Investigational Pompe Disease Agent Avalglucosidase Alfa Shows Positive Results in Phase 3


The data, from the phase 3 COMET trial, will be the basis for global regulatory submissions in the second half of 2020, according to manufacturer Sanofi.

Dr Jordi Diaz-Manera

Jordi Diaz-Manera, MD, PhD, professor of neuromuscular disorders, Translational Medicine and Genetics, John Walton Muscular Dystrophy Research Center, Newcastle University

Jordi Diaz-Manera, MD, PhD

Sanofi has announced that its investigational enzyme replacement therapy, avalglucosidase alfa, was associated with clinically meaningful improvements in respiratory impairment and decreased mobility in patients with late-onset Pompe disease. The company noted that these data will be the basis for global regulatory submissions, including to the FDA, in the second half of 2020.1

The data, from the phase 3 COMET trial (NCT02782741), show that avalglucosidase alfa met the primary end point of the study in demonstrating non-inferiority in improving respiratory function compared to standard of care with alglucosidase alfa (Lumizyme; Sanofi). Those treated with avalglucosidase alfa had a 2.43-point greater improvement (95% CI, —0.13 to 4.99) in percent-predicted forced vital capacity (FVC) compared to standard of care (P = .0074).

“Pompe disease can be debilitating as it progressively deteriorates the muscles. It’s important that potential new treatment options offer patients clinically meaningful improvement across multiple measures of respiratory and motor function,” said Jordi Diaz-Manera, MD, PhD, professor of neuromuscular disorders, Translational Medicine and Genetics, John Walton Muscular Dystrophy Research Center, Newcastle University, in a statement. “The findings from the phase 3 trial are very encouraging and add to the growing body of clinical evidence demonstrating the potential of avalglucosidase alfa to offer a new treatment option in addressing the hallmark symptoms of this disease.”

All told, those in the avalglucosidase alfa group reported a percent-predicted FVC of 2.89 (standard deviation [SD], 0.88) compared to the reported 0.46 (SD, 0.93) with the standard of care group.

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The agent, while achieving statistical significance for the primary end point, did not achieve statistical superiority (P = .0626). Due to the hierarchy of the study protocol, Sanofi noted that the formal statistical testing for all secondary end points was not conducted. Although, a key secondary end point measuring mobility was the 6-minute walk test (6MWT), and those treated with avalglucosidase alfa walked 30.01 m farther (95% CI, 1.33—58.69; distance, 32.21 [SD, 9.93]) than the standard of care group (distance, 2.19 [SD, 10.40]).

Also assessed were the percent-predicted Maximum Inspiratory Pressure and Maximum Expiratory Pressure. Those in the avalglucosidase alfa group reported percentages of -0.29 (SD, 3.84) and 2.39 (SD, 4.00), respectively, compared to -2.87 (SD, 4.04) and 5.00 (SD, 4.20) with standard of care. Those totaled differences of 2.58 (95% CI, -8.54 to 13.71) for Maximum Inspiratory Pressure and -2.61 (95% CI, -14.22 to 9.00) for Maximum Expiratory Pressure.

Hand-held dynamometry Composite Score was reported as 260.69 (SD, 46.07) for the study drug group compared to 153.72 (SD, 48.54) with standard of care, for a difference of 106.97 (95% CI, -26.56 to 240.50). Similarly, Quick Motor Function Test Total Scores were 3.98 (SD, 0.63) and 1.89 (SD, 0.69) for the avalglucosidase alfa and standard of care groups, respectively, for a difference of 2.08 (95% CI, 0.22—3.95).

“We’re pleased that avalglucosidase alfa showed clinically meaningful improvement both in respiratory function and mobility, as measured by well-established standard Pompe disease outcome measures,” said John Reed, MD, PhD, Global Head of Research and Development at Sanofi. “These results underscore our ambition to establish avalglucosidase alfa as a new standard of care treatment for Pompe disease.”

Previously, the FDA offered avalglucosidase alfa both breakthrough therapy and fast track designations for the treatment of patients with Pompe disease. The COMET trial included 100 previously untreated pediatric and adult patients with late-onset Pompe at 56 centers in 20 countries. The participants were randomized to receive either 20-mg/kg avalglucosidase alfa (n = 51) or 20-mg/kg alglucosidase alfa (n = 49) intravenous infusion every 2 weeks for a study period of 49 weeks. After that, those receiving standard of care switched to avalglucosidase alfa for still ongoing open-label treatment portion.

A pre-specified preliminary analysis of percent-predicted FVC and 6MWT scores in those who switched at 49 weeks showed that avalglucosidase alfa demonstrated a 0.15-point improvement in FVC (95% CI, -1.95 to 2.25) and a 23.32-meter improvement in 6MWT (95% CI, -3.87 to 50.51). Notably, because of sequential enrollment, the results at the time of data presentation were available at 97 weeks for 20 out of 49 switch patients for percent-predicted FVC, and 21 out of 49 switch patients for 6MWT.


Sanofi’s investigational enzyme replacement therapy shows clinically meaningful improvement in critical manifestations of late-onset Pompe disease. News release. Sanofi. June 16, 2020. June 19, 2020.

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