First Healthy Volunteers Dosed in Trial of Oral Therapy MZE001

The first healthy volunteers have been dosed in a Phase 1 clinical trial evaluating MZE001, Maze Therapeutics’ experimental oral therapy for Pompe disease.

“The initiation of this study is a significant milestone for both Maze and the Pompe community as we advance into the clinic with a potentially disease-modifying treatment for patients,” Sarah Noonberg, MD, PhD, Maze’s chief medical officer, said in a press release.

Pompe disease is caused by low to no levels of working acid alpha-glucosidase (GAA) — an enzyme that breaks down a large sugar molecule called glycogen — resulting in glycogen’s toxic buildup in several tissues, most often muscle.

Enzyme replacement therapy (ERT), the mainstay treatment for Pompe, works by delivering a lab-made version of the missing GAA enzyme to patients. While this approach has been lifesaving, some patients still show disease progression, namely weakness in the muscles involved in voluntary movement and breathing.

Maze’s lead candidate MZE001 is being developed as a potential substrate reduction therapy for people with late-onset Pompe, which is by characterized by progressive muscle weakness and respiratory insufficiency.

It is an orally available small molecule that suppresses the activity of muscle glycogen synthase (GYS1), the enzyme that makes glycogen in muscle cells. As such, the therapy is expected to lower glycogen production in muscle cells, preventing its toxic accumulation and ultimately slowing Pompe’s progression.

MZE001 was developed with Maze’s proprietary Compass platform, which combines human genetic data, genomic tools, and data science technology to identify therapeutic targets that influence a disease’s susceptibility, timing of onset, and/or rate of progression.

The company believes that, with this platform, it has overcome traditional challenges in targeting GYS1, including its structural complexity and the uncertain tolerability of a long-term reduction in muscle glycogen levels.

Preclinical studies showed that MZE001 is a potent GYS1 blocker and effectively lowers glycogen accumulation through a substrate reduction approach. These data were shared earlier this month in two oral presentations and two posters at the 2022 annual WORLDSymposium.

The therapy was shown to potently and specifically suppress GYS1 in lab-grown cells from healthy volunteers and Pompe disease patients, as well as in mouse and canine models of the disease.

MZE001 did not affect glycogen production in the liver, where it is dependent on a closely related form of GYS1 called glycogen synthase 2.

In animal models, the therapy also reduced glycogen accumulation — as measured directly in tissues and by the levels of circulating biomarkers — and Pompe-associated muscle damage markers. These effects were deepened when MZE001 was combined with ERT, normalizing glycogen levels in tissues and restoring cellular health.

The therapy was generally well-tolerated across the studies, with no signs of toxicity related to GYS1 suppression or potential effects on other molecules.

In addition, analyses of UK Biobank’s participants with lower-than-normal muscle glycogen levels due to genetic mutations suggested that lifelong partial reduction in muscle glycogen is well tolerated. No significant negative effects were observed on evaluated health outcomes and on heart structure and function, exercise capacity, or glucose (sugar) levels in the blood.

“This work demonstrates the potential value of our substrate reduction approach across the Pompe disease spectrum both as combination therapy and as monotherapy,” Noonberg said in a separate press release announcing the preclinical data presentation.

These promising results supported the launch of the first-in-human Phase 1 trial (NCT05249621) of MZE001. The study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of single and multiple ascending doses of the therapy against a placebo in up to 80 healthy adult volunteers.

Pharmacokinetics refers to the therapy’s movement into, through, and out of the body. Pharmacodynamics comprises its effects on the body, which in this study will include assessments of target biomarkers to provide dose-dependent proof-of-mechanism data.

Participants are being recruited at Orange County Research Center, in California, and the trial is expected to be completed at the end of December.

The Phase 1 trial launch was supported by $190 million in financing raised by Maze in the beginning of the year. Proceeds also will be used to advance some of the company’s other programs, including potential therapies for chronic kidney disease and amyotrophic lateral sclerosis, and to expand the Compass platform.

“This rapid transition to a clinical-stage company represents the dedication by our team and underscores the broad potential of our Compass platform to accelerate the drug discovery and development process,” Noonberg said. “This study brings us a step closer in our mission to harness the power of genetic insights and translate them into precision medicines for patients with serious diseases.”