Coverage Policy Manual
Policy #: 2023018
Category: Pharmacy
Initiated: May 2023
Last Review: May 2024
  Velmanase alfa-tycv (e.g., Lamzede®)
Description:
Velmanase alfa-tycv (e.g. Lamzede®) is an enzyme replacement therapy approved by the Food and Drug Administration (FDA) for the treatment of non-central nervous system manifestation of alpha-mannosidosis (AM) in adults and pediatrics.  
 
AM is an ultra-rare genetic lysosomal storage disorder caused by a deficiency of the enzyme alpha-mannosidase due to pathogenic variants in the MAN281 gene.  The estimated prevalence of AM is 1 in every 500,000 to 1 in every 1 million individuals worldwide. The enzyme deficiency leads to progressive accumulation of oligosaccharides with characteristic disease features including intellectual disability, ataxia, coarse face, hearing loss, skeletal dysplasia, and immunodeficiency. Accurate diagnosis is important to differentiate AM from other lysosomal storage disorders and provide appropriate enzyme replacement therapy. There is not a clearly established relationship between genotype and severity of disease. There is significant phenotypic variability in AM, but generally, three types have been described in the literature, representing a spectrum of disease:
 
• Mild AM: Recognized after 10 years of age; characterized by slow disease progression, muscle weakness, and absence of skeletal abnormalities versus the moderate type.
• Moderate AM: Recognized before 10 years of age; characterized by slow disease progression that includes skeletal abnormalities and ataxia.
• Severe AM: Recognized in infancy; characterized by rapid disease progression and early death from central nervous system (CNS) involvement.
 
The life expectancy varies; patients with less severe forms of AM have been reported to live into the sixth decade of life, with the most common cause of death being infection. Diagnosis is confirmed through enzymatic activity measurement or genetic testing.
 
Velmanase alfa (VA) has a black box warning for severe hypersensitivity reactions including anaphylaxis. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during Velmanase alfa administration. If a severe hypersensitivity reaction occurs, Velmanase alfa should be discontinued immediately, and appropriate medical treatment should be initiated. In individuals with severe hypersensitivity reaction, a desensitization procedure to Velmanase alfa may be considered.
 
Regulatory Status
 
Velmanase alfa-tycv (e.g. Lamzede®) was approved by the U.S. Food and Drug Administration (FDA) on February 16, 2023 for the treatment of non–central nervous system manifestations of AM in adult and pediatric patients.  It is the first and only FDA-approved treatment for AM.  Velmanase alfa does not cross the blood-brain barrier and therefore is not expected to treat the neurological aspects of the disease.  
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Prior Approval is required for Velmanase alfa-tycv (e.g. Lamzede®).
 
The initial use of this drug requires documentation of direct physician involvement (MD/DO) by a physician with specialized training at a center with expertise in the diagnosis and treatment of this rare condition and in the ordering and evaluation, as well as signature, in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
Effective May 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Velmanase alfa-tycv (e.g., Lamzede) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
1. Individual is aged 3 years or older; AND
2. There is a diagnosis of mild to moderate alpha-mannosidosis and documentation of one of the following is provided (Malm 2019):
a. Deficiency in acid alpha-mannosidase enzyme activity (<10% of normal activity) in peripheral blood leukocytes or other nucleated cells such as fibroblasts; OR
b. There is identification off biallelic pathogenic variants in MAN2B1 by molecular gene testing; AND
3. Drug is prescribed for treatment of non-central nervous system disease manifestations (FDA 2023); AND
4. Must be able to ambulate independently; AND
5. Individual does not have either of the following:
a. History of a HSCT or bone marrow transplant; OR
b. Diagnosis of severe alpha-mannosidosis; AND
6. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for 1 year:
 
1. Documentation shows there is clinically significant improvement or stabilization in clinical signs and symptoms of disease (including but not limited to improvement in motor function, improvement in pulmonary function, reduction in serum oligosaccharides) compared to the predicted natural history trajectory of disease; AND
2. Must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dosage for Velmanase alfa-tycv is1mg/kg (actual body weight) intravenously administered once a week.  
 
Velmanase alfa-tycv (e.g., Lamzede) is available as a 10 mg single dose vial.
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Velmanase alfa-tycv (e.g., Lamzede) for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, velmanase alfa-tycv (e.g., Lamzede®) for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective May 10, 2023 to April 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Velmanase alfa-tycv (e.g. Lamzede®) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
1. Individual is aged 3 yrs or older; AND
2. There is a diagnosis of mild to moderate alpha-mannosidosis and documentation of one of the following is provided (Malm 2019):
a. Deficiency in acid alpha-mannosidase enzyme activity (<10% of normal activity) in peripheral blood leukocytes or other nucleated cells such as fibroblasts; OR
b. There is identification off biallelic pathogenic variants in MAN2B1 by molecular gene testing; AND
3. Drug is prescribed for treatment of non-central nervous system disease manifestations (FDA 2023); AND
4. Must be able to ambulate independently; AND
5. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for 1 year:
1. Documentation shows there is clinically significant improvement or stabilization in clinical signs and symptoms of disease (including but not limited to improvement in motor function, improvement in pulmonary function, reduction in serum oligosaccharides) compared to the predicted natural history trajectory of disease; AND
2. Must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing per FDA Guidelines
 
Recommended dosage is:
1mg/kg (actual body weight) intravenously administered once a week.  
 
Velmanase alfa-tycv (e.g., Lamzede®) is available as a 10 mg single dose vial.
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Velmanase alfa-tycv (e.g. Lamzede®) for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including:
1. Individual has a history of a HSCT or bone marrow transplant.
2. Individual cannot walk without support.
3. Individual has a diagnosis of severe alpha-mannosidosis.
 
For members with contracts without primary coverage criteria, velmanase alfa-tycv (e.g. Lamzede®) for any indication or circumstance not described above, including the following, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
1. Individual has a history of a HSCT or bone marrow transplant.
2. Individual cannot walk without support.
3. Individual has a diagnosis of severe alpha-mannosidosis.
Rationale:
Trial 1
Approval of velmanase alfa (VA) was based on results from the Phase 3 rhLAMAN-05 study (also known as Trial 1; NCT01681953), which was a double-blind, randomized, placebo-controlled study that evaluated VA over 52 weeks at a dose of 1 mg/kg given weekly as an IV infusion.  A total of 25 patients were enrolled (14 males, 11 females), including 13 adult patients (age range: ≥18 to 35 years; mean: 25 years) and 12 pediatric patients (age range: ≥6 to <18 years.  All patients had alpha-mannosidase activity below 11% of normal and in the range of 8 to 29 µmol/h/mg at baseline.  Fifteen patients (8 adult and 7 pediatric) received VA and 10 patients (5 adult and 5 pediatric) received placebo. All patients completed the trial.
 
The efficacy results for the clinical endpoints assessed at 12 months, 3-minute stair climbing test (3MSCT), 6-minute walking test (6MWT) and forced vital capacity (FVC) (% predicted), favored the VA group and were supported by a reduction in serum oligosaccharide concentration.
 
The most common adverse reactions reported in Trial 1 (incidence >20%) were nasopharyngitis, pyrexia, headache, and arthralgia. Five serious treatment-emergent adverse events (TEAEs) occurred with VA treatment; however, four of the five serious TEAEs were unrelated to treatment. One case of moderate, acute renal failure considered possibly related to treatment occurred after almost 12 months of treatment in a patient known to be receiving long-term concomitant ibuprofen. VA was temporarily suspended, and the patient recovered after 92 days. The patient restarted active treatment with no safety issues reported. No TEAEs led to discontinuation from the study, and no deaths were reported.
 
Trial 2 (Pediatric Study)
Velmanase alfa (VA) was also evaluated in a second study, rhLAMAN-08 (also known as Trial 2; NCT02998879), a Phase 2 single-arm trial that included five pediatric patients less than 6 years of age with AM. Patients received velmanase alfa 1 mg/kg as IV infusion once weekly (four patients for 24 months, one patient for 40 months).   
 
The patient’s ranged from 3.7 to 5.9 years of age, with a mean age of 4.5 years. After >24 months of treatment, wt, and height increased in all children (n=5). At baseline and end of the study, most of the patient’s growth percentiles were within the standard range for gender and age, except for one patient’s head circumference that was consistent with a history of macrocephaly and hydrocephalus.   
 
Adverse reactions that occurred in at least two of five patients (and are in addition to the adverse reactions already identified in Trial 1) included cough, otitis media, rhinitis, conjunctivitis, fall, ligament sprain, oropharyngeal pain, swelling face, and upper respiratory tract infection.
 
VA’s long-term safety and efficacy in children with AM aged less than 6 years was evaluated as well. The safety and tolerability of VA were considered acceptable in all children who participated in the study. Even though all children experienced AEs, most were mild to moderate, and none (IRRs or ADRs) resulted in discontinuation of the study. Efficacy assessment results suggested that long-term treatment with VA may improve serum oligosaccharide levels, hearing impairment, IgG and IgA serum levels, and QoL. Further, children in the study did not demonstrate a marked decline in functional capacity or endurance/physical functioning over the VA treatment period, though additional studies controlling for age-based development are required. The PK profile of VA between the first dose and steady state was comparable.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2024. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
C9399Unclassified drugs or biologicals
J0217Injection, velmanase alfa tycv, 1 mg
J3590Unclassified biologics
References: Borgwardt L. Guffon N. Amraoui Y, et al(2018) Efficacy and safety of Velmanase alfa in treatment of patients with alpha mannosidosis results from the core and extention phase analysis of phase III multicentre double-blind randomised placebo controlled trial J Inherit Metab Dis 2018;41(6) 1215-1223. doi 10 1007/s 10545-018-0185-0

Guffon N, Konstantopoulou V, Hennermann JB, et al.(2023) Long-term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha mannosidosis: A phase2, open label multicenter study (published online ahead of print 2023 Feb 27) J Inherit Metab Dis 2023;10. 1002/jimd 12602, doi:10. 1002/jimd 12602

IDP Analytics(2023) New Drug Review: Lamzede (velmase alfa-tycv) Published online (subscription required) March 2023

Lamzede (velmanase-alfa-tycv) (package insert) Cary NC: Chiesi USA, Inc 2023

Malm D Nilssen(2001) Alpha-Mannosidosis 2001 Oct 11 (Updated 2019 Jul 18) In:Adam MP, Mirzaa GM, Pagon RA, et al editors GeneReviews (Internet) Seattle (WA); Univ of Washington Seattle; 1993-2023 Available from: https://www.ncbi.nlm.nih.gov/books/NBK1396/ Accessed on: April 23, 2023
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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