYLEGTDPDCADPLCCRRGSGLPPASRP GAGYWGEYSKCDLPLRTLESLLSGLGPAGPFDMVYWTGDIPAHDVWHQTRQDQLRALTTV TALVRKFLGPVPVYPAVGNHESTPVNSFPPPFIEGNHSSRWLYEAMAKAWEPWLPAEALR TLRIGGFYALSPYPGLRLISLNMNFCSRENFWLLINSTDPAGQLQWLVGELQAAEDRGDK VHIIGHIPPGHCLKSWSWNYYRIVARYENTLAAQFFGHTHVDEFEVFYDEETLSRPLAVA FLAPSATTYIGLNPGYRVYQIDGNYSGSSHVVLDHETYILNLTQANIPGAIPHWQLLYRA RETYGLPNTLPTAWHNLVYRMRGDMQLFQTFWFLYHKGHPPSEPCGTPCRLATLCAQLSA RADSPALCRHLMPDGSLPEAQSLWPRPLFC
Download FASTA FormatReferences:
- KEGG DRUG: Olipudase alfa [Link]
- Synonyms
- Olipudase alfa
- External IDs
- Gz402665
Pharmacology
- Indication
Olipudase alfa is indicated as an enzyme replacement therapy for the treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients.9
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Acid sphingomyelinase deficiency •••••••••••• •••••• ••••••••• ••••••••• Treatment of Non-central nervous system pathology •••••••••••• •••••• ••••••••• ••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Olipudase alfa is an enzyme replacement therapy that works to ameliorate the signs and symptoms of ASMD by reducing the amount of sphingomyelin that accumulates in organs and causes tissue damage in patients with ASMD.5 It works to reduce the extent of non-neurological manifestations of ASMD, such as splenomegaly and hepatomegaly.4
Ceramide is elevated in plasma of adult and pediatric patients with ASMD. Plasma ceramide levels showed a transient increase after each administration (post infusion) of olipudase alfa. In the dose escalation phase, plasma ceramide levels were substantially increased compared to the baseline level. Plasma ceramide levels gradually decreased following repeated administration of olipudase alfa and the pre-infusion levels were generally lower than the baseline level during the maintenance phase of treatment.9 • In adult patients with ASMD in Trial 1, the mean (standard deviation, SD) pre-infusion plasma ceramide concentration was 3.7 (1.4) mg/L at baseline and decreased to 2.2 (0.6) mg/L at Week 52 following treatment with olipudase alfa.9 • In pediatric patients with ASMD in Trial 2, the mean (SD) pre-infusion plasma ceramide concentration was 4.7 (0.9) mg/L at baseline and decreased to 1.8 (0.3) mg/L at Week 52 following treatment with olipudase alfa.9
Lysosphingomyelin is substantially elevated in plasma of adult and pediatric patients with ASMD. Plasma lysosphingomyelin levels decreased after repeated administration of olipudase alfa.9
• In adult patients with ASMD in Trial 1, the mean (SD) pre-infusion plasma lysosphingomyelin concentration was 379 (204) mcg/L at baseline and decreased to 99 (118) mcg/L at Week 52 following treatment with olipudase alfa.9
• In pediatric patients with ASMD in Trial 2, the mean (SD) pre-infusion plasma lysosphingomyelin concentration was 625 (339) mcg/L at baseline and decreased to 80 (47) mcg/L at Week 52 following treatment with olipudase alfa.9In 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.9
- Mechanism of action
ASMD is an autosomal recessive genetic disorder caused by different mutations in the SMPD1 gene that encodes acid sphingomyelinase. Historically, ASMD has been called Niemann-Pick disease (NPD), with different classifications based on disease onset and severity.3 NPD type A (NPD-A) refers to the severe early-onset form, infantile neurovisceral ASMD and NPD type B (NPD-B) is referred to as the later-onset, chronic visceral form of ASMD. Chronic neurovisceral ASMD (NPD-A/B) is a phenotype with intermediate severity.2 ASMD has a broad spectrum of disease severity and neurological and non-neurological manifestations; thus, it is difficult to classify different types of ASMD using the former classification system of ASMD (A, B, A/B).3 Acid sphingomyelinase typically breaks down metabolically-related lipids such as sphingomyelin in various cell types, such as the monocytes, macrophages, and hepatocytes.3 The deficiency of acid sphingomyelinase thus leads to the accumulation of these lipids in body tissues, causing progressive cell and tissue damage and impairing organ functioning.3 Olipudase alfa is recombinant human acid sphingomyelinase that hydrolyzes sphingomyelin (SM), preventing its accumulation in body organs. As an enzyme replacement therapy, it is an exogenous source of acid sphingomyelinase.5
- Absorption
In adult patients with ASMD, the mean (SD) maximum plasma olipudase alfa-rpcp concentration (Cmax) and area under the concentration-time curve (AUC) at steady state were 30 (5) mcg/mL and 607 (120) mcg∙h/mL, respectively, at the recommended maintenance dose of 3 mg/kg administered once every 2 weeks. Olipudase alfa-rpcp Cmax and AUC increase proportionally over a dose range of 0.1 to 3 mg/kg (0.03 to 1 times the approved recommended maintenance dose).9
- Volume of distribution
After administration of 3 mg/kg olipudase alfa once every two weeks in adults with ASMD, the estimated mean (CV%) volume of distribution of olipudase alfa is 13.1 L (18%). Olipudase alfa is not expected to cross the blood-brain barrier or modulate the CNS manifestations of the disease.5
- Protein binding
There is no information available.
- Metabolism
Olipudase alfa is a recombinant human enzyme and is expected to be eliminated via proteolytic degradation into small peptides and amino acids.5
- Route of elimination
There is no information available.
- Half-life
After administration of 3 mg/kg olipudase alfa once every two weeks in adults with ASMD, the mean terminal half-life (t1/2) ranged from 31.9 to 37.6 hours.5
- Clearance
After administration of 3 mg/kg olipudase alfa once every two weeks in adults with ASMD, the mean (CV%) clearance of olipudase alfa is 0.331 L/h (22%).5
- Adverse Effects
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- Toxicity
Based on findings from animal reproduction studies, XENPOZYME may cause embryo-fetal harm when administered to a pregnant female. olipudase alfa-rpcp dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite levels that may increase the risk of fetal malformations. However, the decision to continue or discontinue olipudase alfa-rpcp maintenance dosing in pregnancy should consider the female’s need for XENPOZYME, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal ASMD disease.9
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-rpcp. There are no available data on olipudase alfa-rpcp use in pregnant females to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise the pregnant female of the potential risk to the fetus.9
Cases of overdosage with XENPOZYME have been reported in pediatric patients during dose escalation. Some patients experienced serious adverse reactions including death within 24 hours of initial dose. The clinical findings included fever, hypotension, gastrointestinal bleeding, marked elevation in liver tests, metabolic acidosis, respiratory failure, and vomiting. There is no known specific antidote for olipudase alfa-rpcp overdosage. In the event of overdosage, immediately stop the infusion, and monitor the patient closely in a hospital setting for the development of hypersensitivity reactions and IARs including acute phase reactions.9
Studies to evaluate the carcinogenic potential of olipudase alfa-rpcp have not been conducted.9
Studies to evaluate the mutagenic potential of olipudase alfa-rpcp have not been conducted.9
Intravenous administration of olipudase alfa-rpcp every other day at doses up to 30 mg/kg had no adverse effects in a combined study of fertility in male and female mice. Exposures at this dose, based on the embryo-fetal development study, were estimated to be approximately 1.5-fold those of the MRHD of olipudase alfa-rpcp.9
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Xenpozyme Injection, powder, for solution 20 mg Intravenous Sanofi S.R.L. 2022-08-02 Not applicable EU Xenpozyme Injection, powder, lyophilized, for solution 4 mg/1.1mL Intravenous Genzyme Corporation 2022-08-29 Not applicable US Xenpozyme Injection, powder, for solution 4 mg Intravenous Sanofi S.R.L. 2023-05-04 Not applicable EU Xenpozyme Injection, powder, for solution 20 mg Intravenous Sanofi S.R.L. 2022-08-02 Not applicable EU Xenpozyme Powder, for solution 20 mg / vial Intravenous Sanofi Aventis Deutschland Gmb H Not applicable Not applicable Canada
Categories
- ATC Codes
- A16AB25 — Olipudase alfa
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 6D5766Q4OP
- CAS number
- 927883-84-9
References
- General References
- Keam SJ: Olipudase Alfa: First Approval. Drugs. 2022 Jun;82(8):941-947. doi: 10.1007/s40265-022-01727-x. [Article]
- Wasserstein MP, Schuchman EH: Acid Sphingomyelinase Deficiency . [Article]
- McGovern MM, Avetisyan R, Sanson BJ, Lidove O: Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD). Orphanet J Rare Dis. 2017 Feb 23;12(1):41. doi: 10.1186/s13023-017-0572-x. [Article]
- Diaz GA, Jones SA, Scarpa M, Mengel KE, Giugliani R, Guffon N, Batsu I, Fraser PA, Li J, Zhang Q, Ortemann-Renon C: One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. Genet Med. 2021 Aug;23(8):1543-1550. doi: 10.1038/s41436-021-01156-3. Epub 2021 Apr 19. [Article]
- EMA Approved Drug Products: Xenpozyme (olipudase alfa) Intravenous Infusion [Link]
- GlobeNewswire News Release: Xenpozyme® (olipudase alfa) approved by European Commission as first and only treatment for ASMD [Link]
- FDA Approved Drug Products: XENPOZYME (olipudase alfa-rpcp) for injection, for intravenous use [Link]
- FDA NEWS RELEASE: FDA Approves First Treatment for Acid Sphingomyelinase Deficiency, a Rare Genetic Disease [Link]
- FDA Approved Drug Products: XENPOZYME® (olipudase alfa-rpcp) for injection, for intravenous use (Dec 2023) [Link]
- External Links
- PubChem Substance
- 347911391
- 2610407
- Wikipedia
- Olipudase_alfa
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Approved for Marketing Not Available Niemann-Pick Disease 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Acid Sphingomyelinase Deficiency (ASMD) 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Acid Sphingomyelinase Deficiency (ASMD) / Niemann-Pick Disease 1 somestatus stop reason just information to hide 2 Completed Treatment Niemann-Pick Disease 1 somestatus stop reason just information to hide 2, 3 Completed Treatment Niemann-Pick Disease 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 20 mg Injection, powder, for solution Intravenous 4 mg Injection, powder, lyophilized, for solution Intravenous 20 mg/5.1mL Injection, powder, lyophilized, for solution Intravenous 4 mg/1.1mL Powder, for solution Intravenous 20 mg / vial Powder, for solution Intravenous 4 mg / vial Powder 20 MG - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Drug created at October 21, 2016 00:36 / Updated at January 24, 2024 05:40