In a randomized, placebo-controlled Phase 1 study in 112 healthy adults, Maze’s SLC6A19 inhibitor MZE782 produced large, dose-dependent pharmacodynamic signals and a clean safety profile. Single and multiple doses drove 24-hour urinary phenylalanine excretion up to 39-fold (single 960 mg) and 42-fold (Day 7, 240 mg twice daily), with glutamine excretion increased 55-fold and 68-fold at the same dose levels. Across multiple-ascending-dose cohorts, the 240 mg twice-daily group showed an initial eGFR dip of -11.5 mL/min/1.73 m2 over seven days versus -2.5 for placebo, reversing after dosing stopped. No serious adverse events or discontinuations occurred, and pharmacokinetics were dose-proportional with a six-hour Tmax and 11-hour half-life, achieving steady state by Day 3.
The company will advance MZE782 into two Phase 2 proof-of-concept trials in 2026: plasma phenylalanine reduction in phenylketonuria and proteinuria reduction in chronic kidney disease. The dual-development path leans on a single mechanism—intestinal and renal inhibition of the neutral amino acid transporter SLC6A19—to address two very different regulatory endpoints. The Phase 1 data establish target engagement in humans and hint at renal hemodynamic effects reminiscent of those seen with SGLT2 and RAAS inhibitor initiation, providing Maze with a translational narrative to test quickly in patient populations.
Strategically, this is an expansion play designed to diversify risk and maximize optionality from one asset. In PKU, an oral, genotype-agnostic approach could circumvent the stratification and complexity that constrain existing options, provided urinary excretion signals convert into sustained plasma phenylalanine lowering without dietary instability. In CKD, the eGFR dip signal is being positioned as an early pharmacodynamic readout associated with long-term benefit in other classes. Still, regulators and payers will want to see additive proteinuria and slope effects on top of contemporary standard-of-care, which now typically includes maximized RAAS blockade and SGLT2 inhibition. The challenge will be to prove complementary value without encroaching on the known nutritional risks associated with chronic aminoaciduria.
For sites and CROs, the operational footprint splits cleanly between rare disease metabolic centers and high-throughput nephrology networks. PKU studies will hinge on rigorous plasma phenylalanine monitoring, potential diet standardization, and feasible 24-hour urine collections; pediatric engagement will matter, even if early cohorts skew toward adults. CKD sites will need tight background therapy management, protocolized timing for eGFR and UACR assessments, and attention to nutrition, dermatologic, and neurologic surveillance aligned with the transporter’s biology. The biomarker-driven design enables shorter, smaller Phase 2 readouts, but it increases the burden on sample logistics and central lab coordination. Vendors supporting home urine collection and adherence monitoring could be pulled into the design to reduce site friction.
Key watch items now turn to Phase 2 protocol choices: dose and schedule selection (once versus twice daily), inclusion criteria by CKD etiology, background therapy requirements, and duration sufficient to demonstrate proteinuria and early slope signals. Safety over more extended dosing will be scrutinized for consequences of sustained neutral amino acid loss, not evident in the short Phase 1 window. Translational credibility rests on whether the dramatic urinary excretion changes in healthy volunteers translate into clinically relevant plasma reductions in PKU and whether the eGFR dip in CKD patients correlates with durable benefits. With the first patient planned for 2026, expect regulatory interactions on surrogate endpoints and an operational build that either concentrates on a single CKD subtype for clarity or runs a broader, etiology-agnostic PoC to surface the strongest signal.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
