advancing R&D in common disease

AKD is a life threatening, genetically driven form of CKD. People who have high-risk coding variants in both copies of the APOL1 gene have a heightened risk of developing CKD. Patients who develop AKD have one or both of the two high-risk variants of the APOL1 gene, G1 and G2, in both copies of their APOL1 gene, which can lead to kidney injury and interference with the kidney’s ability to filter harmful substances from the blood.

The high-risk APOL1 gene variants are most prevalent in people of West African ancestry, including many who identify as Black, African American, Afro-Caribbean and Latina/Latino. These high-risk APOL1 gene variants likely evolved to protect individuals from Human African trypanosomiasis, or HAT, which causes sleeping sickness. HAT is endemic in sub-Saharan Africa and caused by protozoan parasites transmitted by infected tsetse fly bites. Without treatment, HAT is usually fatal.

In the United States, approximately six million, or 13%, of African Americans have mutations of both copies of the high-risk APOL1 gene variants, and are at risk for developing AKD. It is currently estimated that approximately 20%, or over one million, of those individuals have AKD.

Our most advanced lead program, MZE829, is an oral, small molecule inhibitor of APOL1, for the treatment of patients with AKD. Although the link between APOL1 variants and renal dysfunction has been known for over a decade, we have identified a new protective variant that underpins our therapeutic approach for MZE829 and may ultimately allow us to address a broader population of AKD than has previously been possible in the clinical setting. In October 2024, we reported results for our Phase 1 clinical trial of MZE829. We initiated a Phase 2 trial of MZE829 in November 2024 and expect to dose our first patient in the first quarter of 2025 and to report proof of concept data in the first quarter of 2026.

CKD is a serious, progressive condition characterized by the gradual loss of kidney function over time, posing significant health risks and economic burdens. CKD affects approximately 37 million patients in the United States, where it is expected to be the fifth most prevalent chronic disease by 2040, and an estimated 700 million patients worldwide. CKD manifests through various stages, culminating in end-stage renal disease, necessitating dialysis or kidney transplantation for survival. Current treatments for CKD consider patients as falling into clinical categories and focus on slowing disease progression, but do not target the underlying genetic drivers of disease.

Our second most advanced lead program, MZE782, is an oral, small molecule that targets the solute transporter, SLC6A19, with the potential to address approximately five million of the CKD patients in the United States with inadequate responses to currently available CKD therapies. Beyond its use as a potential standalone therapy, MZE782 may also provide a significant benefit to patients in combination with standard of care, including as a complementary treatment to current approved regimens or as an alternative option for those patients who do not adequately respond to today’s standard of care. We identified SLC6A19 using non-public sets of matched, genetic and longitudinal clinical data and discovered a bidirectional allelic series with variants that either improve or worsen renal function. We then applied variant functionalization techniques to understand the characteristics of the naturally occurring protective variants and designed our proprietary small molecule to mimic their inhibitory effects.

We plan to apply a non-invasive biomarker strategy in our Phase 1 trial to establish proof of mechanism and to select doses for a Phase 2 trial. We initiated our Phase 1 trial of MZE782 in September 2024 and expect to report initial data from this trial in the second half of 2025.

People with Pompe disease have insufficient acid alpha-glucosidase (GAA) – the enzyme that breaks down extra glycogen in the body - because of mutations in the gene that encodes GAA. As a result, glycogen builds up in muscle tissues causing progressive problems with ambulation (walking and other movement), respiration (breathing) and heart function. The current standard of care, enzyme replacement therapy, attempts to add back GAA, but this doesn’t always get to the muscle tissues, and in some patients, loses effectiveness over time. In addition, current enzyme replacement therapies are delivered by intravenous infusion every 2 weeks, a time consuming and life-long treatment that places significant constraints on patient quality of life. Substrate reduction therapy slows down the production of glycogen to restore more normal levels of glycogen in muscle, and has the potential to remove the toxic effects of too much glycogen. While the idea for substrate reduction therapy is not new, and has been used to treat other diseases, Maze scientists have been able to solve 2 problems that have daunted the development of an oral medicine to treat Pompe disease by inhibiting Glycogen Synthase 1 (GYS1), the enzyme responsible for making glycogen in muscle. We used our CompassTM platform to analyze genetic and clinical data from large numbers of anonymous people to demonstrate that it would be safe to reduce glycogen production, and determined the molecular structure of GYS1 to allow the discovery of a potential therapy, MZE001, that would specifically slow down glycogen production in muscle but not other tissues that need glycogen for energy. We have already studied MZE001 in healthy people, and found that at safe doses, MZE001 slows down the production of glycogen specifically in muscle to a level that could restore normal muscle glycogen levels in patients with Pompe disease. The next step in bringing MZE001 closer to patients will be a Phase 2 study in patients with late-onset Pompe disease.