Kidney Week

Abstract: TH-PO617

A Phase 1 Study in Healthy Adults of the Safety, Tolerability, and Pharmacokinetics of MZE829, an APOL1 Inhibitor, for the Treatment of APOL1-Mediated Kidney Disease (AMKD)

Session Information

• Membranous Nephropathy, FSGS, and Minimal Change Disease
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics

Authors

• Limb, Susan, Maze Therapeutics Inc, South San Francisco, California, United States

Susan Limb, MD

• Assimon, Victoria, Maze Therapeutics Inc, South San Francisco, California, United States

Victoria Assimon, PhD

• Leeds, Janet M., Maze Therapeutics Inc, South San Francisco, California, United States

Janet M. Leeds, PhD

• Dick, Ryan, Maze Therapeutics Inc, South San Francisco, California, United States

Ryan Dick

• Yu, Cecile, Maze Therapeutics Inc, South San Francisco, California, United States

Cecile Yu

• Beattie, David T., Maze Therapeutics Inc, South San Francisco, California, United States

David T. Beattie, PhD

• Bronner, Sarah, Maze Therapeutics Inc, South San Francisco, California, United States

Sarah Bronner, PhD

• Octaviani, Angela, Maze Therapeutics Inc, South San Francisco, California, United States

Angela Octaviani

• Hoek, Maarten, Maze Therapeutics Inc, South San Francisco, California, United States

Maarten Hoek, PhD

• Bernstein, Harold S., Maze Therapeutics Inc, South San Francisco, California, United States

Harold S. Bernstein, MD, PhD

Background

Genetic variants of apolipoprotein L1 (APOL1) are associated with an increased risk of chronic kidney disease and disease progression in individuals of West African ancestry. MZE829 is a highly potent, small molecule inhibitor of APOL1 currently under investigation for the treatment of APOL1-mediated kidney disease (AMKD). We conducted a first-in-human trial to assess the safety, tolerability, and pharmacokinetics of MZE829 in healthy participants.

Methods

The randomized, blinded, placebo-controlled Phase 1 trial evaluated single and multiple ascending doses of MZE829 in healthy participants ages 18 years and older. Assessment of potency and selection of the Phase 1 clinical starting dose were based on the efficacy of MZE829 for reducing albuminuria in a transgenic mouse model of AMKD, where mice homozygous for the APOL1 G2 (G2_HOM) variant were administered an IFN-γ challenge to elevate APOL1 levels and induce albuminuria. An exposure-response curve from this in vivo pharmacology model was used to assess the minimum anticipated biological effect level and target efficacious exposure range (~EC_50-98). Safety and tolerability were evaluated through the assessment of multiple primary endpoints including, the incidence and severity of adverse events, clinically significant abnormalities in laboratory assessments, physical examinations, vital signs, and 12-lead ECGs. Noncompartmental analysis and population pharmacokinetic analysis were used to estimate doses for subsequent patient studies. Selected probes for potential drug-drug interactions were performed to inform use of MZE829 with other medications used in patients with proteinuric kidney disease.

Results

The study is in progress. Final safety and pharmacokinetic results will be presented.

Conclusion

MZE829 is a potent, selective, small molecule APOL1 inhibitor. Phase 1 evaluation in healthy participants demonstrated that safe and well-tolerated doses of MZE829 achieve exposures through the target efficacious range. Trials in patients with AMKD will be conducted to demonstrate clinical proof of concept for proteinuria reduction

Funding

• Commercial Support – Maze Therapeutics