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, patients 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 patients 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 patients 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 patients.  

Policy
Initial criteria 

1. Diagnosis of late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) as confirmed by one of the following:
   1. Absence or deficiency (less than 40% of the lab specific normal mean) of GAA enzyme activity in lymphocytes, fibroblasts, or muscle tissues as confirmed by an enzymatic assay
   2. Molecular genetic testing confirms mutations in the GAA gene
2. Member is 1 year of age or older
3. Presence of clinical signs and symptoms of the disease (e.g., respiratory distress, skeletal muscle weakness, cardiac hypertrophy, etc.)
4. Trial and failure, contraindication, or intolerance to Lumizyme

Auth duration: Six months

Reauthorization criteria

1. Documentation of positive clinical response to therapy as demonstrated by improvement or slowing of disease progression for one of the following: muscle strength, motor function, walking capacity, respiratory function or cardiac function

Auth duration: 12 months

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).

References

1. American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).(2021) Pompe. Available at: https://www.aanem.org/Patients/Disorders/Pompe. Accessed on July 19, 2021.
2. American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).(2021) Pompe. Available at: https://www.aanem.org/Patients/Disorders/Pompe. Accessed on July 19, 2021.
3. 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
4. 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
5. 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.
6. 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.

Coding Section

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