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Maze Therapeutics September 11, 2025 Harnessing the power of human genetics to transform the lives of patients MZE782 – Oral SLC6A19 Inhibitor For Phenylketonuria (PKU) and Chronic Kidney Disease (CKD) Phase 1 Results
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Forward-Looking Statements This presentation contains forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securiti es Litigation Reform Act of 1995. These forward-looking statements reflect the current beliefs and expectations of management. All statements other than statement s of historical fact are statements that could be deemed forward-looking statements, including, without limitation, statements concerning the company’s f uture plans and prospects, any expectations regarding the safety, efficacy or mechanism of action of MZE829, MZE782 and other candidates under development, the ability of MZE829 to treat APOL1-mediated Kidney Disease (AMKD) or other indications, the ability of MZE782 to treat Chronic Kidney Disease (CKD), Phenylke tonuria (PKU) or other indications, the market size of AMKD, CKD and PKU, the planned design and timing of the company’s clinical trials, data resul ts and further development of MZE829, MZE782 and other therapeutic candidates, potential pipeline expansion, and the sufficiency of the company’s cash and cash equivalents to fund its operating expenses and capital expenditure requirements. 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 th e company may identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Although the company b elieves 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 abi lity to advance MZE829, MZE782 and its other therapeutic candidates, obtain regulatory approval of and ultimately commercialize the company’s therapeutic ca ndidates, 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 company’s annual and quarter ly reports and other filings filed 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 Maze undertakes no obligation to revise or update any forward -looking statements to reflect events or circumstances after the date hereof. This presentation also contains estimates and other statistical data made by independent parties and by us relating to our in dustry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, a ssumptions, and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. 2
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T oday’s Presenters HAROLD BERNSTEIN, M.D., Ph.D. President, Research & Development and Chief Medical Officer JASON COLOMA, Ph.D. Chief Executive Officer 3
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Agenda Introduction Jason Coloma, Ph.D. Chief Executive Officer MZE782 Phase 1 Data Harold Bernstein, M.D., Ph.D. President of Research & Development, Chief Medical Officer Closing Remarks Jason Coloma, Ph.D. Chief Executive Officer Q&A 4
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Introduction 5
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Focused Pipeline in Kidney & Metabolic Diseases Small molecule precision medicines targeting validated genetic targets for improved patient care Program Target Indication Target Validation Lead Optimization IND- Enabling Phase 1 Phase 2 Phase 3 Anticipated Catalysts MZE829 APOL1 APOL1-mediated Kidney Disease (AMKD) • Initial topline Phase 2 data in Q1 2026 MZE782 SLC6A19 Chronic Kidney Disease (CKD) • Initiate Phase 2 in 2026 Phenylketonuria (PKU) • Initiate Phase 2 in 2026 Research & Discovery Multiple Kidney & Metabolic Diseases MZE001 / S606001 GYS1 Pompe Disease Phase 2 enrolling Phase 1 completed Phase 1 completed Phase 1 completed Strong cash position with expected runway into 2028 6
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GENETIC PRECISION Focus on genetically- validated targets (APOL1, SLC6A19) MECHANISTIC MODULATION Understanding variant function in context of disease pathophysiology ORAL THERAPIES Best / first-in-class potential small molecule programs EARLIER DE-RISKING Biomarker-based trials; proven regulatory path Unlocking Precision Pathways in Kidney & Metabolic Disease Maze is built to turn complex genetics into targeted, oral medicines that change the course of disease VARIANT DISCOVERY VARIANT FUNCTIONALIZATION SMALL MOLECULE DISCOVERY PRECISION CLINICAL TRIAL DESIGN 7
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SLC6A19: A Genetically Validated T arget with Direct Clinical Path Novel therapeutic target validated by human genetic data Third clinical program discovered and advanced via the Maze Compass platform Human loss-of-function mutations (Hartnup disease) demonstrates safety of SLC6A19 inhibition Direct clinical path leveraging well-established regulatory endpoints Robust preclinical data confirm target engagement and potential for efficacy 8
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MZE782: Broad Therapeutic Potential in PKU & CKD PKU Unmet need: >60% of patients – especially with classical (severe) PKU – remain inadequately controlled; diets are burdensome and neurocognitive issues persist MZE782 aims to deliver: Potential best-in-class plasma phenylalanine (Phe) reduction with a good safety profile Direct path: Urinary Phe excretion correlates with plasma Phe reduction, providing a direct path to regulatory approval CKD Target population: Potential to be first-in-class mechanism for ~25% who don’t respond adequately and / or discontinue SGLT2 inhibitors; real-world one-year discontinuation >30% Emerging evidence: Preclinical in vivo proof of concept and early clinical estimated glomerular filtration rate (eGFR) data support potential kidney health benefit and clarify mechanism of action Development path: Phase 2 proof of concept study with proteinuria reduction endpoint 9
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Phase 1 Results Exceed Expectations • MZE782 has an excellent safety profile; no serious adverse events observed • Linear and consistent PK across SAD and MAD • Up to 42-fold increase in urinary Phe and 68-fold increase in urinary Gln at Day 7 ⎼ Well above the 10-fold increase demonstrated by competing SLC6A19 inhibitor in healthy volunteers1 • Dose-dependent, initial eGFR dip similar to SGLT2 inhibitors and other approved kidney disease medicines that is predictive of long-term CKD benefit2 • Plan to initiate Phase 2 trials in both PKU and CKD in 2026 ⎼ PKU: leverage prior clinical proof-of-concept data demonstrating validated MoA in lowering plasma Phe levels by increasing urinary Phe excretion; plasma Phe reduction is the approval endpoint ⎼ CKD: Initial proof of concept focused on proteinuria reduction 1. Wobst, Heike J et al. “SLC6A19 inhibition facilitates urinary neutral amino acid excretion and lowers plasma phenylalanine.” JCI insight vol. 9,21 e182876. 8 Nov. 2024, doi:10.1172/jci.insight.182876 2. Bailey, Clifford J et al. “Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease.” Current diabetes reports vol. 22,1 (2022): 39-52. doi:10.1007/s11892-021-01442-z Phase 1 data supports best-in-class profile and advancement into Phase 2 for both PKU and CKD 10
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Phase 1 Data in Healthy Volunteers MZE782 11
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MZE782: Phase 1 SAD and MAD Healthy Volunteer Trial 1. 30 mg tablet strength used (120 mg tablet strength in other cohorts) 2. Doses administered with standard meal (versus fasting in prior MAD cohorts) 3. Dose administered with high-fat meal 4. Dose administered with low-fat meal 5. No placebo-treated participants Randomized, Double-blind, Placebo-controlled SAD and MAD in 112 Healthy Adult Volunteers Single Ascending Dose (SAD) N = 56 Multiple Ascending Dose (MAD) N = 40; 7 days 120 mg QD 720 mg QD 240 mg BID 240 mg BID2 120 mg BID 30 mg1 960 mg 240 mg 4x30 mg1 480 mg 60 mg1 120 mg Dosing: • 8 individuals per cohort randomized 6:2 (MZE782:Placebo) Endpoints: • Primary: Safety and tolerability • Secondary: PK, urinary excretion of Phe and Gln, food effect • Exploratory: eGFR 480 mg Single Dose Preliminary Food Effect3 N = 8 Multiple Dose Crossover Food Effect4 N = 8 480 mg5 12
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SAD/MAD Demographics MZE782 (n = 86) Placebo (n = 26) Total (n = 112) Gender, n (%) Female 40 (46.5) 9 (34.6) 49 (43.8) Male 46 (53.5) 17 (65.4) 63 (56.3) Age, years, median (range) 36.5 (20, 61) 40.0 (20, 60) 38.0 (20, 61) Ethnicity, n (%) Hispanic or Latino 37 (43.0) 7 (26.9) 44 (39.3) Non-Hispanic or Latino 49 (57.0) 19 (73.1) 68 (60.7) Race, n (%) White 51 (59.3) 16 (61.5) 67 (59.8) Black or African American 26 (30.2) 9 (34.6) 35 (31.3) Asian 3 (3.5) 1 (3.8) 4 (3.6) Native Hawaiian or Pacific Islander 1 (1.2) 0 (0) 1 (0.9) American Indian or Alaska Native 1 (1.2) 0 (0) 1 (0.9) Mixed/Other 4 (4.7) 0 (0) 4 (3.6) Well-Balanced and Comparable Between Placebo and Treatment Arms 13
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MZE782: Safety & T olerability • No SAEs • No severe AEs • 3 TRAEs: all mild in severity • No dose-dependent pattern in TRAEs • No TRAEs leading to discontinuation • No clinically relevant changes in vital signs, laboratory tests and ECGs SAE: Serious Adverse Event; AE: Adverse Event; TRAE: Treatment Related Adverse Event MZE782 Well-T olerated Across All Doses Evaluated TRAEs by Preferred Term: SAD Cohorts MZE782 (n=56) Placebo (n=16) Headache 2 (4%) 0 Diarrhea 1 (2%) 0 TRAEs by Preferred Term: MAD Cohorts MZE782 (n=30) Placebo (n=10) None - - 14
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Treatment-Related Adverse Events (TRAEs) PFE: Preliminary food effect; CFE: Crossover food effect 1. Values in columns represent # of participants with reported TRAE 2. 30-mg tablet strength utilized in these cohorts 3. All MAD cohorts administered fasted except this 240 mg BID cohort that was administered with standard meal SAD Cohort TRAE1 30 mg2 (N=6) 60 mg2 (N=6) 120 mg (N=6) 4 x 30 mg2 (N=6) 240 mg (N=6) 480 mg (N=6) 480 mg (N=6) PFE 480 mg (N=8) CFE 960 mg (N=6) Placebo (N=16) Headache 1 - - - - - - 1 - - Diarrhea - 1 - - - - - - - - MAD Cohort TRAE1 120 mg QD (N=6) 120 mg BID (N=6) 240 mg BID (N=6) 720 mg QD (N=6) 240 mg BID3 (N=6) Placebo (N=10) Any - - - - - - 15
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Treatment-Emergent Adverse Events (TEAEs) Not Related to MZE782 PFE: Preliminary food effect; CFE: Crossover food effect 1. Values in columns represent # of participants with reported TEAE 2. 30-mg tablet strength utilized in these cohorts 3. All MAD cohorts administered fasted except this 240 mg BID cohort that was administered with standard meal SAD Cohort TEAE1 30 mg2 (N=6) 60 mg2 (N=6) 120 mg (N=6) 4 x 30 mg2 (N=6) 240 mg (N=6) 480 mg (N=6) 960 mg (N=6) 480 mg (N=6) PFE Placebo (N=16) Venipuncture Site Pain 1 Device Site Rash 1 URI 1 Viral Infection 1 Headache 1 Light Sensitivity 1 Ventricular extrasystoles 1 MAD Cohort TEAE1 120 mg QD (N=6) 120 mg BID (N=6) 240 mg BID (N=6) 720 mg QD (N=6) 240 mg BID3 (N=6) 480 mg (N=8) CFE Placebo (N=10) Rhinorrhea 1 Epistaxis 1 Diarrhea 1 1 Abdominal Pain 1 1 Headache 1 Anxiety 1 Somnolence 1 16
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MZE782: Favorable PK Profile With Single and Multiple Dosing N=6 per cohort Mean ± SD are plotted. PK samples were collected for up to 168h postdose in SAD and 96h post last dose in MAD (Day 7). Linear PK across single doses (30 to 960 mg) with t½ ~11 hours Single Ascending Dose Multiple Ascending Dose Multiple dose PK consistent with single dose and accumulation consistent with t½ 0 24 48 72 96 120 144 168 192 216 240 264 288 1 10 100 1000 10000 Time (hr) MZE782 Plasma Concentration (ng/mL) 120 mg QD 120 mg BID 240 mg BID 720 mg QD 17
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Placebo 120 QD 120 BID 720 QD 240 BID 240 BID Fed Placebo 120 QD 120 BID 720 QD 240 BID 240 BID Fed Placebo 120 QD 120 BID 720 QD 240 BID 240 BID Fed 0 5 10 15 20 25 30 35 40 45 50 55 60 65 12 17 28 42 39 13 24 38 55 48 10 11 27 27 33 Dose Groups Urine Phe - Change from Baseline Ratio (0-24h) 1 1 1 MZE782: Dose-Dependent Phenylalanine Excretion Exceeding 40-Fold N=6 treated with MZE782 per cohort Geometric Mean ± GSD values are plotted. Amount excreted (Ae) in urine polled over specified time interval. Baseline is defined as the day before treatment (Day -1). Ratio=Ae post-dose/Ae at baseline. Ratio of 1 indicates no change. >1 indicates increase, <1 indicates decrease. e.g., Ratio of 10 indicates 10x increase over baseline. Up to 39x increase in urinary L-phenylalanine excretion over 24h following MZE782 administration Day 1 Day 3 Day 7 Urine Phe - Change from Baseline Ratio (0-24h) Multiple Ascending Dose Up to 42x increase in urinary L-phenylalanine excretion on Day 7 of MZE782 administration Dose Groups (mg) Placebo 30 60 4x30 120 240 480 960 0 5 10 15 20 25 30 35 40 45 50 55 60 65 9 8 15 23 39 Dose Groups Urine Phe - Change from Baseline Ratio (0-24h) 1 2 Urine Phe - Change from Baseline Ratio (0-24h) Day 1 10x Fold Threshold Single Ascending Dose Dose Groups (mg) 5 18
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MZE782: Dose-Dependent Glutamine Excretion Exceeding 60-Fold N=6 treated with MZE782 per cohort Geometric Mean ± SD values are plotted. Amount excreted (Ae) in urine polled over specified time interval. Baseline is defined as the day before treatment (Day -1). Ratio=Ae post-dose/Ae at baseline. Ratio of 1 indicates no change. >1 indicates increase, <1 indicates decrease. e.g., Ratio of 10 indicates 10x increase over baseline. Up to 55x increase in urinary L-glutamine excretion over 24h following MZE782 administration Up to 68x increase in urinary L-glutamine excretion on Day 7 of MZE782 administration Urine Gln - Change from Baseline Ratio (0-24h) Day 1 Single Ascending Dose Placebo 30 60 4x30 120 240 480 960 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 15 19 17 28 35 55 Dose Groups Urine Gln - Change from Baseline Ratio (0-24h) 1 4 Dose Groups (mg) Urine Gln - Change from Baseline Ratio (0-24h) Multiple Ascending Dose Day 1 Day 3 Day 7 Placebo 120 QD 120 BID 720 QD 240 BID 240 BID Fed Placebo 120 QD 120 BID 720 QD 240 BID 240 BID Fed Placebo 120 QD 120 BID 720 QD 240 BID 240 BID Fed 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 29 37 52 68 50 28 43 50 64 50 20 24 39 40 37 Dose Groups Urine Gln - Change from Baseline Ratio (0-24h) 1 1 1 Dose Groups (mg) 19
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Proximal tubule Glomerulus Distal tubule NEPHRON SGLT2 inhibitor MZE782 (SLC6A19 inhibitor) Glucose Amino acids Metabolites SLC6A19 SLC6A19 SGLT2 SGLT2 1 2 3 4 MZE782: Kidney Detoxification with Improved Filtration Complementary to - and potentially independent of - SGLT2 inhibition 5 • SGLT2 inhibitors reduce glucose and sodium reabsorption • SLC6A19 dysfunction allows harmful metabolites into kidney cells • MZE782 blocks this process, protecting cells from damage • Measuring amino acids in the urine can serve as a biomarker to test for target engagement • Measuring eGFR 'dip' can serve as a biomarker for improved filtration 1 2 3 4 5 20
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Initial eGFR Dip on SGLT2i Therapy Predicts Slower Chronic eGFR Decline in CKD 1. Bailey, Clifford J et al. “Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease.” Current diabetes reports vol. 22,1 (2022): 39-52. doi:10.1007/s11892-021-01442-z 2. Holtkamp, Frank A et al. “An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function.” Kidney international vol. 80,3 (2011): 282-7. doi:10.1038/ki.2011.79 3. Meraz-Muñoz, Alejandro Y et al. “eGFR Decline after SGLT2 Inhibitor Initiation: The Tortoise and the Hare Reimagined.” Kidney360 vol. 2,6 1042-1047. 26 Mar. 2021, doi:10.34067/KID.0001172021 Strengthens rationale for MZE782 to potentially improve CKD outcomes Typical eGFR Trajectory1 Initial Dip Slower rate of decline following initial dip Initial eGFR dip is a transient hemodynamic effect seen with renoprotective therapies2,3 Observed with CKD therapies including SGLT2 inhibitors and RAAS inhibitors2,3 Moderate initial dip associated with slower chronic eGFR decline and better long-term kidney outcomes2,3 Provides a pharmacodynamic readthrough supporting potential efficacy in CKD 21
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MZE782: Preliminary Data Support Potential Protective Mechanism in CKD Dose-dependent initial dip in eGFR with reversal upon treatment cessation Treatment (7 Days) N=10 Placebo N=6 120 mg QD N=6 120 mg BID N=6 720 mg QD N=12 240 mg BID (fed + fasted) N=4 Matched Placebo N=12 240 mg BID (fed + fasted) All MAD Doses ΔeGFR for empagliflozin 25 mg QD1 Early data appears to have comparable effect to other renoprotective therapies eGFR derived using the 2021 CKD-EPI Creatinine Equation; . † Baseline eGFR = mean of the 3 pre-dose measurements ; 1Range of placebo-adjusted and non-adjusted % change from baseline eGFR (“eGFR dip”) at 4 weeks’ treatment with empagliflozin 25 mg QD on background ramipril in patients without significant renal impairment provided for approximate reference (Lytvyn Y, 2022) 240 mg BID vs. Matched Placebo No Treatment Treatment (7 Days) No Treatment 22
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Safety & Tolerability • MZE782 was well tolerated with an excellent safety profile at all dose levels evaluated ‒ Single doses up to 960 mg and multiple doses up to 720 mg QD for 7 days Pharmacokinetics • MZE782 has linear PK across single doses of 30-960 mg with half-life ~11 hrs • Multiple dose PK consistent with single dose Food Effect • Moderate positive food effect observed only with single doses of MZE782 • When MZE782 administered twice daily, steady state plasma exposures similar with or without food administration Urinary Phe & Gln • Consistent increases in urinary excretion of Phe & Gln observed with increasing doses and plasma exposures to MZE782 ‒ Up to 42X increase in urinary Phe and 68X increase in urinary Gln at Day 7 eGFR • MZE782 demonstrated initial eGFR dip similar to SGLT2 & RAAS inhibitors Phase 2 • Supportive of advancement into Phase 2 studies Strong Phase 1 Data Enables Phase 2 in PKU & CKD 23
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Closing Remarks 24
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❑ CKD • Demonstrate PoC with proteinuria reduction endpoint ⎼ MZE782 could be a new MoA to address patients with inadequate response to current therapies, including SGLT2i ⎼ Initial eGFR dip consistent with MoA and supports mechanistic hypothesis ⎼ Potential for accelerated approval with change in eGFR slope + proteinuria reduction • Finalizing trial design details, subject to regulatory alignment MZE782 Phase 1 Data Enable Phase 2 Advancement ❑ PKU • Demonstrate PoC with plasma Phe reduction endpoint ⎼ Increase in urinary Phe correlates with plasma Phe reduction ⎼ 42-fold urinary Phe increase reinforces MZE782 potential in all PKU patients, including classic PKU not responsive to PAH activators ⎼ Plasma Phe: approvable endpoint in registrational studies with direct path to approval • Finalizing trial design details, subject to regulatory alignmentInitiate Phase 2 Trials in 2026 25
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Q&A 26
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Maze Therapeutics September 11, 2025 Harnessing the power of human genetics to transform the lives of patients MZE782 – Oral SLC6A19 Inhibitor For Phenylketonuria (PKU) and Chronic Kidney Disease (CKD) Phase 1 Results