COMET trial supports avalglucosidase alfa as ‘new standard’ for late-onset Pompe disease

Avalglucosidase alfa provided “substantial improvements in clinically meaningful outcome measures” and a more favorable safety profile for late-onset Pompe disease compared with Lumizyme, according to findings from the phase 3 COMET trial.

Researchers presented results of the phase 3, double-blind COMET trial at the American Academy of Neurology annual meeting, which is being held virtually.

“Patients with late-onset Pompe disease have a variable clinical response to the current FDA-approved treatment known as Lumizyme (alglucosidase alfa, Sanofi Genzyme),” Hani A. Kushlaf, MD, FAAN, FANA, FAANEM, associate professor of neurology and pathology and director of neuromuscular research at the University of Cincinnati, told Healio Neurology. “The disease continues to progress in some patients. Therefore, there is an unmet need for better therapy.”

Kushlaf and colleagues reported results from baseline through week 49 of the COMET trial at the AAN Annual Meeting, which compared avalglucosidase alfa with Lumizyme in previously untreated patients with late-onset Pompe disease. Avalglucosidase alfa is an enzyme replacement therapy specifically indicated to increase M6P-receptor targeting and enzyme uptake, with the goal of increased glycogen clearance and better clinical efficacy vs. Lumizyme, according to the study results.

The impact of avalglucosidase alfa on respiratory muscle function, as measured by upright forced vital capacity (FVC) percentage predicted, served as the primary outcome. Secondary outcomes included avalglucosidase alfa’s impact on functional endurance, inspiratory and expiratory muscle strength, lower and upper extremity muscle strength and motor function, as well as health-related quality of life and safety.

The analysis involved 100 patients, including 51 patients treated with avalglucosidase alfa and 49 patients treated with Lumizyme. Each group comprised more men than women (n = 27 men in the avalglucosidase alfa group; n = 25 in the Lumizyme group). The researchers reported a mean age of 46 years in the avaglucosidase group and 50 years in the Lumizyme group.

Treatment with avalglucosidase alfa led to greater improvements in upright FVC percentage predicted at all timepoints and a 2.43% greater increase in FVC percentage predicted compared with Lumizyme at week 49. The researchers achieved the primary study objective of statistical noninferiority (P = .0074), with borderline significance for testing for superiority (P = .0626). Avalglucosidase alfa treatment led to increased improvements in the 6-Minute Walk Test (meters and percentage predicted), with 30.01-meter and 4.71% greater increases, respectively. Kushlaf and colleagues also observed positive results with avalglucosidase alfa for all secondary and other efficacy endpoints, according to the study results, including positive trends for measures of muscle strength/function and health-related quality of life.

The researchers reported treatment-emergent adverse events in 86.3% of patients treated with avalglucosidase alfa and 91.8% of patients treated with Lumizyme, as well as serious adverse events in eight patients treated with avalglucosidase alfa and 12 patients treated with Lumizyme. In the Lumizyme arm, five participants withdrew from the study, including four due to adverse events. The study results demonstrated similar IgG antidrug antibody responses in both groups, with high titers and neutralizing antibodies more commonly seen with Lumizyme.

According to Kushlaf, “a pleasant point” of the findings was that avalglucosidase demonstrated a better safety profile than Lumizyme.

“Avalglucosidase is undergoing FDA review for approval,” Kushlaf said. “The results of the COMET trial support its approval to become the new standard treatment for late-onset Pompe disease.”