The Potential of Avalglucosidase Alfa in Late-Onset Pompe Disease Treatment


With promising data presented at WORLDSymposium 2021 and a PDUFA date looming in May, investigator Priya S. Kishnani, MD, offered her insight on Sanofi’s investigational therapy.

Priya S. Kishnani, MD, C.L. and Su Chen Professor of Pediatrics; medical director, YT and Alice Chen Pediatrics Genetics and Genomics Center; and division chief, Medical Genetics, Duke University Medical Center

Priya S. Kishnani, MD

Recently, data from the phase 3 COMET trial (NCT02782741) were presented at WORLDSymposium 2021, suggesting that Sanofi’s investigational agent avalglucosidase alfa may hold clinically meaningful promise in treating patients with late-onset Pompe disease (LOPD).1

The study compared the enzyme replacement agent with another of Sanofi’s products, alglucosidase alfa (Lumizyme), and met the primary end point of noninferiority in respiratory function, as measured by forced vital capacity percent predicted (FVC%P), with a substantial improvement from baseline out to week 49 of 2.43%. The study was conducted by Priya S. Kishnani, MD, C.L. and Su Chen Professor of Pediatrics; medical director, YT and Alice Chen Pediatrics Genetics and Genomics Center; and division chief, Medical Genetics, Duke University Medical Center, and colleagues.

In November 2020, the FDA accepted a biologics license application (BLA) for avalglucosidase alfa for long-term enzyme replacement therapy in the treatment of patients with Pompe disease. A prescription drug user fee act (PDUFA) date has been set for May 18, 2021.2 With that in mind, to find out more about the study data that were presented and what the clinical community can learn from them, NeurologyLive inquired with Kishnani, who offered her insight on the potential of the therapy.

NeurologyLive: What should the clinical LOPD community take away from the COMET and mini-COMET data? How do they add to what you’ve already learned?

Priya S. Kishnani, MD: The data presented at WORLDSymposium 2021 strengthens the growing body of clinical evidence supporting the use of avalglucosidase alfa to treat LOPD and infantile-onset Pompe disease. Data on avalglucosidase alfa from the COMET study show that the study was a success and met its primary endpoint. The data shows clinically meaningful improvements in respiratory muscle function, mobility, muscle strength and function, and disease-specific biomarkers (urine Hex4), in patients with LOPD, translating into improved health-related quality of life in both adult and pediatric patients. We also see the sustained benefit of treatment with avalglucosidase alfa in patients with LOPD who have participated in the NEO-EXT study for up to 6 years. Data on participant-level analyses from the Mini-COMET study confirmed previous group-level results, showing that avalglucosidase alfa has the ability to improve or better stabilize symptoms of IOPD compared to alglucosidase alfa, with additional benefits from the higher 40 mg/kg dose of avalglucosidase alfa. Avalglucosidase alfa was also shown to improve ptosis in long-term IOPD survivors who have been treated with alglucosidase alfa.

What is your opinion on the safety profile?

The safety profile of avalglucosidase alfa has been found to be potentially more favorable than alglucosidase alfa. In COMET, over the double-blinded 49-week period, fewer participants treated with avalglucosidase alfa experienced treatment-related adverse events, serious adverse events, and infusion associated reactions compared to those treated with alglucosidase alfa. Fewer patients receiving avalglucosidase alfa in the COMET study had high sustained antibody titers and neutralizing antibodies compared to alglucosidase alfa.

Did any of these data reveal any other unique or particularly interesting information about the agent?

Avalglucosidase alfa was designed to target the key pathway to transport GAA enzyme into the lysosomes within the cell, through the mannose-6-phosphate (M6P) receptor. Avalglucosidase alfa has an approximately 15-fold increase in M6P content compared to alglucosidase alfa (standard of care), aiming to increase cellular enzyme uptake and enhance glycogen clearance in certain muscle cells.

With its PDUFA date upcoming and approval being a potential outcome, what impact do you believe avalglucosidase alfa could have on the treatment of LOPD?

If approved, avalglucosidase alfa would represent a potential new standard of care for people living with Pompe disease and would serve as a meaningful clinical advancement for the Pompe community. The COMET head-to-head phase 3 trial was designed to evaluate the effect of investigational avalglucosidase alfa on LOPD manifestations compared to the current standard of care. These manifestations include impaired respiratory muscle function and reduced mobility, which are hallmark manifestations of this progressive and debilitating rare disease. The trial primary and secondary endpoints were specifically selected to investigate the most prominent clinical features of LOPD. While there is one treatment currently approved for Pompe disease, muscle damage can be progressive, and even patients currently on the standard of care therapy may progress and experience a decline in muscle function over time.

Transcript edited for clarity.

1. Krishnani P, Attarian S, Borges JL, et al. Efficacy and Safety Results of the Avalglucosidase alfa Phase 3 COMET Trial. Presented at: WorldSymposium. February 12, 2021. Poster 121.
2. FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease. News release. Sanofi. November 18, 2020. Accessed February 12, 2021.
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