Avalglucosidase Alfa Improves Breathing, Mobility in Late-onset Patients in Phase 3 Trial

Avalglucosidase alfa, an investigational next-generation enzyme replacement therapy (ERT), leads to clinically meaningful improvements in respiratory muscle strength and mobility in children and adults with late-onset Pompe disease (LOPD), according to top-line data from a Phase 3 trial.

The findings will be the foundation for applications that Sanofi Genzyme plans to submit to regulatory authorities worldwide this year, requesting approval of avalglucosidase alfa to treat late-onset Pompe.

Trial findings were presented by Jordi Diaz-Manera, MD, PhD, during a scientific webcast hosted by the company on June 16, after the postponement of the International Congress of Neuromuscular Diseases in Valencia, Spain.

LOPD is caused by mutations in the GAA gene that lower the production of acid alpha-glucosidase (GAA), an enzyme responsible breaking down a sugar molecule called glycogen. Without the enzyme, glycogen accumulates to toxic levels inside cells, impairing certain organs and systems in the body, including the muscles involved in respiration.

ERT is the current standard treatment, providing patients with the enzyme they are missing.

Lumizyme (alglucosidase alfa), sold under the brand name Myozyme in the European Union, is an ERT marketed by Sanofi Genzyme that has been approved in the U.S. to treat patients of all ages and types of Pompe disease.

Avalglucosidase alfa is an experimental ERT derived from Lumizyme, designed to improve the delivery of the artificial GAA enzyme to muscle cells, and enhance glycogen clearance from target tissues.

Preclinical studies have shown that avalglucosidase alfa has a cellular uptake (entry) that is about 15 times higher than Lumizyme. Avalglucosidase alfa’s use also reduced levels of glycogen to the same extent of Lumizyme, when given at a dose five times lower in a mouse model of Pompe disease.

COMET, a multicenter, randomized and double-blind Phase 3 trial (NCT02782741), is assessing if avalglucosidase alfa is better than — or at least not inferior to — Lumizyme in improving respiratory health, functional abilities, muscle strength, and quality of life in previously untreated LOPD patients.

The trial enrolled 100 patients, ages 3 and older, who had never received any form of treatment for their disease at 56 sites across 20 countries.

Participants were randomly assigned to either avalglucosidase alfa or Lumizyme, both administered by intravenous infusions (directly into the bloodstream) every two weeks at a dose of 20 mg/kg.

After completing 49 weeks of treatment, patients being given Lumizyme moved to avalglucosidase alfa for the study’s open-label portion. During this second part of the trial, which will last 240 weeks (over 4.5 years), all are being treated with 20 mg/kg of avalglucosidase alfa every two weeks.

The trial’s main goal was the effect of avalglucosidase alfa on patients’ respiratory muscles — assessed by percent-predicted forced vital capacity (FVC) measured in the upright position — compared to Lumizyme. (FVC measures the total amount of air a patient is able to exhale after a deep breath.)

Secondary goals included assessing the effects of avalglucosidase alfa on mobility, muscle strength (respiratory and lower extremity muscles), muscle function, health-related quality of life, and treatment safety.

Mobility was evaluated with the six-minute walk test (6MWT), which measures the distance a patient is able to walk in that time.

Of the 100 patients enrolled, 51 were treated with avalglucosidase alfa and 49 with Lumizyme. A total of 95 people completed the first 49 weeks of COMET and entered in the study’s second part. Ninety-one are still being treated with avalglucosidase alfa, and four discontinued.

Top-line data showed that the study exceeded its primary goal of respiratory improvements, with avalglucosidase alfa being at least not inferior to Lumizyme. Over the course of the trial’s first part, FVC improvements in patients treated with avalglucosidase alfa were 2.43 points higher than those recorded in Lumizyme-treated patients.

This benefit became apparent early on, around week 13, and was maintained through week 49. However, the extent of this respiratory improvement with avalglucosidase alfa was not statistically significant.

Substantial gains were also seen in mobility, with patients taking avalglucosidase alfa able to walk about 30 meters (about 98 feet) farther in six minutes than those given Lumizyme.

“We’re pleased that avalglucosidase alfa showed clinically meaningful improvements both in respiratory function and mobility, as measured by well-established standard Pompe disease outcome measures,” John Reed, MD, PhD, global head of Research and Development at Sanofi, said in a press release.

“These results underscore our ambition to establish avalglucosidase alfa as a new standard of care treatment for Pompe disease,” Reed added.

No statistically significant differences were observed in inspiratory and expiratory muscle strength between the two groups.

Both treatments improved patients’ lower extremity muscle strength — measured using a hand-held dynamometer — and health-related quality of life, as assessed with the 12-item short form survey. Again, no significant differences were seen between the groups.

Improvements in motor abilities — assessed by the Quick Motor Function Test — seemed to be stronger among patients on avalglucosidase alfa.

The safety profile of avalglucosidase alfa was similar to that of Lumizyme.

Nearly all patients in both groups experienced at least one adverse event during the study. However, fewer patients treated with avalglucosidase alfa had serious adverse events and infusion-associated reactions, indicating that avalglucosidase alfa may be safer than Lumizyme, Diaz-Manera said.

Four patients in the Lumizyme group stopped treatment due to adverse events, and one died after a heart attack deemed unrelated to treatment. No treatment discontinuations or deaths were observed among those on avalglucosidase alfa.

“In front of these results, we can conclude that COMET has shown clinically meaningful improvements with avalglucosidase alfa compared to alglucosidase alfa [Lumizyme],” said Diaz-Manera, who is a professor of Neuromuscular Disorders, Translational Medicine and Genetics at the John Walton Muscular Dystrophy Research Center in Newcastle, U.K.

“The primary objective of noninferiority in pulmonary function was met. … There were [also] consistent positive numerical trends across muscle measures and health-related quality of life [and] a potentially more favorable safety profile [with avalglucosidase alfa] when compared to alglucosidase alfa,” he added.

The presentation also included data from an analysis of 20 patients who switched to avalglucosidase alfa from Lumizyme in the extension portion of the study.

Preliminary findings at week 97 showed that after switching, patients had a 0.15-point improvement in FVC, and walked approximately 23 meters farther.

While calling these preliminary findings promising, Diaz-Manera said more time is needed for the full data to become available, “in order to see the effects of the new drug in patients switching from alglucosidase alfa to avalglucosidase alfa.”

In addition to COMET, an open-label Phase 2 extension study (NCT02032524), called NEO-EXT, is assessing the safety, tolerability, efficacy, and pharmacological properties of avalglucosidase alfa in late-onset Pompe patients.