FDA Accepts BLA for Avalglucosidase Alfa for Pompe Disease


Evidence from 2 clinical trials were the basis of the biologics license application, with an FDA decision expected to be made by May 18, 2021.

Karin Knobe, MD, PhD

The FDA has accepted the biologics license application (BLA) for avalglucosidase alfa (Sanofi) for long-term enzyme replacement therapy for the treatment of patients with Pompe disease. A prescription drug user fee act (PDUFA) date has been set for May 18, 2021.1

Avalglucosidase alfa has received FDA breakthrough therapy and fast track designations for the treatment of people with Pompe disease. The basis for the BLA originates from positive data from both the phase 3 COMET trial (NCT02782741) and the phase 2 mini-COMET trial (NCT03019406), which showed improvements over standard of care.

The investigational enzyme replacement therapy was designed to improve the delivery of acid alpha-glucosidase (GAA) enzyme to muscle cells, in which patients with Pompe disease are deficient. It has approximately a 15-fold increase in mannose-6-phosphate (M6P) content, compared to standard of care alglucosidase alfa, and aims to help improve cellular enzyme uptake and enhance glycogen clearance in target tissues. Sanofi noted that the M6P receptor plays a key role in the transport of GAA.

"The hallmarks of Pompe disease are the relentless and debilitating deterioration of the muscles, which causes decreased respiratory function and mobility,” Karin Knobe, MD, PhD, head of development for rare diseases and rare blood disorders, Sanofi, said in a statement. “Avalglucosidase alfa is specifically designed to deliver more GAA enzyme into the lysosomes of the muscle cells. We have been greatly encouraged by positive clinical trial results in patients with late-onset and infantile-onset Pompe disease.”

READ MORE: Centralizing Neuromuscular Disease Data With the MDA MOVR Database

Data from the double-blind, global comparator-controlled COMET trial showed that avalglucosidase alfa met the primary end point of the study in demonstrating non-inferiority in improving respiratory function compared to the standard of care with alglucosidase alfa (Lumizyme; Sanofi) in patients with late-onset Pompe disease.2

Those treated with the drug showed a 2.43-point greater improvement (95% CI, –0.13 to 4.99) in percent-predicted forced vital capacity (FVC) compared to the standard of care (P = .0074). 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.

The agent, while achieving statistical significance for the primary end point, did not achieve statistical superiority (= .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 m [SD, 9.93]) than the standard of care group (distance, 2.19 m [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.

Mini-COMET is an ongoing, phase 2, open-label, ascending-dose, 3-cohort study of avalglucosidase alfa in 22 patients under 18 years of age with infantile-onset Pompe disease, who were previously treated with avalglucosidase alfa and showed incomplete treatment response in pre-specified clinical outcomes.3

Presented at the WORLDSymposium in February 2020, results showed that treatment with avalglucosidase alfa was well-tolerated at 20mg/kg and 40mg/kg dose every 2 weeks at the 6-month period. The most common adverse events (AEs) reported were all mild to moderate in nature, including vomiting and pyrexia (6 patients each), upper respiratory tract infections (5 patients), and cough and rash (4 patients each). There were no serious or severe treatment-related AEs, including no AEs that resulted in permanent discontinuation or death.

1. FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease. News release. Sanofi. November 18, 2020. Accessed November 19, 2020. http://www.news.sanofi.us/2020-11-18-FDA-grants-priority-review-for-avalglucosidase-alfa-a-potential-new-therapy-for-Pompe-disease
2. Sanofi’s investigational enzyme replacement therapy shows clinically meaningful improvement in critical manifestations of late-onset Pompe disease. News release. Sanofi. June 16, 2020. Accessed November 19, 2020. https://www.sanofi.com/en/media-room/press-releases/2020/2020-06-16-14-00-00
3. Avalglucosidase alfa showed positive exploratory efficacy and was well-tolerated in phase 2 trials in Pompe disease. News release. February 10, 2020. Accessed November 19, 2020. https://www.sanofigenzyme.com/en/about-us/newsroom/2020/2020-02-10-04-45-00
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