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A New Enzyme Replacement Therapy for Pompe Disease?

A new treatment for late-onset Pompe disease—avalglucosidase alfa—appears to provide patients with a second treatment option and possibly a better safety profile, researchers reported at the 2021 virtual AAN Annual Meeting.  

“The current trial demonstrated a clinically meaningful improvement in respiratory function, ambulation, and functional endurance in this rare and relentlessly progressive disease," said the lead study author Hani Kushlaf, MD, FAAN, FANA, FAANEM, associate professor of neurology and pathology and director of neuromuscular research at the University of Cincinnati.

“Avalglucosidase alfa is the new effective armor to shield these patients from limitations in mobility and the need for respiratory support," Dr. Kushlaf said.

Patients with Pompe disease have a deficiency of the enzyme that breaks down glycogen—acid alpha-glucosidase. “The deficiency in this enzyme leads to glycogen accumulation in tissues predominantly involving skeletal (limb and respiratory) muscles and the heart," Dr. Kushlaf explained. “The glycogen accumulation leads to tissue damage and the progressive symptoms of the disease."

Both avalglucosidase alfa and alglucosidase alfa are recombinant human enzyme replacement therapies, but avalglucosidase alfa has 15-fold more mannose-6- phosphate residues per molecule than alglucosidase alfa. This increases enzyme uptake in targeted tissues via mannose-6-phosphate receptors, Dr. Kushlaf pointed out. This increased uptake aims at increased glycogen clearance with avalglucosidase alfa in comparison with alglucosidase alfa, he said.

The double-blinded, phase 3 study sponsored by Sanofi Genzyme included 51 patients who were treated with avalglucosidase alfa and 49 patients who were treated with alglucosidase alfa. The participants had been treatment-naïve before entering the trial.

In the late-onset form of Pompe disease, the skeletal and respiratory muscles progressively weaken. Without treatment, the disease leads to wheelchair dependence and a need for respiratory support, increasing both morbidity and mortality.

Dr. Kushlaf reported that treatment with avalglucosidase alfa resulted in greater improvements in upright forced vital capacity (FVC) predicted—a measure of lung function often impaired in Pompe disease—at all timepoints and a 2.43 percent greater increase in FVC predicted compared to alglucosidase alfa at week 49.

The study met its primary objective, achieving statistical non-inferiority (p=0.0074), and testing for superiority was borderline significant (p=0.0626), he said. Dr. Kushlaf also noted that avalglucosidase alfa treatment resulted in greater improvements in the 6-Minute Walk Test. Similarly, positive results for avalglucosidase alfa were seen for all secondary and other efficacy endpoints, he reported.

Treatment-emergent adverse events were reported in 86.3 percent of avalglucosidase alfa-treated and 91.8 percent of alglucosidase alfa-treated participants. Five participants withdrew—four due to adverse events, all in the alglucosidase alfa arm. Eight avalglucosidase alfa-treated patients had serious adverse events, as did 12 alglucosidase alfa-treated participants.

The immunoglobulin G anti-drug antibody responses were similar in both groups, Dr. Kushlaf reported. High titers and neutralizing antibodies were more common for alglucosidase alfa, he noted.

“Avalglucosidase is undergoing regulatory review by the US Food and Drug Administration," Dr. Kushlaf said. “The totality of the results of this study will support its approval and use as the new standard treatment for this rare disease."

In commenting on the study, Anthony P. Geraci, MD, FAAN, director of neuromuscular medicine at Northwell Health's Institute for Neurology and Neurosurgery in Manhasset, NY, said: “The results of this study give hope to patients with late-onset Pompe disease who may not tolerate side effects of alglucosidase alfa. Avalglucosidase alfa may represent the first alternative treatment option with similar efficacy and fewer side effects."

However, Dr. Geraci cautioned that the differences seen in the trial between the two agents were modest.  “Alglucosidase alfa is an FDA-approved enzyme replacement therapy for late-onset Pompe disease and, therefore, the study was designed to demonstrate “non-inferiority" of the newer enzyme, avalglucosidase alfa.

“This is a common clinical trial design in cases where using a placebo would be unethical, but it is important to note that these types of studies can diminish observed treatment effects between the two study arms. 

“Although the authors conclude that their results 'demonstrate substantial improvements in clinically meaningful outcome measures,' this conclusion must be tempered by the modest improvement in the primary outcome of percent predicted value of upright forced vital capacity,'' Dr. Geraci said.​

“These results were statistically significant in proving that avalglucosidase alfa was 'non-inferior,' or in other words, 'at least as good as' alglucosidase alfa currently on the market.  The most significant finding was the safety of avalglucosidase alfa over alglucosidase alfa, as demonstrated by the lower rate of adverse events and the lack of withdrawal from the study due to adverse events in the avalglucosidase alfa study arm versus five withdrawals due to adverse events in the alglucosidase alfa study arm."​

Dr. Kushlaf disclosed relationships with Akcea, Alexion Pharmaceuticals, Argenx, Catalyst Pharmaceuticals, Sanofi Genzyme, and Takeda. Dr. Geraci disclosed no relationships with industry.

Link Up for More Information:

AAN Abstract: Kushlaf H, Attarian S, Borges JL, et al. Efficacy and safety results of the avalglucosidase alfa phase 3 COMET trial in late-onset Pompe disease patients