Maze Therapeutics Shares Phase II HORIZON Data: MZE829 Cuts Proteinuria in APOL1 Kidney Disease

Key Points

• MZE829 showed meaningful proteinuria reductions in the Phase II HORIZON trial: in the per‑protocol set 50% of patients achieved ≥30% uACR reduction at 12 weeks and the mean uACR decline was ~36%, with an especially large effect in the FSGS subgroup (~62% mean reduction).
• Favorable safety profile: MZE829 was well tolerated with no serious adverse events or safety signals reported; treatment‑related events were generally mild or moderate (most commonly headache and diarrhea).
• Company plans and funding: Maze intends to advance MZE829 into a pivotal program and will provide regulatory/clinical updates this year, saying it is well‑capitalized with a cash runway into 2028 (and a recent $20M milestone from a Shionogi collaboration).

Maze Therapeutics NASDAQ: MAZE outlined positive Phase II results from its open-label HORIZON study evaluating MZE829 in patients with APOL1-mediated kidney disease (AMKD), highlighting reductions in proteinuria across a “broad” AMKD population that included patients with and without type 2 diabetes and patients with focal segmental glomerulosclerosis (FSGS).

Executives said the company plans to advance MZE829 into a pivotal program and expects to provide updates on regulatory progress and clinical development plans over the course of the year. Maze also reiterated that it is “well-capitalized” to advance its pipeline, with an expected cash runway into 2028 based on its current business plan.

AMKD landscape and MZE829’s mechanism

Maze described itself as a clinical-stage biopharmaceutical company using human genetics to develop small-molecule precision medicines for kidney and metabolic diseases. The company said an estimated 6 million patients in the U.S. have genetic variants that cause AMKD, with 1 million having some form of kidney disease. Using a proteinuria cutoff of 300 mg per gram (the threshold used for HORIZON), Maze said at least 250,000 individuals could potentially benefit from a therapeutic approach.

Maze also cited prior conference and external data indicating that about 40% of AMKD patients are diabetic and about 60% are non-diabetic, and said there is currently no approved therapy for AMKD.

Management positioned MZE829 as differentiated due to a dual mechanism of action: it blocks the APOL1 pore and disrupts pore assembly in kidney cells. Maze argued that disrupting pore assembly could be important because APOL1 pores “rapidly turn over” in kidney cells, potentially making MZE829 more potent than other molecules in AMKD.

HORIZON trial design and endpoints

According to Maze, HORIZON is a Phase II, open-label, basket-design trial enrolling patients with broad AMKD who carry two high-risk APOL1 alleles (G1 and G2). The study includes patients with baseline proteinuria of at least 300 mg albumin per gram of creatinine and is designed to include patients with more moderate disease.

Key design elements discussed on the call included:

• An eight-week lead-in period on standard of care before starting MZE829, intended to minimize confounding from improved adherence during the trial.
• Dosing of 250 mg MZE829 once daily for 12 weeks, followed by four weeks of follow-up on standard of care alone.
• Primary endpoints of safety and tolerability; secondary endpoints including pharmacokinetics and proteinuria reduction.
• Proteinuria assessed using urinary albumin-to-creatinine ratio (uACR), with a key efficacy measure defined as the percentage of subjects achieving a ≥30% reduction from baseline at week 12.

Maze noted that a ≥30% reduction in uACR is broadly accepted in the field as clinically meaningful and has previously guided that meeting or exceeding that threshold in HORIZON would constitute proof of concept and inform plans for a pivotal AMKD program.

Efficacy: uACR reductions across broad AMKD, FSGS, and non-diabetic patients

The company’s presentation focused on 15 patients with AMKD (eight without type 2 diabetes and seven with). Maze said all patients who received at least one dose were included in the safety analysis, while 12 patients who received at least 80% of scheduled doses were included in the per-protocol efficacy analysis.

In the per-protocol efficacy set, Maze reported that 50% of patients achieved at least a 30% reduction in uACR at week 12, and the mean uACR reduction across subgroups was 36% (also described as 35.6% in a summary statement).

Maze also highlighted subgroup results presented from HORIZON:

• FSGS patients: 61.8% mean uACR reduction at week 12; the company also reported a 59.4% mean reduction in uPCR in FSGS.
• Patients without diabetes: 48.6% mean uACR reduction at week 12, with a 57% response rate based on achieving a ≥30% reduction.

Company representatives said the data represent the first results in “broader, more moderate” AMKD patients, including patients with diabetes. They also discussed early data in diabetic AMKD, noting that two of five treated patients showed meaningful responses, which the company described as the first clinical confirmation of potential benefit with an APOL1 inhibitor in this population. Maze detailed two diabetic cases: one patient had a 47% reduction in proteinuria despite stable background therapies for at least eight weeks prior to MZE829, and another had a 35% reduction despite receiving an SGLT2 inhibitor, finerenone (KERENDIA), and antihypertensives.

Safety and tolerability

Maze said MZE829 was well tolerated in HORIZON, consistent with prior Phase I studies, and reported no serious adverse events and no safety or tolerability signals. Treatment-related adverse events were described as mild or moderate, with headache and diarrhea the most common treatment-related events (each occurring in two participants).

The company said there were no clinically relevant changes in vital signs, laboratory tests, or ECGs. One severe adverse event was reported: bilateral cataracts in a diabetic AMKD patient on day two of dosing. Maze said the patient had been scheduled for cataract surgery prior to enrollment and the event was deemed unrelated to MZE829. One discontinuation occurred due to mild nausea; the patient met the compliance threshold for inclusion in both safety and efficacy analyses.

Next steps: pivotal planning, additional data, and other corporate updates

Management said it intends to advance MZE829 into a pivotal program and is still evaluating details such as patient populations, dose selection, and timing of regulatory interactions. Executives indicated they would like to see more data in diabetic AMKD as HORIZON continues enrolling to inform next steps in that subgroup, and they expect to present additional HORIZON data at a medical conference later this year.

In Q&A, Maze said uACR reductions showed a steady decline over the 12-week treatment period, with proteinuria returning toward baseline after stopping therapy, which the company argued supports an on-treatment drug effect. Maze also said it does not expect to see an eGFR response over a 12-week period and characterized serum creatinine monitoring as reassuring from a safety standpoint.

Separately, Maze highlighted pipeline and corporate developments, including continued advancement of MZE782 into two Phase II trials (one in PKU and one in chronic kidney disease). The company also announced that Shionogi Pharma dosed the first patient in its Phase II Pompe disease study, which Maze said triggers a $20 million milestone payment under the companies’ global collaboration agreement. Maze additionally announced Dr. Neil Kumar, founder and CEO of BridgeBio Pharma, joined its board of directors.

About Maze Therapeutics NASDAQ: MAZE

Maze Therapeutics, Inc NASDAQ: MAZE is a clinical‐stage biotechnology company focused on the discovery and development of novel therapeutics by leveraging insights from human genetics and genomics. The company applies advanced data analytics and proprietary platforms to identify targets with strong genetic validation, aiming to de‐risk early drug discovery and accelerate the development of medicines for patients with serious diseases. Maze's approach centers on translating naturally occurring human mutations into a deeper understanding of disease biology, with an emphasis on validating therapeutic hypotheses before advancing into the clinic.

Since its inception, Maze has assembled a diversified pipeline of programs across metabolic, immunological and other therapeutic areas.

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