Pompe disease is a rare genetic disorder of glycogen metabolism that is caused by the absence or marked deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). This disease is also known as glycogen storage disease type II, GSD II, glycogenosis type II, or acid maltase deficiency. GAA is necessary for proper muscle functioning and is used by the heart and muscle cells to convert a form of sugar called glycogen into energy. Without the GAA enzyme action, glycogen builds up in the cells of the heart, skeletal muscles, and hepatic tissues. Ultimately, these body organs are weakened by the intralysosomal accumulation of glycogen. Pompe disease encompasses a range of phenotypes, each including myopathy, but with significant variability in the age of onset, organ involvement, and clinical severity.
Infantile-onset Pompe disease occurs in an estimated one in every 40,000 to 300,000 births. Symptoms begin in the first months of life, with feeding problems, poor weight gain, muscle weakness, floppiness, and head lag. The primary symptom is heart and skeletal muscle weakness, which leads to the development of cardiomyopathy, progressing respiratory weakness, and death, usually from respiratory failure. Younger individuals generally have a much more aggressive form of the disease.
Juvenile/adult-onset Pompe disease results in intralysosomal accumulation of glycogen that is limited primarily to skeletal muscle, resulting in progressive muscle weakness. The onset can be as early as the first decade of childhood or as late as the sixth decade of adulthood. The primary symptom is muscle weakness progressing to respiratory weakness and death from respiratory failure over several years. The heart is usually spared.
Enzyme replacement therapy has been shown to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen accumulation. Enzyme replacement therapy is currently not recommended for individuals with no symptoms or objective signs (proximal muscle weakness or reduced forced vital capacity [FVC] in either upright or supine position) of Pompe disease.
Alglucosidase alfa (Lumizyme®) is US Food and Drug Administration (FDA)-approved for individuals with Pompe disease (GAA deficiency). The safety and efficacy was assessed in 57 treatment-naïve individuals with infantile-onset Pompe disease, aged 0.2 months to 3.5 years at first infusion, in three separate clinical trials. In all three trials, ventilator-free survival improved significantly compared with an untreated historical control. The safety and efficacy of alglucosidase alfa (Lumizyme®) were also assessed in 90 individuals with juvenile/adult-onset Pompe disease in a randomized, double-blinded, placebo-controlled trial. Alglucosidase alfa (Lumizyme®) was shown to have a significant increase in FVC and the distance an individual with juvenile/adult-onset Pompe disease can walk within 6 minutes (6- minute walk test).
Avalglucosidase alfa-ngpt (Nexviazyme®) is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme that is FDA approved for individuals with mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome).
The safety analysis was pooled from four clinical trials (mean exposure of 26 months, up to 85 months of treatment) and included 141 avalglucosidase alfa-ngpt (Nexviazyme®)-treated individuals (118 adult and 23 pediatric individuals). Serious adverse reactions reported in two or more individuals treated with avalglucosidase alfa-ngpt (Nexviazyme®) were respiratory distress, chills, and pyrexia. Serious adverse events were similar across both adult and pediatric populations. Five avalglucosidase alfa-ngpt (Nexviazyme®)–treated individuals in clinical trials permanently discontinued the medication due to adverse reactions, including two individuals who discontinued the treatment because of a serious adverse reaction. The most frequently reported adverse reactions (>5%) in the pooled safety population were headache, diarrhea, nausea, fatigue, arthralgia, myalgia, dizziness, rash, vomiting, pyrexia, abdominal pain, pruritus, erythema, abdominal pain upper, chills, cough, urticaria, dyspnea, hypertension, and hypotension.
The safety and efficacy of cipaglucosidase alfa-atga (Pombiliti) was investigated in randomized, double-blind PROPEL study (ATB200-03; NCT03729362) that compared investigational enzyme-replacement therapy (ERT) cipaglucosidase alfa+miglustat (cipa+mig) with
alglucosidase alfa+placebo (alg) in adult individuals with late-onset Pompe disease
(LOPD). ERT-experienced individuals that remained on alg (n=30) showed
worsening or stability. Individuals who switched to cipa+mig (n=65) showed improvement or
stability. Individuals who remained on alg demonstrated statistically significant
within-group worsening for sitting and supine forced vital capacity, slow vital
capacity, maximal expiratory pressure, and creatine kinase (CK) and hexose
tetrasaccharide (Hex4) levels, and no significant improvements for any
outcomes. Individuals who switched to cipa+mig did not demonstrate significant
within-group worsening for any outcomes and showed significant improvements for
6-minute walk distance (absolute and % predicted); upper, lower, and overall
manual muscle test; PROMIS fatigue; physician and subject global impression of
change (five of eight subdomains); and CK and Hex4 levels.
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
