Maze Therapeutics announced positive first-in-human Phase 1 results for MZE782, an oral small molecule inhibitor targeting the SLC6A19 transporter, demonstrating robust pharmacodynamic effects that support its potential as a dual-indication therapy for phenylketonuria (PKU) and chronic kidney disease (CKD). The randomized, double-blind, placebo-controlled study in 112 healthy volunteers exceeded expectations and positions MZE782 for Phase 2 advancement in both indications.
Significant Biomarker Response Validates Target Engagement
The Phase 1 trial demonstrated compelling dose-dependent increases in urinary amino acid excretion across all single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. MZE782 achieved a 42-fold increase in urinary phenylalanine excretion over 24 hours on Day 7 in the 240 mg twice-daily dose cohort, with single doses reaching up to 39-fold increases at 960 mg. These results confirm robust SLC6A19 inhibition and target engagement.
"The rapid and profound increase in urinary phenylalanine excretion confirms SLC6A19 inhibition in healthy individuals that we anticipate will translate to meaningful reductions in plasma phenylalanine levels in patients with PKU, based on the biology of this transporter," said Harold Bernstein, M.D., Ph.D., president of R&D and chief medical officer of Maze.
Glutamine excretion showed even more pronounced effects, with increases up to 68-fold in the 240 mg twice-daily cohort and 55-fold with single 960 mg doses, further validating the mechanism of action.
Kidney Function Changes Mirror Established Renoprotective Therapies
MZE782 demonstrated dose-dependent initial eGFR changes similar to those observed with SGLT2 inhibitors, a class of drugs known for kidney protection in CKD patients. The combined 240 mg twice-daily cohorts showed a change of -11.5 mL/min/1.73m² after seven days of dosing, compared to -2.5 mL/min/1.73m² in the matched placebo cohort. This initial eGFR dip rapidly reversed following the end of dosing, strongly suggesting a drug-related effect.
"We observed dose-dependent changes in eGFR in healthy individuals with MZE782, similar to those seen with SGLT2 inhibitors, suggesting a potential beneficial effect on kidney physiology in CKD patients," Dr. Bernstein noted. With other renoprotective therapies, this initial dip correlates to slower eGFR decline and better preservation of kidney function over longer periods in CKD patients.
Excellent Safety Profile Supports Clinical Advancement
The drug demonstrated an excellent safety and tolerability profile across all doses tested. There were no serious adverse events, no severe adverse events, and no treatment-related adverse events leading to discontinuation. In the SAD portion involving 56 participants, only three mild treatment-related adverse events were reported: headache in two patients (4%) and diarrhea in one patient (2%). Notably, no treatment-related adverse events were reported in the MAD portion of the study, and no clinically relevant changes in vital signs, laboratory tests, or ECGs were observed.
Favorable Pharmacokinetic Profile Supports Convenient Dosing
MZE782 exhibited favorable pharmacokinetic characteristics with consistent absorption, a time to maximum concentration of six hours, and a half-life of 11 hours. Exposure increased proportionally with dose, and steady-state was achieved by Day 3, supporting once- or twice-daily dosing regimens for Phase 2 evaluation.
Dual-Indication Therapeutic Approach
MZE782 targets SLC6A19, a sodium-dependent neutral amino acid transporter expressed in the small intestine and kidney proximal tubule. In PKU, the transporter enables phenylalanine uptake from the gut and reabsorption in the kidney, contributing to elevated plasma phenylalanine levels in patients with deficient PAH activity. Inhibiting SLC6A19 offers a genotype- and PAH-agnostic oral approach to lowering plasma phenylalanine by limiting its entry into circulation.
For CKD, SLC6A19-mediated reabsorption potentially contributes to metabolic overload in the kidney's proximal tubule. Blocking this transporter may reduce the burden of amino acids and toxins, potentially slowing disease progression through a mechanism complementary to, yet distinct from, SGLT2 inhibition.
Clinical Development Timeline
Based on these positive Phase 1 results, Maze plans to initiate two Phase 2 proof-of-concept trials of MZE782 in 2026, evaluating plasma phenylalanine reduction in PKU patients and proteinuria reduction in CKD patients. The findings also represent important clinical validation of Maze's Compass platform, with MZE782 being the third clinical program to emerge from this genetics-driven drug discovery approach.
The comprehensive Phase 1 study included 56 participants in SAD cohorts, 40 in MAD cohorts, and 16 in food effect cohorts, with SAD doses ranging from 30 to 960 mg and MAD doses ranging from 120 to 240 mg twice daily and 120 to 720 mg once daily.
