A Phase 1 Randomized, Double-blind, Dose-Escalating Study to Assess the Safety, Tolerability, and Pharmacokinetics of MTX-439 in Healthy Adults and Adults With Diabetic Kidney Disease

This is a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) study to assess the safety, tolerability, and PK of single- and multiple-ascending doses of MTX-439 administered in healthy adults and adults with DKD (Diabetic Kidney Disease). The SAD portion of the study with healthy participants will consist of 5 planned intravenous (IV) dosing cohorts, comprising 8 participants. Dosing will be weight based, and the starting dose will be 100 fold below the top of the safety window (1 mg/kg). Doses will then be increased, depending on the safety, tolerability and drug exposure levels, in subsequent Cohorts, with increases proceeding in either 2x or 3x increments. The exact doses are yet to be determined. Planned doses may be adjusted in response to the data after a cohort-by-cohort safety review committee meeting. Additional participants and/or additional dosing cohorts may be added as needed based on the data. Within each Healthy Participant (HP) cohort, participants will be randomly assigned to receive MTX-439 or matched placebo. The first 2 participants (sentinel participants) within each HP cohort will be randomized 1:1 to receive MTX-439 or placebo on Day 1. These participants will be monitored for 24 hours and, after review of the safety data from both participants and approval by the study Investigator, Medical Monitor, and Sponsor's Responsible Medical Officer (SRMO), the additional 6 participants will be randomized to study drug (n=5 MTX-439; n=1 placebo). In addition, a minimum of 2 planned IV dosing cohorts comprising 8 DKD participants will receive MTX439 or matched placebo to assess the PK in patients vs healthy controls. DKD Cohort 1 may be dosed any time after the dose escalation meeting for HP Cohort 2 is completed, and the decision is made to dose escalate. The starting dose of study drug in DKD Cohort 1 will be the same as the dose for Cohort 1 in healthy volunteers. No dose can be administered to DKD participants until the same or higher dose has been safely administered to healthy participants. Participants in the DKD SAD portion of the study will be randomized 3:1 to receive MTX-439 or matched placebo on Day 1. Sentinel dosing will not be required in DKD cohorts. The MAD portion of the study will consist of 4 planned IV dosing cohorts comprising 8 healthy participants (n=6 MTX-439; n=2 placebo). Participants from the SAD portion of the study will not be permitted to participate in the MAD portion of the study, Dosing for each MAD cohort is planned for Day 1, Day 15 and Day 29. Cohort 1 of the MAD portion of the study can begin following completion of the SAD Cohort 2 safety meeting and once the study Investigator, Medical Monitor, and SRMO decide to proceed to HP SAD Cohort 3. Dose escalation will occur depending on the safety, tolerability and PK in previous cohorts. Participants will be in the study will be followed for safety and be assessed for PK and immunogenicity. For SAD cohorts, participation will be 85 days and for MAD cohorts 113 days.