Olipudase alfa

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
References:
  1. KEGG DRUG: Olipudase alfa [Link]
Download FASTA Format
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

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAcid sphingomyelinase deficiency•••••••••••••••••• ••••••••••••••••••
Treatment ofNon-central nervous system pathology•••••••••••••••••• ••••••••••••••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
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.9

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.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
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
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 regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
XenpozymeInjection, powder, for solution20 mgIntravenousSanofi B.V.2022-08-02Not applicableEU flag
XenpozymeInjection, powder, for solution20 mgIntravenousSanofi B.V.2022-08-02Not applicableEU flag
XenpozymeInjection, powder, lyophilized, for solution4 mg/1.1mLIntravenousGenzyme Corporation2022-08-29Not applicableUS flag
XenpozymeInjection, powder, for solution4 mgIntravenousSanofi B.V.2023-05-04Not applicableEU flag
XenpozymeInjection, powder, for solution20 mgIntravenousSanofi B.V.2022-08-02Not applicableEU flag

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
  1. Keam SJ: Olipudase Alfa: First Approval. Drugs. 2022 Jun;82(8):941-947. doi: 10.1007/s40265-022-01727-x. [Article]
  2. Wasserstein MP, Schuchman EH: Acid Sphingomyelinase Deficiency . [Article]
  3. 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]
  4. 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]
  5. EMA Approved Drug Products: Xenpozyme (olipudase alfa) Intravenous Infusion [Link]
  6. GlobeNewswire News Release: Xenpozyme® (olipudase alfa) approved by European Commission as first and only treatment for ASMD [Link]
  7. FDA Approved Drug Products: XENPOZYME (olipudase alfa-rpcp) for injection, for intravenous use [Link]
  8. FDA NEWS RELEASE: FDA Approves First Treatment for Acid Sphingomyelinase Deficiency, a Rare Genetic Disease [Link]
  9. FDA Approved Drug Products: XENPOZYME® (olipudase alfa-rpcp) for injection, for intravenous use (Dec 2023) [Link]
PubChem Substance
347911391
RxNav
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
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableRecruitingNot AvailableAcid Sphingomyelinase Deficiency (ASMD) / Niemann-Pick Disease1somestatusstop reasonjust information to hide
2CompletedTreatmentNiemann-Pick Disease1somestatusstop reasonjust information to hide
2, 3CompletedTreatmentNiemann-Pick Disease1somestatusstop reasonjust information to hide
1CompletedTreatmentAcid Sphingomyelinase Deficiency (ASMD)1somestatusstop reasonjust information to hide
1, 2CompletedTreatmentNiemann-Pick Disease1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous20 mg
Injection, powder, for solutionIntravenous4 mg
Injection, powder, lyophilized, for solutionIntravenous20 mg/5.1mL
Injection, powder, lyophilized, for solutionIntravenous4 mg/1.1mL
Powder, for solutionIntravenous20 mg / vial
Powder, for solutionIntravenous4 mg / vial
Powder20 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