Velmanase Alfa – Description
- Velmanase alfa is an enzyme replacement therapy approved for the treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients.68624
- Alpha-mannosidosis is a rare genetic condition characterized by the lack of the enzyme alpha-D-mannosidase, resulting in accumulation of mannose-rich oligosaccharides in lysosomes.
- Symptoms of alpha-mannosidosis may include distinctive facial features, skeletal abnormalities, hearing loss, intellectual disability, and immune system dysfunction.6862468636
- Treatment with velmanase alfa in a randomized study of 25 patients resulted in a reduction of serum oligosaccharide concentration, and improved a 3-minute stair climbing test, 6-minute walking test, and forced vital capacity.
- Serious hypersensitivity reactions including anaphylaxis and infusion-related reactions can occur.
- Administration requires a specialized care setting where cardiopulmonary resuscitation equipment is readily available. Pretreatment with antihistamines, antipyretics, and/or corticosteroids may be required.68624
Indications & Dosage
- alpha-mannosidosis
For the treatment of non-central nervous system manifestations of alpha-mannosidosis
NOTE: The FDA has designated velmanase alfa as an orphan drug for this indication.
Intravenous dosage
Adults:
1 mg/kg/dose IV once weekly.68624
Children and Adolescents:
1 mg/kg/dose IV once weekly.68624
Maximum Dosage Limits:
•Adults
1 mg/kg/dose IV once weekly.
•Geriatric
Safety and efficacy have not been established.
•Adolescents
1 mg/kg/dose IV once weekly.
•Children
1 mg/kg/dose IV once weekly.
•Infants
Safety and efficacy have not been established.
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
- infusion-related reactions
- pregnancy
- pregnancy testing
- reproductive risk
- requires a specialized care setting
- serious hypersensitivity reactions or anaphylaxis
Pregnancy
- Velmanase alfa may cause fetal harm if administered during pregnancy based on data from animal studies.
- Advise patients of reproductive potential of the potential hazard to the fetus and to avoid pregnancy during velmanase alfa therapy.
- Consider the patient’s need for treatment, potential risks to the fetus, and potential adverse outcomes of untreated disease when deciding whether to discontinue velmanase alfa during pregnancy.
- Skeletal and visceral malformations were observed in pregnant rats and rabbits after velmanase alfa doses that were approximately 7- and 2.5-fold, respectively, the human exposure (at the recommended dose).68624
Lactation
- It is not known whether velmanase alfa is excreted in human milk or if it has effects on the breast-fed child or on milk production.
- Consider the developmental and health benefits of breast-feeding along with the patient’s clinical need for velmanase alfa, and any potential adverse effects on the breastfed child.68624
Interactions
There are no drug interactions associated with Velmanase Alfa products.
Adverse Reactions
- abdominal pain
- agitation
- anorexia
- antibody formation
- arthralgia
- asthenia
- ataxia
- back pain
- chills
- conjunctivitis
- cough
- cyanosis
- dental pain
- edema
- erythema
- fatigue
- fever
- furunculosis
- headache
- hearing loss
- hypotension
- infection
- influenza
- infusion-related reactions
- lacrimation
- ocular pruritus
- odynophagia
- palpitations
- pharyngitis
- psychosis
- rash
- renal failure
- rhinitis
- seizures
- serious hypersensitivity reactions or anaphylaxis
- serious hypersensitivity reactions or anaphylaxis
- sinus tachycardia
- syncope
- tremor
- urticaria
- vasculitis
- vomiting
- weight gain
- wheezing
Mechanism of Action
Velmanase alfa is a recombinant human lysosomal alpha-mannosidase enzyme, an enzyme that catalyzes the degradation of accumulated mannose-containing oligosaccharides. Alpha-mannosidosis is a lysosomal storage disease caused by reduced activity of alpha-mannosidase, resulting in accumulation of mannose-rich oligosaccharides in lysosomes. Velmanase alfa binds the mannose-6-phosphate receptor and is transported into lysosomes where it exerts enzymatic breakdown of mannose-containing oligosaccharides.68624
Pharmacokinetics
Velmanase alfa is administered intravenously. The mean volume of distribution in patients with alpha-mannosidosis was 276 mL/kg. Velmanase alfa is expected to be metabolized into small peptides by catabolic pathways. The mean total body clearance was 5.7 mL/hour/kg, and the mean terminal half-life was 33.6 hours.68624
Serum oligosaccharide concentrations are elevated in patients with alpha-mannosidosis; velmanase alfa treatment reduces serum oligosaccharaide concentrations.68624
Affected cytochrome P450 isoenzymes and drug transporters: none
•Route-Specific Pharmacokinetics
Intravenous Route
After intravenous administration of 1 mg/kg/dose in adult patients with alpha-mannosidosis, the mean Cmax was 7.9 mcg/mL and the AUC was 159.8 mcg x hour/mL.68624
•Special Populations
Pediatrics
Children and Adolescents 6 to 17 years
In patients with alpha-mannosidosis administered 1 mg/kg/dose velmanase alfa intravenously once a week, the mean Cmax and AUC at steady state were 6.6 mcg/mL and 109.8 mcg x hour/mL, respectively.68624
Children 3 to 5 years
In patients with alpha-mannosidosis administered 1 mg/kg/dose velmanase alfa intravenously once a week, the mean Cmax and AUC at steady state were 7 mcg/mL and 75.9 mcg x hour/mL, respectively.68624
Monitoring Parameters
Monitoring Parameters
- pregnancy testing
Classifications
- Alimentary Tract and Metabolism
- Metabolic Disorder Agents
- Lysosomal Storage Disorder Agents
- Alpha-mannosidosis Agents
- Lysosomal Storage Disorder Agents
- Metabolic Disorder Agents
References
68624.Lamzede (velmanase alfa-tycv) injection package insert. Parma, Italy: Chiesi Farmaceutici S.p.A; 2023 Feb.
68636.National Organization for Rare Disorders (NORD). Alpha-Mannosidosis. Accessed February 23, 2023. Available on the World Wide Web at https://rarediseases.org/rare-diseases/alpha-mannosidosis/.
