Avalglucosidase Alfa, Next-gen ERT for Pompe, Under FDA Priority Review

Sanofi Genzyme‘s application requesting the approval of avalglucosidase alfa, an investigational enzyme replacement therapy (ERT) for Pompe disease, was accepted and place under priority review by the U.S. Food and Drug Administration (FDA).

An agency decision on this next-generation ERT is expected on May 18, 2021, Sanofi reported in a press release.

This announcement came around a month after the European Medicines Agency (EMA) said it had accepted to review a similar request for avalglucosidase alfa’s approval as a long-term treatment for Pompe patients in Europe. Its decision is expected next year.

Lumizyme (alglucosidase alfa), also developed by Sanofi Genzyme, is the only currently approved ERT for Pompe in the U.S. and Europe. Sold under the brand name Myozyme in Europe, Lumizyme works by providing patients with a man-made version of the acid alpha-glucosidase (GAA) enzyme they are missing, which is needed to prevent the sugar molecule glycogen from building to toxic levels inside muscle cells.

Avalglucosidase alfa is an investigational, next-generation ERT intended to enhance glycogen clearance from target tissues. If approved, it might become the new standard treatment for patients.

“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,” said Karin Knobe, head of development for rare diseases and rare blood disorders at Sanofi.

Applications filed in the U.S. and Europe were supported by positive data from two clinical trials: the Phase 3 COMET (NCT02782741) and the Phase 2 mini-COMET (NCT03019406) studies.

COMET, a multicenter and double-blind trial, is comparing avalglucosidase alfa to Lumizyme at improving respiratory health, functional abilities, muscle strength, and quality of life in 100 patients with late-onset Pompe disease, ages 3 and older.

Participants had never taken any form of treatment for their condition. Following enrollment, patients were randomly assigned to  intravenous (into the vein) infusions of either Lumizyme or avalglucosidase alfa, both at a dose of 20 mg/kg given every two weeks, for about one year (49 weeks).

After completing this initial treatment period, patients were invited to enroll in the study’s open-label portion, where all are being treated with avalglucosidase alfa for more than 4.5 years (240 weeks).

Top-line data from COMET showed that treatment with avalglucosidase alfa led to meaningful improvements in respiratory muscle function and mobility, indicating that the potential therapy was at least not inferior to Lumizyme.

Both treatments led to similar improvements in patients’ lower extremity muscle strength and quality of life, and were equally safe and well tolerated.

Preliminary data from 20 patients who switched from Lumizyme to avalglucosidase alfa in the open-label part of the trial showed improved lung function and mobility, suggesting that avalglucosidase alfa may potentially be superior to Lumizyme.

This trial is expected to conclude by September 2024.

Mini-COMET is a three-year study evaluating the safety and preliminary effectiveness of avalglucosidase alfa in 22 children and adolescents with infantile-onset Pompe disease, who failed to respond adequately to Lumizyme.

Patients were randomly assigned to one of two doses (20 or 40 mg/kg) of avalglucosidase alfa, given every other week, or their current stable dose of Lumizyme.

Six-month data from mini-COMET showed that both doses of avalglucosidase alfa were well tolerated, with no severe side effects.

In addition, early study data indicated that children treated with avalglucosidase alfa had lower or stable levels of the disease biomarkers creatine kinase and hexose (or glucose) tetrasaccharide.

Mini-COMET is due to be finish by December 2024.

Avalglucosidase alfa has been given both breakthrough therapy and fast track status in the U.S. to support and speed its development.