Maze Therapeutics Announces Positive First-in-Human Results from Phase 1 Trial of MZE782, Establishing Proof of Mechanism for a Potent, Oral SLC6A19 Inhibitor with Potential to Treat Phenylketonuria (PKU) and Chronic Kidney Disease (CKD)
Maze Therapeutics (NASDAQ:MAZE) announced positive Phase 1 results for MZE782, its oral SLC6A19 inhibitor targeting Phenylketonuria (PKU) and Chronic Kidney Disease (CKD). The trial demonstrated exceptional safety and efficacy metrics, including up to a 42-fold increase in urinary phenylalanine excretion and dose-dependent eGFR changes similar to SGLT2 inhibitors.
The study involved 112 healthy volunteers across single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. MZE782 showed favorable pharmacokinetics supporting once or twice-daily dosing, with no serious adverse events reported. The drug achieved a 39-fold increase in urinary Phe excretion with a single 960mg dose and demonstrated significant glutamine excretion increases.
Based on these promising results, Maze plans to advance MZE782 to Phase 2 trials for both PKU and CKD in 2026.
Maze Therapeutics (NASDAQ:MAZE) ha comunicato risultati positivi di Fase 1 per MZE782, il suo inibitore orale di SLC6A19 studiato per la fenilchetonuria (PKU) e la malattia renale cronica (CKD). Lo studio ha mostrato metriche di sicurezza ed efficacia eccellenti, inclusi fino a un incremento di 42 volte nell'escrezione urinaria di fenilalanina e variazioni dell'eGFR dipendenti dalla dose paragonabili agli inibitori SGLT2.
La sperimentazione ha coinvolto 112 volontari sani in coorti a dose singola ascendente (SAD) e a dosi multiple ascendenti (MAD). MZE782 ha evidenziato una farmacocinetica favorevole che supporta somministrazioni una o due volte al giorno, senza eventi avversi gravi segnalati. Il farmaco ha raggiunto un aumento di 39 volte nell'escrezione urinaria di Phe con una singola dose da 960 mg e ha mostrato incrementi significativi nell'escrezione di glutammina.
Sulla base di questi risultati promettenti, Maze prevede di avanzare MZE782 a trial di Fase 2 per PKU e CKD nel 2026.
Maze Therapeutics (NASDAQ:MAZE) anunció resultados positivos de Fase 1 para MZE782, su inhibidor oral de SLC6A19 dirigido a fenilcetonuria (PKU) y enfermedad renal crónica (CKD). El ensayo mostró excelentes métricas de seguridad y eficacia, incluyendo hasta un incremento de 42 veces en la excreción urinaria de fenilalanina y cambios en el eGFR dependientes de la dosis similares a los de los inhibidores SGLT2.
El estudio incluyó a 112 voluntarios sanos distribuidos en cohortes de dosis únicas ascendentes (SAD) y de dosis múltiples ascendentes (MAD). MZE782 presentó una farmacocinética favorable que permite dosificaciones una o dos veces al día, sin eventos adversos graves reportados. El fármaco alcanzó un aumento de 39 veces en la excreción urinaria de Phe tras una dosis única de 960 mg y mostró incrementos significativos en la excreción de glutamina.
Con base en estos resultados prometedores, Maze planea avanzar MZE782 a ensayos de Fase 2 para PKU y CKD en 2026.
Maze Therapeutics (NASDAQ:MAZE)는 페닐케톤뇨증(PKU)과 만성신장질환(CKD)을 표적으로 하는 경구용 SLC6A19 억제제 MZE782의 1상 긍정적 결과를 발표했습니다. 시험은 뛰어난 안전성 및 효능 지표를 보였으며, 최대 요중 페닐알라닌 배설이 42배 증가하고 용량 의존적 eGFR 변화가 SGLT2 억제제와 유사하게 나타났습니다.
연구에는 단회 용량 상승(SAD) 및 다회 용량 상승(MAD) 코호트에서 건강한 지원자 112명이 참여했습니다. MZE782는 하루 1회 또는 2회 투여를 뒷받침하는 유리한 약동학을 보였고 중대한 이상반응은 보고되지 않았습니다. 약물은 단회 960mg 투여로 요중 Phe 배설이 39배 증가했으며 글루타민 배설도 유의하게 증가했습니다.
이러한 유망한 결과를 바탕으로 Maze는 MZE782를 2026년에 PKU 및 CKD에 대한 2상 시험으로 진전시킬 계획입니다.
Maze Therapeutics (NASDAQ:MAZE) a annoncé des résultats positifs de phase 1 pour MZE782, son inhibiteur oral de SLC6A19 destiné à la phénylcétonurie (PKU) et à la maladie rénale chronique (CKD). L'essai a montré des indicateurs de sécurité et d'efficacité remarquables, y compris jusqu'à une augmentation de 42 fois de l'excrétion urinaire de phénylalanine et des modifications de l'eGFR dépendantes de la dose, comparables à celles des inhibiteurs SGLT2.
L'étude a porté sur 112 volontaires sains répartis en cohortes à dose unique ascendante (SAD) et à doses multiples ascendantes (MAD). MZE782 a présenté une pharmacocinétique favorable permettant une administration une ou deux fois par jour, sans événements indésirables graves signalés. Le médicament a entraîné une augmentation de 39 fois de l'excrétion urinaire de Phe après une dose unique de 960 mg et a montré des augmentations significatives de l'excrétion de glutamine.
Sur la base de ces résultats prometteurs, Maze prévoit d'avancer MZE782 vers des essais de phase 2 pour la PKU et la CKD en 2026.
Maze Therapeutics (NASDAQ:MAZE) meldete positive Phase‑1‑Ergebnisse für MZE782, seinen oralen SLC6A19‑Inhibitor zur Behandlung von Phenylketonurie (PKU) und chronischer Nierenerkrankung (CKD). Die Studie zeigte hervorragende Sicherheits‑ und Wirksamkeitsparameter, darunter eine bis zu 42-fache Erhöhung der renalen Phenylalanin‑Ausscheidung und dosisabhängige eGFR‑Veränderungen, die denen von SGLT2‑Inhibitoren ähneln.
An der Untersuchung nahmen 112 gesunde Freiwillige in Single‑Ascending‑Dose‑(SAD)‑ und Multiple‑Ascending‑Dose‑(MAD)‑Kohorten teil. MZE782 zeigte eine vorteilhafte Pharmakokinetik, die einmal- oder zweimal tägliche Dosierung ermöglicht, und es wurden keine schwerwiegenden unerwünschten Ereignisse berichtet. Das Medikament erzielte bei einer einmaligen 960‑mg‑Dosis eine 39‑fache Steigerung der urinären Phe‑Ausscheidung und führte zu signifikanten Anstiegen der Glutamin‑Ausscheidung.
Auf Basis dieser vielversprechenden Ergebnisse plant Maze, MZE782 2026 in Phase‑2‑Studien für PKU und CKD zu überführen.
- Significant 42-fold increase in urinary phenylalanine excretion, validating drug efficacy
- Excellent safety profile with no serious adverse events reported
- Favorable pharmacokinetics supporting once or twice-daily dosing regimen
- Dose-dependent eGFR changes similar to successful SGLT2 inhibitors
- Potential for best-in-class therapy for PKU and first-in-class for CKD
- Phase 2 trials not starting until 2026, indicating a lengthy development timeline
- Initial eGFR dip of -11.5 mL/min/1.73m2 in treatment group vs -2.5 mL/min/1.73m2 in placebo
Insights
Maze's Phase 1 results for MZE782 show impressive amino acid excretion and kidney function signals, supporting advancement to Phase 2 for PKU and CKD.
The Phase 1 results for MZE782 demonstrate a compelling dual-indication mechanism through SLC6A19 inhibition. The data revealed dose-dependent increases in urinary phenylalanine excretion of up to
The observed eGFR dip of -11.5 mL/min/1.73m² in the 240mg BID cohorts (compared to -2.5 mL/min/1.73m² for placebo) mirrors what's seen with established renoprotective agents like SGLT2 inhibitors. This physiological response is particularly significant as it predicts long-term kidney protection in CKD patients, despite being a temporary effect that reverses after discontinuation.
The safety profile is exceptionally clean for a first-in-human study, with only three mild treatment-related adverse events in the SAD portion and none in the MAD cohorts. No serious adverse events were reported, which significantly de-risks the program heading into Phase 2.
The pharmacokinetic data supports either once-daily or twice-daily dosing with predictable exposure that increases proportionally with dose and reaches steady-state by Day 3. The 11-hour half-life and 6-hour tmax are favorable parameters for chronic administration.
This represents the third clinical program from Maze's Compass platform, validating their genetic-based approach to drug discovery. The planned Phase 2 trials in 2026 will be crucial in determining whether these compelling biomarker changes translate to clinical benefits in both PKU and CKD patient populations.
The pharmacodynamic results for MZE782 are particularly notable, showing robust target engagement across all tested doses. The
What's especially interesting is the dual mechanism potential demonstrated by the amino acid excretion and eGFR effects. The SLC6A19 transporter inhibition impacts both phenylalanine handling (relevant for PKU) and kidney physiology (relevant for CKD) through distinct but related mechanisms. The glutamine excretion increase of
The pharmacokinetic profile reveals a favorable dosing paradigm with proportional exposure across the dose range. The 11-hour half-life positions this compound nicely for either once or twice-daily administration, and the predictable accumulation to steady-state by Day 3 suggests minimal dose adjustments would be needed during chronic treatment.
The food effect data, while not detailed in the release, will be crucial for determining administration requirements. Most importantly, the clean safety profile with no serious adverse events and only three mild treatment-related adverse events in the SAD portion (none in MAD) provides a solid foundation for Phase 2 development.
The reversibility of the eGFR dip after drug discontinuation confirms this is a pharmacological effect rather than a safety concern, similar to what's observed with SGLT2 inhibitors that have proven long-term renoprotective benefits despite initial eGFR decreases.
Phase 1 data in healthy volunteers exceed expectations and support best-in-class potential, enabling Phase 2 advancement for both intended indications of PKU and CKD
Dose-dependent urinary amino acid excretion demonstrated across all SAD and MAD cohorts, including up to a 42-fold increase in urinary phenylalanine (Phe) excretion, a well-validated biomarker for PKU and predictive for CKD
Dose-dependent initial eGFR dip similar to SGLT2 inhibitors observed, supporting a potential kidney protective effect in CKD
Well tolerated across all doses with an excellent safety profile and no serious adverse events observed
Phase 2 trials in both PKU and CKD expected to initiate in 2026
Maze to host investor conference call and webcast today at 8:30 am EDT
SOUTH SAN FRANCISCO, Calif., Sept. 11, 2025 (GLOBE NEWSWIRE) -- Maze Therapeutics, Inc. (Nasdaq: MAZE), a clinical-stage biopharmaceutical company developing small molecule precision medicines for patients with kidney and metabolic diseases, today announced positive clinical results from the Phase 1 healthy volunteer study of MZE782, an oral small molecule targeting the solute transporter, SLC6A19. MZE782 has potential to be a best-in-class therapy for patients with PKU, an inherited metabolic disorder, and a first-in-class therapy for patients with CKD.
“These first-in-human results for MZE782 mark an important milestone, demonstrating an excellent safety profile, robust target engagement and compelling pharmacodynamic effects, consistent with our therapeutic hypothesis,” said Harold Bernstein, M.D., Ph.D., president of R&D and chief medical officer of Maze. “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.”
“We also 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. We look forward to advancing MZE782 into Phase 2 studies in both PKU and CKD in 2026,” Dr. Bernstein continued. “These findings also serve as important clinical validation of our Compass platform. MZE782 is the third clinical program to come out of our Compass platform, further demonstrating our ability to harness the power of human genetics to develop small molecule precision medicines designed to transform the lives of patients with kidney and metabolic diseases.”
Study Design
The Phase 1 trial of MZE782 was a randomized, double-blind, placebo-controlled study evaluating single ascending doses (SAD) and multiple ascending doses (MAD) of orally administered MZE782 in 112 healthy adult volunteers. The study included 56 participants in the SAD, 40 participants in the MAD and 16 participants in the food effect cohorts. Each SAD and MAD cohort included eight participants randomized 6:2 (MZE782: placebo). The SAD doses ranged from 30 to 960 mg. The MAD doses, with dosing once or twice daily for seven days, ranged from 120 to 240 mg twice daily and 120 to 720 mg once daily. One food effect cohort included eight participants administered 480 mg MZE782 or placebo (6:2) with a high-fat meal. The second food effect cohort included eight participants administered 480 mg MZE782 fasted or with a low-fat meal in a crossover design.
The primary objective was to evaluate the safety and tolerability of single and multiple ascending oral doses of MZE782 in healthy volunteers. Secondary and exploratory endpoints included pharmacokinetics, food effect, pharmacodynamic measures of target engagement, specifically urinary excretion of phenylalanine (Phe) and glutamine (Gln) as predictive biomarkers of SLC6A19 inhibition and disease control, and estimated glomerular filtration rate (eGFR).
Safety and Tolerability Profile
MZE782 was well tolerated across all doses in all cohorts. There were no serious adverse events (SAEs), no severe adverse events and no treatment-related adverse events (TRAEs) leading to discontinuation. In the SAD portion of the study (n=56), there were a total of three TRAEs reported that were all mild in severity and not seen at the higher doses. Headache was reported in two patients (
Pharmacokinetics (PK)
MZE782 demonstrated a favorable plasma PK profile after single and multiple oral doses. Oral administration was associated with consistent absorption, with a tmax of six hours and a half-life of 11 hours. Exposure increased proportionally with dose, and steady-state was achieved by Day 3. This is supportive of a once- or twice-daily dosing regimen to be evaluated in Phase 2.
Pharmacodynamics (PD)
Neutral Amino Acid Excretion
MZE782 produced dose-dependent increases in 24-hour urinary excretion of the neutral amino acids Phe and Gln across both SAD and MAD cohorts, confirming target engagement and SLC6A19 inhibition.
A 39-fold increase in urinary Phe excretion over 24 hours was observed with a single dose of 960 mg of MZE782. A 42-fold increase in urinary Phe excretion over 24 hours on Day 7 was observed in the 240 mg twice-daily dose cohort.
A 55-fold increase in urinary Gln excretion over 24 hours was observed with a single dose of 960 mg of MZE782. A 68-fold increase in urinary Gln excretion over 24 hours on Day 7 was observed in the 240 mg twice-daily dose cohort.
Estimated Glomerular Filtration Rate (eGFR)
All participants in the MAD cohorts of the Phase 1 study were assessed for changes in eGFR. MZE782 demonstrated a dose-dependent initial eGFR dip over seven days of dosing that was similar in magnitude to what has been observed in patients initiating SGLT2 and RAAS inhibitors. With other renoprotective therapies, this initial dip is correlated to a slower rate of eGFR decline and better preservation of kidney function over longer periods of time in CKD patients. The combined 240 mg BID cohorts (n=12) demonstrated a change of -11.5 mL/min/1.73m2 after seven days of dosing, compared to a change of -2.5 mL/min/1.73m2 in the matched placebo cohort (n=4). This initial eGFR dip rapidly reversed following the end of dosing as assessed at Day 11, strongly suggestive of a drug-related effect on eGFR.
Next Steps
Maze plans to initiate two Phase 2 proof-of-concept trials of MZE782, evaluating plasma Phe reduction in PKU and proteinuria reduction in CKD in 2026.
Conference Call and Webcast
Maze will host a conference call and webcast with members of the executive team today at 8:30 am EDT to discuss the data.
To access the call, please dial (877) 407-3982 (domestic) or (201) 493-6780 (international) and provide the Conference ID 13755793 to the operator.
To access the live webcast and subsequent archived recording of this and other company presentations, please visit the Investors section of Maze’s website. The archived webcast will remain available for replay on Maze’s website for 90 days.
About MZE782
MZE782 is an investigational, potent, selective, oral inhibitor of SLC6A19, a sodium-dependent neutral amino acid transporter expressed in the small intestine and kidney proximal tubule that plays a key role in the absorption and reabsorption of neutral amino acids, including Phe. MZE782 is being advanced in two indications: PKU and CKD. In PKU, SLC6A19 enables Phe uptake from the gut and reabsorption in the kidney – two key contributors to elevated plasma Phe levels in patients with deficient PAH activity. Inhibiting SLC6A19 with MZE782 offers a genotype- and PAH-agnostic, oral approach to lowering plasma Phe by limiting its entry into circulation. In CKD, SLC6A19-mediated reabsorption has the potential to contribute to metabolic overload in the proximal tubule of the kidney. Blocking this transporter may therefore reduce the burden of amino acids and toxins, potentially slowing disease progression. The potential mechanism is complementary to, as well as distinct from, SGLT2 inhibition. Loss-of-function mutations in SLC6A19, as seen in Hartnup disease, a generally benign condition, support the potential safety of SLC6A19 inhibition and reinforce the therapeutic rationale for MZE782. In the Phase 1 clinical study in healthy volunteers, MZE782 demonstrated an excellent safety profile, sustained urinary neutral amino acid excretion as well as potential to improve kidney filtration.
About Maze Therapeutics
Maze Therapeutics is a clinical-stage biopharmaceutical company harnessing the power of human genetics to develop novel small molecule precision medicines for patients with kidney and metabolic diseases. Guided by its Compass™ platform, Maze pursues genetically validated targets by integrating variant discovery and functionalization to discover and advance small molecule programs with first- or best-in-class potential. Maze’s pipeline is led by MZE829, a dual-mechanism APOL1 inhibitor in Phase 2 development for APOL1-mediated kidney disease (AMKD), and MZE782, a SLC6A19 inhibitor advancing to Phase 2 with the potential to treat both phenylketonuria (PKU) and chronic kidney disease (CKD). Maze is headquartered in South San Francisco. For more information, please visit mazetx.com, or follow the company on LinkedIn and X.
Forward Looking Statements
This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect the current beliefs and expectations of management. All statements other than statements of historical fact are statements that could be deemed forward-looking statements, including, without limitation, statements concerning the company’s future plans and prospects, any expectations regarding the safety or efficacy of MZE829, MZE782 and other candidates under development, the ability of MZE829 to treat AMKD or other indications, the ability of MZE782 to treat CKD, PKU or other indications, the planned timing of the company’s clinical trials, data results and further development of MZE829, MZE782 and other therapeutic candidates, and the ability to drive financial results and stockholder value. In addition, when or if used in this press release, the words “may,” “could,” “should,” “anticipate,” “believe,” “estimate,” “expect,” “intend,” “plan,” “predict” and similar expressions and their variants, as they relate to the company may identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Although the company believes the expectations reflected in such forward-looking statements are reasonable, the company can give no assurance that such expectations will prove to be correct. Readers are cautioned that actual results, levels of activity, safety, performance or events and circumstances could differ materially from those expressed or implied in the company’s forward-looking statements due to a variety of factors, including risks and uncertainties related to the company’s ability to advance MZE829, MZE782 and its other therapeutic candidates, obtain regulatory approval of and ultimately commercialize the company’s therapeutic candidates, the timing and results of preclinical studies and clinical trials, the company’s ability to fund development activities and achieve development goals, its ability to protect its intellectual property, general business and economic conditions, and risks related to the impact on its business of macroeconomic conditions, including inflation, volatile interest rates, tariffs, instability in the global banking sector, and public health crises. Further information on potential risk factors that could affect the company’s business and its financial results are detailed under the heading “Risk Factors” included in the documents the company files from time to time with the U.S. Securities and Exchange Commission, including the company’s Annual Report on Form 10-K and Quarterly Reports on Form 10-Q. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. These forward-looking statements speak only as of the date of this press release and the company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof.
For further information, please contact:
IR/Corporate Contact:
Amy Bachrodt, Maze Therapeutics
abachrodt@mazetx.com
Media Contact:
Amanda Lazaro, 1AB Media
Amanda@1ABMedia.com
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