Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Cipaglucosidase alfa-atga (e.g., Pombiliti)

Description:

Pompe disease (also known as glycogen storage disease type II, acid maltase deficiency, and

glycogenosis type II) is an inherited disorder of glycogen metabolism caused by a deficiency of

lysosomal acid alpha-glucosidase (GAA) that degrades glycogen to glucose in the lysosome.

GAA deficiency results in intra-lysosomal accumulation of glycogen in various tissues.

Cipaglucosidase alfa-atga provides an exogenous source of GAA. The bis-M6P on

cipaglucosidase alfa-atga mediates binding to M6P receptors on the cell surface with high

affinity. After binding, it is internalized and transported into lysosomes where it undergoes

proteolytic cleavage and N-glycans trimming which are both required to yield the most mature

and active form of GAA. Cipaglucosidase alfa-atga then exerts enzymatic activity in cleaving

glycogen.

Miglustat binds with, stabilizes, and reduces inactivation of cipaglucosidase alfa-atga in the

blood after infusion.

Regulatory Status

On September 28, 2023, the Food and Drug Administration approved Cipaglucosidase alfa-atga (e.g., Pombiliti) for the treatment of adult individuals with late-onset Pompe disease weighing > 40 kg and who are not improving on their current enzyme replacement therapy. Cipaglucosidase alfa-atga (e.g., Pombiliti), an intravenous enzyme replacement therapy (ERT), and Miglustat (e.g., Opfolda), an oral enzyme stabilizer, are approved for use in combination only.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Prior Approval is required for Cipaglucosidase alfa-atga (e.g., Pombiliti).

The initial use of this drug requires documentation of direct physician involvement (MD/DO) 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.

Approval timeframes may differ for members/participants of Self-Insured plans.

Effective December 19, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 12 months

Late Onset Pompe Disease (FDA, 2023)

Cipaglucosidase alfa-atga 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 > 18 years of age; AND

2. Individual weighs > 40 kg; AND

3. 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

4. Individual has measurable signs of Pompe disease, such as impairment in pulmonary function or progressive proximal motor weakness; AND

5. Individual has a sitting forced vital capacity (FVC) > 30% of the predicted value for healthy adults; AND

6. Individual has a 6-minute walk test (6MWT) > 75 meters; AND

7. Individual is not improving on current ERT (e.g., avalglucosidase alfa-ngpt or alglucosidase alfa) (FDA, 2023); AND

8. Prescribed by, or in consultation with, a neurologist or specialist in Pompe disease; AND

9. Cipaglucosidase alfa-atga will be used in combination with Miglustat (e.g., Opfolda); AND

10. Will not be used in the following circumstances:

a. Concomitantly with another ERT for Pompe disease (e.g., avalglucosidase alfa-ngpt or alglucosidase alfa); AND

b. Individual requires invasive ventilation; AND

11. 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 the FDA label; AND

3. Will not be used in combination with other ERTs (e.g., avalglucosidase alfa-ngpt or alglucosidase alfa).

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose of Cipaglucosidase alfa-atga is 20 mg/kg (of actual body weight) administered every other week as an intravenous infusion over approximately 4 hours.

Start Cipaglucosidase alfa-atga in combination with Miglustat (e.g., Opfolda) 2 weeks after the last ERT dose.

Initiate the Cipaglucosidase alfa-atga infusion approximately 1 hour after oral administration of Miglustat. If the Cipaglucosidase alfa-atga infusion cannot be started within 3 hours of oral administration of Miglustat, reschedule Cipaglucosidase alfa-atga in combination with Miglustat at least 24 hours after Miglustat was last taken. If Cipaglucosidase alfa-atga in combination with Miglustat are both missed, re-start treatment as soon as possible.

See FDA label for full prescribing information for administration instructions.

Cipaglucosidase alfa-atga is available as a 105 mg lyophilized powder in a single-dose vial for reconstitution.

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

Cipaglucosidase alfa-atga, 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, Cipaglucosidase alfa-atga, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Pompe disease is a rare disorder characterized by progressive loss of muscle and respiratory function due to acid α-glucosidase deficiency. Enzyme replacement therapy with recombinant human acid α-glucosidase, alglucosidase alfa, is the first approved treatment for the disease, but some patients do not respond, and many do not show a sustained benefit. The safety and efficacy of an investigational two-component therapy (cipaglucosidase alfa, a novel recombinant human acid α-glucosidase, plus miglustat, an enzyme stabilizer) for late-onset Pompe disease was assessed.

A randomized, double-blind, parallel-group, phase 3 trial was conducted at 62 neuromuscular and metabolic medical centers in 24 countries in the Americas, Asia-Pacific, and Europe. Eligible participants were aged 18 years or older with late-onset Pompe disease and had either been receiving alglucosidase alfa for at least 2 years or were enzyme replacement therapy-naive. Participants were randomly assigned (2:1) using interactive response technology software, stratified by 6-min walk distance and previous enzyme replacement therapy status, to intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or to intravenous alglucosidase alfa (20 mg/kg) plus oral placebo once every 2 weeks for 52 weeks. Patients, investigators, and outcome assessors were masked to treatment assignment. The primary endpoint was change from baseline to week 52 in 6-min walk distance, assessed using a mixed-effect model for repeated measures analysis for comparison of superiority in the intention-to-treat population (all patients who received at least one dose of study drug). This study is now complete and is registered with ClinicalTrials.gov, NCT03729362.

Between Dec 3, 2018, and Nov 26, 2019, 130 patients were screened for eligibility and 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20·8 m (SE 4·6) in the cipaglucosidase alfa plus miglustat group versus 7·2 m (6·6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13·6 m [95% CI -2·8 to 29·9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths.

Cipaglucosidase alfa plus miglustat did not achieve statistical superiority in the primary outcome measure to alglucosidase alfa plus placebo for improving 6-min walk distance in the overall population of patients with late-onset Pompe disease; however, a statistically significant difference was found in a secondary outcome measure of percent predicted forced vital capacity. Pre-specified analyses showed patients who were previously treated with an ERT and switched to cipaglucosidase alfa plus miglustat achieved superior results compared with patients who were ERT-naïve.

2024 Update

A phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD. (Schoser B, Kishnani PS, Bratkovic D, et.al., 2024)

CPT/HCPCS:

References:

American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).(2023) Pompe. Available at: https://www.aanem.org/Patients/Disorders/Pompe. Accessed on November 30, 2023.

American College of Medical Genetics (ACMG) Work Group on Management of Pompe Disease.(2006) Pompe disease diagnosis and management guideline. Genetics in Med. 2006; 8(5):267-288.

Pombiliti [package insert]. Philadelphia, PA: Amicus Therapeutics US, LLC; 2023

Schoser B, Kishnani PS, Bratkovic D, Byrne BJ, al.etc.(2024) 104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study. J Neurol. 2024 May;271(5):2810-2823. doi: 10.1007/s00415-024-12236-0. Epub 2024 Feb 28. PMID: 38418563; PMCID: PMC11055775.

Schoser B, Roberts M, Byrne BJ, Sitaraman S, Jiang H, Laforêt P, Toscano A, Castelli J, Díaz-Manera J, Goldman M, van der Ploeg AT, Bratkovic D, Kuchipudi S, Mozaffar T, Kishnani PS; PROPEL Study Group.(2021) Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial. Lancet Neurol. 2021 Dec;20(12):1027-1037. doi: 10.1016/S1474-4422(21)00331-8. Erratum in: Lancet Neurol. 2023 Oct;22(10):e11. PMID: 34800400.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.