Continuous Avalglucosidase Alfa Is Safe, Effective for Late-Onset Pompe Disease

Patients with late-onset Pompe disease who are treated with avalglucosidase alfa for up to 97 weeks maintain improvements in pulmonary function, muscle strength, motor function, and health-related quality of life (HRQoL), according to findings from an extension study published in JAMA Neurology.

Individuals with Pompe disease, a rare autosomal-recessive neuromuscular disorder, experience lysosomal glycogen accumulation, which leads to respiratory dysfunction, progressive muscle weakness, and functional disabilities. In patients with Pompe disease, the lysosomal buildup of glycogen is caused by a deficiency in the enzyme acid α-glucosidase, whose function is to break down glycogen in the lysosomes. Among those who present with late-onset Pompe disease, progressive muscle weakness is associated with mobility and respiratory dysfunction, which, in turn, often leads to the need for wheelchair use and respiratory support for many patients.

In the current phase 3, randomized extension of the Comparative Enzyme Replacement Trial With neoGAA Versus rhGAA study (COMET; ClinicalTrials.gov Identifier: NCT02782741), researchers sought to report treatment outcomes after 97 weeks of avalglucosidase alfa treatment in patients with late-onset Pompe disease. All of the participants received treatment between November 2, 2016 and February 10, 2021, at 1 of 55 referral centers located in 20 different countries.

In the initial phase 3, double-blind COMET study, all patients were randomly assigned in a 1:1 ratio to receive intravenous infusions of avalglucosidase alfa 20 mg/kg or alglucosidase alfa, which was administered every other week for 49 weeks. Following this, all participants were treated with avalglucosidase alfa 20 mg/kg every other week.

All efficacy outcomes were evaluated at 97 weeks and safety outcomes were evaluated up to the last follow-up. The data cutoff was February 10, 2021. All of the data were assessed between May and June 2021.

The primary study outcome was least squares (LS) mean change from baseline in forced vital capacity (FVC) percent predicted. Secondary study outcomes were the following:

• LS mean change from baseline in 6-minute walk test (6MWT)
• LS mean change from baseline in muscle strength
• LS mean change from baseline in motor function
• LS mean change from baseline in HRQoL
• LS mean change from baseline in biomarkers of disease

A total of 95 of 100 individuals completed the double-blind treatment period
(49 weeks) and were enrolled in the extension study. Overall, 54% (51 of 95) of the participants were men. The mean patient age was 48.3 years (range, 10-79 years). In all, 91% (86 of 95) of the participants underwent treatment for the entire time — that is, through week 97. Among these individuals, 46 continued treatment with avalglucosidase alfa, whereas 40 switched from alglucosidase alfa to avalglucosidase alfa following week 49.

As of the data cutoff, the mean duration of exposure to avalglucosidase alfa throughout the extension phase was 21.96±9.40 months (range, 1.8-38.7 months) among individuals who continued treatment with avalglucosidase alfa, compared with 21.78±10.26 months (range, 1.8-40.0 months) among those patients who switched to avalglucosidase alfa.

At study initiation, the mean upright percent predicted FVC was similar between the 2 treatment groups, whereas the 6MWT distance was greater among those in the avalglucosidase alfa cohort. Values from baseline to week 97 among those continuing avalglucosidase alfa compared with those switching to avalglucosidase alfa were as follows:

• LS mean FVC percent predicted increased by 2.65±105 vs 0.36±1.12, respectively  
• LS mean 6MWT distance increased by 18.60±12.01 meters vs 4.56±12.44, respectively

In the group of individuals who switched from alglucosidase alfa to avalglucosidase alfa, the following values were reported:

• FVC percent predicted remained stable: LS mean change from week 49 to
  week 97, 0.09±0.88
• 6MWT distance improved: LS mean change from week 49 to week 97,
  5.33±10.81 meters

Potentially treatment-related adverse events (AEs) occurred with similar frequency among those who continued avalglucosidase alfa compared with those who switched to avalglucosidase alfa (56.9% vs 56.8%, respectively). Rates of severe AEs were similar among those who continued avalglucosidase alfa compared with those who switched to avalglucosidase alfa overall (ie, primary analysis plus extension phase combined: 21.6% vs 20.5%, respectively) and during the extension period (17.6% vs 20.5%, respectively).

A key limitation of the present study was that the extension period of COMET had no comparator arm — all of the patients received treatment with avalglucosidase alfa with no direct comparison with long-term alglucosidase alfa.

“Data from the COMET trial support long-term maintenance of positive clinical outcomes for patients receiving avalglucosidase alfa treatment,” the researchers concluded.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.