New preclinical data support the promising role of MZE001, an orally active muscle glycogen synthase 1 (GYS1) inhibitor, in the treatment of Pompe disease (PD). The new findings were presented by Maze Therapeutics at the 18th Annual WORLDSymposium.

“This work demonstrates the potential value of our substrate reduction approach across the Pompe disease spectrum both as combination therapy and as monotherapy. We are excited to continue our efforts with this program as we advance MZE001 toward the clinic,” Sarah Noonberg, MD, PhD, chief medical officer of Maze Therapeutics said.

In vitro studies identified MZE001 as a potent inhibitor of glycogen synthesis in several human and animal models, including in cells from healthy volunteers and patients with PD. Moreover, MZE001 showed a high degree of selectivity for GYS1 over the closely related liver isoform glycogen synthase 2 and other off-target effects.

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Treatment with MZE001 led to reduced tissue glycogen in a canine model. Also, chronic treatment with MZ-101, an MZE001 precursor, reduced the elevated glycogen levels in mice’s skeletal muscles. This was associated with improvements in markers of cellular dysfunction.

Cotreatment with MZ-101 and enzyme replacement therapy (ERT) normalized tissue glycogen and restored its cellular homeostasis. Additional in vitro and in vivo analyses with small molecule inhibitors of GYS1 revealed that, in general, GYS1 inhibition was well tolerated. Treatment of preclinical models with GYS1 inhibitors also demonstrated:

  • A potent and specific inhibition of GYS1
  • A dose dependent inhibition of glycogen synthesis with no effect on glycogen synthesis in the liver
  • A reduced accumulation of glycogen in tissues
  • Lower muscle glycogen and improved cellular markers of muscle pathology
  • Enhanced glycogen reduction in skeletal muscle when combined with standard of care ERT

Genetic reduction of muscle glycogen was well tolerated by individuals in the UK Biobank, indicating that lifelong partial reduction of muscle glycogen levels is well tolerated. No significant impact was observed on health outcomes or other parameters evaluated (including in quantitative measures of cardiac structure or function, exercise capacity, or circulating glucose).

“These data are the first to be presented from a program that has emerged from our proprietary Compass platform, providing validation for our approach focused on translating genetic insights from disease-associated pathways to design and develop novel therapeutics,” Dr. Noonberg said.

MZE001 will now advance into clinical development. Maze Therapeutics plans to initiate a phase 1 clinical trial in the first half of 2022.


Maze Therapeutics presents new preclinical data supporting advancement of MZE001 as a potential treatment for Pompe disease. News release. Maze Therapeutics; February 10, 2022.