Velmanase alfa

Identification

Summary

Velmanase alfa is a recombinant human lysosomal alpha-mannosidase used to treat non-neurological symptoms of mild to moderate alpha-mannosidosis.

Generic Name
Velmanase alfa
DrugBank Accession Number
DB12374
Background

Velmanase alfa is a recombinant human lysosomal alpha-mannosidase developed for enzyme replacement therapy to treat alpha-mannosidosis. Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder. Patients with alpha-mannosidosis have a genetic mutation that causes a deficiency in the lysosomal enzyme alpha-mannosidase, which is an enzyme responsible for breaking down complex sugars in the body. The resulting accumulation of sugars in the body leads to an array of clinical manifestations leading to progressive neuromuscular and skeletal deterioration, such as skeletal abnormalities, motor function impairment, intellectual disability, and respiratory dysfunction.1

As long-term enzyme replacement therapy, velmanase alfa supplements or restores the function of deficient alpha-mannosidase. Velmanase alfa has an amino acid sequence of the monomeric protein identical to the naturally occurring human alpha-mannosidase.4 It was granted marketing authorization by the European Commission in March 2018 under the market name Lamzede 5 as the first human recombinant form of alpha-mannosidase for the treatment of alpha-mannosidosis.1 In February 2023, the FDA also approved velmanase alfa for the same indication.6 Velmanase alfa is currently not approved in Canada.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
>Sequence
GGYETCPTVQPNMLNVHLLPHTHDDVGWLKTVDQYFYGIKNDIQHAGVQYILDSVISALL
ADPTRRFIYVEIAFFSRWWHQQTNATQEVVRDLVRQGRLEFANGGWVMNDEAATHYGAIV
DQMTLGLRFLEDTFGNDGRPRVAWHIDPFGHSREQASLFAQMGFDGFFFGRLDYQDKWVR
MQKLEMEQVWRASTSLKPPTADLFTGVLPNGYNPPRNLCWDVLCVDQPLVEDPRSPEYNA
KELVDYFLNVATAQGRYYRTNHTVMTMGSDFQYENANMWFKNLDKLIRLVNAQQAKGSSV
HVLYSTPACYLWELNKANLTWSVKHDDFFPYADGPHQFWTGYFSSRPALKRYERLSYNFL
QVCNQLEALVGLAANVGPYGSGDSAPLNEAMAVLQHHDAVSGTSRQHVANDYARQLAAGW
GPCEVLLSNALARLRGFKDHFTFCQQLNISICPLSQTAARFQVIVYNPLGRKVNWMVRLP
VSEGVFVVKDPNGRTVPSDVVIFPSSDSQAHPPELLFSASLPALGFSTYSVAQVPRWKPQ
ARAPQPIPRRSWSPALTIENEHIRATFDPDTGLLMEIMNMNQQLLLPVRQTFFWYNASIG
DNESDQASGAYIFRPNQQKPLPVSRWAQIHLVKTPLVQEVHQNFSAWCSQVVRLYPGQRH
LELEWSVGPIPVGDTWGKEVISRFDTPLETKGRFYTDSNGREILERRRDYRPTWKLNQTE
PVAGNYYPVNTRIYITDGNMQLTVLTDRSQGGSSLRDGSLELMVHRRLLKDDGRGVSEPL
MENGSGAWVRGRHLVLLDTAQAAAAGHRLLAEQEVLAPQVVLAPGGGAAYNLGAPPRTQF
SGLRRDLPPSVHLLTLASWGPEMVLLRLEHQFAVGEDSGRNLSAPVTLNLRDLFSTFTIT
RLQETTLVANQLREAASRLKWTTNTGPTPHQTPYQLDPANITLEPMEIRTFLASVQWKEV
DG
References:
  1. KEGG DRUG: Velmanase alfa [Link]
Download FASTA Format
Synonyms
  • Lamazym
  • Recombinant Human Alpha Mannosidase
  • Rhlaman
  • Velmanase alfa
  • Velmanase alfa-tycv

Pharmacology

Indication

Velmanase alfa is an enzyme replacement therapy for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis.4,6

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofNon-neurological symptoms••••••••••••
Management ofNon-neurological symptoms••••••••••••
Management ofNon-neurological symptoms••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Velmanase alfa is an enzyme replacement therapy that aims to reduce oligosaccharide levels in patients with alpha-mannosidosis. In clinical trials, reduced serum oligosaccharide levels and improvements in biochemical and functional measures were seen at 18 months 2 and for up to four years of treatment.3

Reversing the organ damage or showing improvements in alpha-mannosidosis becomes increasingly difficult as the accumulation of end-organ damage progresses over time. Velmanase alfa has no effects on irreversible complications of the disorder, such as skeletal deformities, dysostosis multiplex, neurological manifestations, and impaired cognitive function.4

Mechanism of action

Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder: it is a multi-systemic disease, characterized by a wide range of clinical manifestations including skeletal abnormalities, motor function impairment, intellectual disability, hearing loss, respiratory dysfunction, recurrent infections, and immunodeficiency usually presenting in early childhood. Alpha-mannosidosis is caused by pathogenic sequence variants in the MAN2B1 gene, leading to the deficiency of the lysosomal enzyme, alpha-mannosidase. Alpha-mannosidase is a lysosomal enzyme involved in glycoprotein catabolism. Deficient alpha-mannosidase results in the accumulation of mannose-rich oligosaccharides, causing impaired cellular function and apoptosis in all tissues.1,2

Velmanase alfa is a recombinant form of human alpha-mannosidase. Upon administration, velmanase alfa supplements or replaces natural alpha-mannosidase to properly break down hybrid and complex high-mannose oligosaccharides in the lysosome, reducing the amount of accumulated mannose-rich oligosaccharides.4

Absorption

Following weekly intravenous infusion of 1 mg/kg of velmanase alfa, the mean Cmax of 8 µg/mL at steady-state was reached at 1.8 hours after the start of administration.4

Volume of distribution

The steady-state volume of distribution is 0.27 L/kg, indicating distribution confined to plasma. It does not cross the blood-brain barrier.4

Protein binding

There is no information.

Metabolism

Velmanase alfa is expected to undergo nonspecific degradation into small peptides and subsequently amino acids, similar to other natural occurring proteins.4

Route of elimination

There is no information.

Half-life

At the end of intravenous infusion, velmanase alfa plasma concentrations fell in a biphasic fashion with a mean terminal elimination half-life of about 30 hours.4

Clearance

The mean clearance of velmanase alfa from plasma is 6.7 mL/h/kg: it is consistent with rapid cellular uptake of velmanase alfa via mannose receptors.4

Adverse Effects
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Toxicity

There is no information regarding the LD50 of velmanase alfa.

There is no experience with overdose of velmanase alfa. In clinical studies, a single dose of 100 units/kg (approximately corresponding to 3.2 mg/kg) velmanase alfa led to a mild fever that lasted for five hours in one patient; however, no treatment was necessary.4

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

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LamzedeInjection, powder, lyophilized, for solution10 mg/1IntravenousChiesi USA, Inc.2023-03-01Not applicableUS flag
LamzedeInjection, powder, for solution10 mgIntravenousChiesi Farmaceutici S.P.A.2020-12-16Not applicableEU flag
LamzedeInjection, powder, for solution10 mgIntravenousChiesi Farmaceutici S.P.A.2020-12-16Not applicableEU flag
LamzedeInjection, powder, for solution10 mgIntravenousChiesi Farmaceutici S.P.A.2020-12-16Not applicableEU flag

Categories

ATC Codes
A16AB15 — Velmanase 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
M91TG242P2
CAS number
1492823-75-2

References

General References
  1. Harmatz P, Cattaneo F, Ardigo D, Geraci S, Hennermann JB, Guffon N, Lund A, Hendriksz CJ, Borgwardt L: Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis. Mol Genet Metab. 2018 Jun;124(2):152-160. doi: 10.1016/j.ymgme.2018.04.003. Epub 2018 Apr 18. [Article]
  2. Borgwardt L, Guffon N, Amraoui Y, Dali CI, De Meirleir L, Gil-Campos M, Heron B, Geraci S, Ardigo D, Cattaneo F, Fogh J, Van den Hout JMH, Beck M, Jones SA, Tylki-Szymanska A, Haugsted U, Lund AM: Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial. J Inherit Metab Dis. 2018 Nov;41(6):1215-1223. doi: 10.1007/s10545-018-0185-0. Epub 2018 May 30. [Article]
  3. Lund AM, Borgwardt L, Cattaneo F, Ardigo D, Geraci S, Gil-Campos M, De Meirleir L, Laroche C, Dolhem P, Cole D, Tylki-Szymanska A, Lopez-Rodriguez M, Guillen-Navarro E, Dali CI, Heron B, Fogh J, Muschol N, Phillips D, Van den Hout JMH, Jones SA, Amraoui Y, Harmatz P, Guffon N: Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis. J Inherit Metab Dis. 2018 Nov;41(6):1225-1233. doi: 10.1007/s10545-018-0175-2. Epub 2018 May 3. [Article]
  4. Summary of Product Characteristics: Lamzede (velmanase alfa) solution for intravenous infusion [Link]
  5. European Medicines Agency: Lamzede (velmanase alfa) [Link]
  6. FDA Approved Drug Products: LAMZEDE (velmanase alfa-tycv) for injection, for intravenous use [Link]
PubChem Substance
347911328
RxNav
2630725
Wikipedia
Velmanase_alfa

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAlpha-Mannosidosis4
3WithdrawnTreatmentAlpha-Mannosidosis1
2CompletedTreatmentAlpha-Mannosidosis2
2Unknown StatusTreatmentAlpha-Mannosidosis1
1CompletedTreatmentAlpha-Mannosidosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous10 mg
Injection, powder, lyophilized, for solutionIntravenous10 mg/1
Powder, for solutionIntravenous; Parenteral10 MG
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Drug created at October 20, 2016 22:07 / Updated at April 23, 2023 14:17