Coverage Policy Manual
Policy #: 2021041
Category: Pharmacy
Initiated: November 2021
Last Review: December 2023
  Avalglucosidase alfa-ngpt (e.g., Nexviazyme)
Description:
Avalglucosidase alfa is hydrolytic lysosomal glycogen-specific recombinant human GAA enzyme replacement therapy designed for enhanced M6P-receptor targeting and enzyme uptake aimed at increased glycogen clearance targeting to skeletal muscles. The M6P of avalglucosidase alfa binds to cation-independent mannose-6-phosphate receptor (CI-MPR) on the cell surface with high affinity, which allows drug uptake into cells. Avalglucosidase alfa is internalized and transported into lysosomes to undergo proteolytic cleavage. It then exerts GAA enzymatic activity to cleave glycogen.  
 
Avalglucosidase alfa, or NeoGAA, is a drug for enzyme replacement therapy specifically designed for Pompe disease, a rare autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Clinically, Pompe disease or glycogen storage disease type II (GSDII) presents as a wide spectrum ranging from the severe rapidly progressive infantile-onset form to a more slowly progressive late-onset form. The level of residual activity of the GAA enzyme drives Pompe disease severity and age of symptoms onset. GAA gene sequencing may be used to confirm a diagnosis or when there is      discordant GAA enzyme activity studies (American Association of Neuromuscular and Electrodiagnostic Medicine [AANEM] 2009)
 
The diagnosis of late-onset Pompe disease can be difficult because it can clinically resemble a myriad of other neuromuscular disorders.  By clinical definition, individuals with late-onset Pompe disease present with symptoms at any time after the age of 12 months.  Progressive myopathy is a common feature; muscle weakness is generally more pronounced in proximal muscles of the lower extremities, with lesser involvement of the distal muscles and upper extremities. The distribution of muscle pathology may be asymmetric or symmetric; the trunk, thigh, and pelvic girdle muscles are the groups most likely to be affected, and there may be selective involvement of specific muscle groups (e.g., the paraspinal muscles and hip adductors). In children with late-onset Pompe disease, achievement of motor development milestones is often delayed.
 
Regulatory Status
 
On August 6, 2021, avalglucosidase alfa-ngpt was approved under the market name Nexviazyme to treat individuals one year of age and older with late-onset Pompe disease. Late-onset Pompe disease is associated with a range of debilitating physical symptoms, such as progressive muscle weakness, including respiratory muscle weakness, and loss of motor function.  In clinical trials, avalglucosidase alfa improved lung function in individuals with Pompe disease.
 
Avalglucosidase has black box warnings for severe hypersensitivity reactions including anaphylaxis, infusion-associated reactions, and risk of acute cardiorespiratory failure in susceptible individuals.
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Prior Approval is required for avalglucosidase alfa (e.g., Nexviazyme)
 
The initial use of this drug requires documentation of direct physician (MD/OD) involvement in the ordering and evaluation as well as a signature in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.  
 
Effective December 19, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of avalglucosidase alfa intravenous infusion meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients with late-onset Pompe disease when ALL the following criteria are met:  
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months
 
Late Onset Pompe Disease (ACMG, 2006, FDA label 2021; Hani, 2021)
 
1. Individual is > 1 years of age; AND
2. Individual has a diagnosis of late-onset Pompe disease (LOPD) as evidenced by ONE of the following:
a. Enzyme assay showing a deficiency (< 40% of normal mean) of acid alpha-glucosidase (GAA) activity in the blood, skin, or muscle; AND
b. Genetic testing showing a mutation in the GAA gene (documentation must be submitted); AND
3. Individual has measurable signs of Pompe disease, such as impairment in pulmonary function or motor weakness (when applicable, baseline results documentation of percent predicted forced  vital capacity (FVC) AND 6-MINUTE WALK TEST (6MWT) IS REQUIRED); AND
4. Prescribed by, or in consultation with, a neurologist or specialist in Pompe disease; AND
5. Will not be used:
a. Concomitantly with alglucosidase alfa or cipaglucosidase alfa-atga) or had a previous failure of alglucosidase alfa; OR  
b. In an individual with Pompe specific cardiac hypertrophy; OR
c. In an individual that requires invasive ventilation; OR
d. In an individual that has a percent predicted FVC of < 30% or > 85%; AND
7. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for up to 1 year
 
1. Individual has experienced a positive clinical response to therapy as evidenced by an improvement or stabilization in percent predicted FVC and/or 6-MWT; AND
2. Must be dosed in accordance with FDA labeling; AND
3. Will not be used in combination with other enzyme replacement therapies (e.g., alglucosidase-alfa or cipaglucosidase alfa-atga)
 
Dosing and administration
Dosing per FDA Guidelines
 
See the full prescribing information for dosage modifications (due to hypersensitivity reactions or IARs) and IV infusion volumes.  For individuals weighing:
1. > 30 kg, the recommended dosage is 20 mg/kg (of actual body weight) every two weeks.
2. < 30 kg, the recommended dosage is 40 mg/kg (of actual body weight) every two weeks.    
 
Avalglucosidase alfa-ngpt is available as 100 mg lyophilized powder in a single-dose vial for reconstitution.
 
Please refer to a 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
  
The use of avalglucosidase alfa, 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, the use of avalglucosidase alfa 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 December 2022 to December 18, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of avalglucosidase alfa intravenous infusion to treat patients 1 year and older meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for patients with late-onset Pompe disease and they meet ALL the following criteria:  
 
Initial Approval (6 months) Late onset (ACMG, 2006, FDA label 2021; Hani, 2021)
 
    1. Has a diagnosis of late-onset Pompe disease with clinical manifestations. AND
    2. Member has an absence or deficiency (<40% of normal mean) GAA activity (AANEM 2009), [documentation of a second GAA enzyme activity assay in a separate sample (from purified lymphocytes, fibroblasts, or muscle) or by GAA sequencing when results are indeterminate] OR  
    3. Molecular genetic testing for deletion or mutations in GAA gene (documentation must be submitted) AND
    4. Documentation of baseline percent predicted FVC and 6MWT (In adolescents and adults). AND  
    5. Prescribed by, or in consultation with, a neurologist or specialist in Pompe disease
    6. Will not be used concomitantly with alglucosidase alfa or had a previous failure of alglucosidase alfa.  
 
Continuation of therapy – no more than 12 months
 
    1. Member has experienced a positive clinical response to therapy as evidenced by an improvement or stabilization in percent predicted FVC and/ or 6MWT.
    2. Dosed in accordance with FDA labeling
    3. Will not be used in combination with other enzyme replacement therapies (i.e., alglucosidase-alfa)
 
Dosing and administration
 
See the full prescribing information for dosage modifications (due to hypersensitivity reactions or IARs) and IV infusion volumes.  For patients weighing:
    1. >30 kg, the recommended dosage is 20 mg/kg (of actual body weight) every two weeks.
    2. <30 kg, the recommended dosage is 40 mg/kg (of actual body weight) every two weeks.   
 
Please refer to a 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
  
The use of avalglucosidase alfa does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication or any circumstance other than those outlined above including:
 
    1. The patient has Pompe specific cardiac hypertrophy.
    2. Requires invasive ventilation
    3. Has a percent predicted FVC of <30% or >85%
 
For members with contracts without primary coverage criteria, the use of avalglucosidase alfa (Nexviazyme) for any indication or circumstance other those outlined above are considered investigational including:
 
    1. The patient has Pompe specific cardiac hypertrophy.
    2. Requires invasive ventilation
    3. Has a percent predicted FVC of <30% or >85%
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective November 24, 2021 to November 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of avalglucosidase alfa intravenous infusion to treat patients 1 year and older meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for patients with late-onset Pompe disease and they meet ALL the following criteria:  
 
Initial Approval (6 months) Late onset (ACMG, 2006, FDA label 2021; Hani, 2021)
 
    1. Has a diagnosis of late-onset Pompe disease with clinical manifestations. AND
    2. Member has an absence or deficiency (<40% of normal mean) GAA activity (AANEM 2009), [documentation of a second GAA enzyme activity assay in a separate sample (from purified lymphocytes, fibroblasts, or muscle) or by GAA sequencing when results are indeterminate] OR  
    3. Molecular genetic testing for deletion or mutations in GAA gene (documentation must be submitted) AND
    4. Documentation of baseline percent predicted FVC and 6MWT (In adolescents and adults). AND  
    5. Prescribed by, or in consultation with, a neurologist or specialist in Pompe disease
    6. Will not be used concomitantly with alglucosidase alfa or had a previous failure of alglucosidase alfa.  
 
Continuation of therapy – no more than 12 months
 
    1. Member has experienced a positive clinical response to therapy as evidenced by an improvement or stabilization in percent predicted FVC and/ or 6MWT.
    2. Dosed in accordance with FDA labeling
    3. Will not be used in combination with other enzyme replacement therapies (i.e., alglucosidase-alfa)
 
Dosing and administration
 
See the full prescribing information for dosage modifications (due to hypersensitivity reactions or IARs) and IV infusion volumes.  For patients weighing:
    1. >30 kg, the recommended dosage is 20 mg/kg (of actual body weight) every two weeks.
    2. <30 kg, the recommended dosage is 40 mg/kg (of actual body weight) every two weeks.   
 
Please refer to a 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
  
The use of avalglucosidase alfa does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication or any circumstance other than those outlined above including:
 
    1. The patient has Pompe specific cardiac hypertrophy.
    2. Requires invasive ventilation
    3. Has a percent predicted FVC of <30% or >85%
 
For members with contracts without primary coverage criteria, the use of avalglucosidase alfa (Nexviazyme) for any indication or circumstance other those outlined above are considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
The approval of avalglucosidase alfa (Nexviazyme) was based on the results of the Phase 3 COMET trial (Hani 2021), a 49-week randomized, double-blind, and multinational noninferiority study between avalglucosidase alfa (n=51) and alglucosidase alfa (n=49) in treatment-naïve patients with late-onset Pompe disease (LOPD).
 
The primary endpoint was to determine the effect of avalglucosidase alfa on respiratory muscle function, measured by upright forced vital capacity (FVC) % predicted.  Secondary endpoints included the effect of avalglucosidase alfa on functional endurance, inspiratory and expiratory muscle strength, upper and lower muscle strength, motor function and health related quality of life and safety.  
 
Treatment with avalglucosidase alfa resulted in greater improvements in upright FVC % predicted at all timepoints and a 2.43% greater increase in FEC %predicted compared to alglucosidase alfa at Week 49.  It also resulted in greater improvements in the 6-Minute Walk Test (6MWT) with 30.01-m and 4.71% greater increases, respectively.  The primary study objective, achieving statistical non-inferiority, was met (p=0.0074) and testing for superiority was borderline significant (p=0.0626). Treatment -emergent adverse events (AE) were reported in 86.3% of avalglucosidase alfa-treated and 91.8% of alglucosidase alfa-treated participants.  Serious AEs were reported in 8 avalglucosidase alfa-treated and 12 alglucosidase alfa-treated participants.  High titers and neutralizing antibodies were more prevalent for alglucosidase alfa.  (Hani, 2021)
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
In a phase 3 double-blind randomized clinical trial with crossover in the extension period patients 3 years and older with previously untreated late-onset Pompe disease (LOPD) were enrolled between November 2, 2016, and February 10, 2021, with primary analysis after 49 weeks. Patients were treated at 55 referral centers in 20 countries. Efficacy outcomes were assessed at 97 weeks and safety outcomes to last follow-up, with data cutoff on February 10, 2021. Data were analyzed from May to June 2021.
 
Random assignment (1:1) to receive 20 mg/kg of avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks; thereafter, all patients received 20 mg/kg of avalglucosidase alfa every other week.
The primary outcome was the least squares (LS) mean change from baseline in FVC percent predicted. Secondary outcomes included the LS mean change from baseline in 6MWT, muscle strength, motor function, quality of life, and disease biomarkers. Safety and tolerability were also assessed.
 
Of 100 participants from the double-blind treatment period, 95 entered the extension period. Of these, 51 (54%) were men, and the mean (range) age was 48.3 (10-79) years. At the start of this study, mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) for those who continued avalglucosidase alfa and 0.36 (1.12) for those who switched to avalglucosidase alfa. The LS mean (SE) 6MWT distance increased by 18.60 (12.01) m and 4.56 (12.44) m, respectively. For participants who switched to avalglucosidase alfa, FVC percent predicted remained stable (LS mean [SE] change from week 49 to 97, 0.09 [0.88]) and 6MWT distance improved (LS mean [SE] change from week 49 to 97, 5.33 [10.81] m). Potentially treatment-related adverse events were reported in 29 patients (56.9%) who continued avalglucosidase alfa and in 25 patients (56.8%) who switched.
 
In this randomized clinical trial extension, maintenance of positive clinical outcomes was demonstrated for patients continuing avalglucosidase alfa treatment. (Kishnani, 2023)
CPT/HCPCS:
C9085Injection, avalglucosidase alfa-ngpt, 4 mg
J0219Injection, avalglucosidase alfa-ngpt, 4 mg
References: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).(2021) Pompe. Available at: https://www.aanem.org/Patients/Disorders/Pompe. Accessed on July 19, 2021.

FDA Press Announcements:(2021) FDA Approves New Treatment for Pompe Disease. Last accessed 11/16/2021 https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-pompe-disease

Xu S, Lun Y, Frascella M, Garcia A, Soska R, Nair A, Ponery AS, Schilling A, Feng J, Tuske S, Valle MCD, Martina JA, Ralston E, Gotschall R, Valenzano KJ, Puertollano R, Do HV, Raben N, Khanna R:(2019) Improved efficacy of a next-generation ERT in murine Pompe disease. JCI Insight. 2019 Mar 7;4(5). pii: 125358. doi: 10.1172/jci.insight.125358. eCollection 2019 Mar 7.
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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