Avalglucosidase Alfa Betters Standard of Care for Late-Onstage Pompe Disease

Investigational recombinant human lysosomal acid α-glucosidase (GAA) enzyme replacement therapy avalglucosidase alfa generated substantial clinical improvements in patients with late-onset Pompe disease (LOPD) versus alglucosidase alfa in new phase 3 findings.

The results, presented in late-breaking sessions during the WORLDSymposium 2021 Virtual meeting this week, indicate the investigative therapy from Sanofi Genzyme may become the new standard treatment for the rare autosomal neuromuscular disorder.

Led by Priya Kishnani, MBBS, of the Division of Medical Genetics, Department of Pediatrics, at Duke University Medical Center, an international team of investigators conducted a 49-week, double-blind, primary analysis of avalglucosidase alfa versus standard-care alglucosidase alfa, dubbed the COMET trial.

The observed therapy from Sanofi Genzyme is specifically designed for enhanced targeting of the M6P receptor, while improving enzyme uptake aimed at increased glycogen clearance.

Pompe disease is characterized by the accumulation of glycogen in lysosomes, resulting in cellular dysfunction, progressive muscle damage, and functional disabilities. LOPD symptoms can occur at any age and, if left untreated, can result in progressive muscle damage which can lead to respiratory support and wheelchair use—and eventually, significant morbidity and mortality risk.

Kishnani and colleagues sought a primary objective of observed efficacy of the investigative therapy on patient respiratory muscle function, as per percent-predicted forced vital capacity (FVC). Key secondary objectives included assessment of avaglucosidase alfa’s effect on functional endurance, inspiratory and expiratory muscle strength, lower and upper extremity muscle strength, motor function, and quality of life. They additionally observed for safety outcomes.

The double-blinded trial population included 100 treatment-naïve patients with LOPD treated with either avalglucosidase alfa (n = 51) or alglucosidase alfa (n = 49). Eligible patients were able to perform repeated FVC measurements of ≥30% and ≤85% (upright) and ambulate 40 meters without stopping and without an ambulation device.

From baseline, investigators observed greater improvements in percent-predicted FVC at all clinical timepoints with avalglucosidase alfa than standard therapy, and a 2.43% overall greater increase in FVC at 49 weeks.

The investigative therapy achieved statistical noninferiority (P = .0074) and tested for borderline significant superiority (P = .0626). Treated patients additionally experienced greater improvements in the 6-Minute Walk Test (6MWT), at both meters (30.01) and percent-predicted FVC (4.71%).

Patients on avalglucosidase alfa achieved all other secondary endpoints. Treatment-emergent adverse events were reported in 86.3% of patients on investigative therapy, versus 91.8% of those on alglucosidase alfa.

Serious adverse events were reported in 8 patients treated with avalglucosidase alfa and 12 patients treated with alglucosidase alfa. All 5 trial participants to withdraw from the trial were in the latter treatment arm—4 being due to adverse events.Kishnani and colleagues concluded the COMET findings provide clinical evidence of improved pulmonary function retention, ambulation, and functional endurance in patients with Pompe disease. Avalglucosidase alfa may be an opportune new standard-of-care for the observed patient population.

“These results demonstrate substantial improvements in clinically meaningful outcome measures as well as a more favorable safety profile in patients with LOPD treated with avalglucosidase alfa compared to alglucosidase alfa,” they wrote.