Pompe disease treatment MZE001 shows promise in Phase 1 trial

Oral therapy well tolerated, lowered glycogen in healthy volunteers

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Single and multiple ascending doses of MZE001, Maze Therapeutics‘ experimental oral substrate reduction treatment for Pompe disease, were well tolerated and reduced glycogen levels in healthy volunteers in a Phase 1 trial, data show.

These findings support a Phase 2 trial of MZE001 in people with Pompe disease, scheduled for this year, according to Jason Coloma, PhD, CEO at Maze.

“MZE001 has the potential to be the first oral therapy for Pompe disease and is intended to be used as a monotherapy option and in combination with the current standard of care to potentially treat all patients with Pompe disease,” Coloma said in a company press release.

The trial findings were presented at the recent 19th Annual WORLDSymposium, by Julie C. Ullman, PhD, Maze’s associate director of translational sciences. Her presentation was titled, “Results from a first in human study of MZE001, an orally bioavailable inhibitor of glycogen synthase 1 and potential substrate reduction therapy for Pompe disease.”

“We are committed to the efficient execution of this program so that we may reach patients in need as soon as possible and are finalizing plans to initiate our Phase 2 clinical program in patients in 2023,” Coloma said.

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Pompe disease is caused by a deficiency of acid alpha-glucosidase (GAA) — an enzyme that breaks down a large sugar molecule called glycogen — due to mutations in the GAA gene.

This results in the toxic accumulation of glycogen levels inside cells, with muscle cells — which normally store glycogen as an energy source — most heavily affected. Enzyme replacement therapy, which provides a lab-made GAA enzyme, is the current standard approach for treating people with Pompe disease.

“While enzyme replacement therapy has brought significant benefit to patients, glycogen accumulation in muscle continues to allow the disease to progress, specifically impacting ambulation [walking ability] and respiratory function,” said Harold Bernstein, MD, PhD, president of research and development and chief medical officer at Maze.

MZE001 works as a substrate reduction therapy, lowering glycogen levels inside muscle cells by blocking the activity of glycogen synthase (GYS1), the enzyme responsible for producing glycogen in muscle cells.

Targeting GYS1 has been challenging, given its complex structure and the uncertainty regarding the tolerability of reducing muscle glycogen levels in the long term, according to Maze.

Overcoming such challenges was made possible with Compass, the company’s proprietary platform, that combines human genetics with genomic tools and data science technology to characterize links between genes and their influence on disease susceptibility, timing of onset and rate of progression.

The Phase 1 trial (NCT05249621), completed in December 2022, randomly assigned 112 healthy adults to single or multiple doses of MZE001, or a placebo, administered in fed and fasted states.

Its aims were to assess the therapy’s safety, tolerability, pharmacological profile, and the impact of food.

MZE001 was well tolerated in single doses up to 480 mg, and in multiple doses up to 720 mg given twice daily. As for adverse events, there were 27 in all — 25 were mild and two were moderate. Five adverse events were related to MZE001, but four of them were ultimately deemed the result of a lab error. No significant food effect was found.

MZE001 has the potential to be the first oral therapy for Pompe disease and is intended to be used as a monotherapy option and in combination with the current standard of care to potentially treat all patients with Pompe disease.

Glycogen levels were reduced in a dose-dependent manner in the 10 days after dosing, confirming binding to GYS1. In this study, glycogen levels were assessed using a new biomarker — peripheral blood mononuclear cell glycogen. However, levels of hex4, a biomarker of glycogen storage, were not changed with MZE001.

“We are highly encouraged by the clinical data for MZE001, which showcases its ability to potently and selectively inhibit GYS1, the enzyme that controls glycogen production, a key driver of Pompe disease,” Bernstein said.