This is a phase 1 randomized, double-blind, single ascending dose (SAD) and multiple ascending dose (MAD) study to assess the safety, tolerability, and Pharmacokinetics (PK) of single and multiple ascending doses of MTX-439 administered in healthy adults and adults with diabetic kidney disease (DKD)
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. 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. 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. . Planned doses may be adjusted in response to the data. Additional participants and/or additional dosing cohorts may be added as needed based on the data. Within each 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).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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
QUADRUPLE
Enrollment
88
Doherty Clinical Trials
Melbourne, Victoria, Australia
RECRUITINGIncidence of Dose-Limiting Toxicities (DLTs)
Number and percentage of participants who experience a dose-limiting toxicity (DLT) as defined in the protocol. Unit of Measure: Number of participants; Percentage of participants (%)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Incidence of Treatment-Emergent Adverse Events (TEAEs)
Number and percentage of participants with at least one treatment-emergent adverse event (TEAE). TEAEs will be summarized by seriousness and maximum severity according to protocol-defined criteria Unit of Measure: Number of participants; Percentage of participants (%)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Incidence of Treatment-Related Adverse Events (TRAEs)
Number and percentage of participants with at least one adverse event considered related to study intervention by the investigator. Unit of Measure: Number of participants; Percentage of participants (%)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Incidence of Dose Modifications Due to Adverse Events
Number and percentage of participants requiring dose interruption, dose reduction, or permanent discontinuation of study intervention due to adverse events. Unit of Measure: Number of participants; Percentage of participants (%)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Clinically Significant Changes in Physical Examination Findings
Number and percentage of participants with clinically significant abnormalities in physical examination findings. Unit of Measure: Number of participants; Percentage of participants (%)
Time frame: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
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Clinically Significant Changes in Vital Signs
Number and percentage of participants with clinically significant changes from baseline in vital signs measurements (including blood pressure, heart rate, respiratory rate, temperature, and pulse oximetry). Unit of Measure: Number of participants; Percentage of participants (%)
Time frame: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Clinically Significant Changes in Electrocardiogram (ECG) Parameters
Number and percentage of participants with clinically significant abnormalities in ECG parameters (including but not limited to PR interval, QRS duration, and QT/QTc interval). Unit of Measure: Number of participants; Percentage of participants (%)
Time frame: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Clinically Significant Changes in Clinical Laboratory Parameters
Number and percentage of participants with clinically significant changes from baseline in hematology, clinical chemistry, urinalysis, and other protocol-specified laboratory parameters. Unit of Measure: Number of participants; Percentage of participants (%)
Time frame: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Maximum Observed Plasma Concentration (Cmax) of MTX-439
Maximum observed plasma concentration (Cmax) of MTX-439 following single and multiple ascending doses. Unit of Measure: Nanograms per milliliter (ng/mL)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Area Under the Plasma Concentration-Time Curve From Time Zero to Time t (AUC0-t) of MTX-439
Area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t) of MTX-439. Unit of Measure: Nanogram·hour per milliliter (ng·h/mL)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of MTX-439
Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-∞) of MTX-439. Unit of Measure: Nanogram·hour per milliliter (ng·h/mL)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Area Under the Plasma Concentration-Time Curve Over the Dosing Interval (AUC0-tau) of MTX-439
Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) of MTX-439 at steady state, where applicable Unit of Measure: Nanogram·hour per milliliter (ng·h/mL)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Time to Maximum Plasma Concentration (Tmax) of MTX-439
Time to reach maximum observed plasma concentration (Tmax) of MTX-439 following dosing. Unit of Measure: Hours (h)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Terminal Elimination Half-Life (t1/2) of MTX-439
Terminal elimination half-life (t1/2) of MTX-439 following dosing. Unit of Measure: Hours (h)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Incidence and Characterization of Anti-Drug Antibodies (ADA)
Number and percentage of participants with detectable anti-drug antibodies (ADA), including ADA titer and assessment of the impact of ADA on PK and safety, if applicable. Unit of Measure: Number of participants; Percentage of participants (%); Titer (unitless dilution factor)
Time frame: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Change From Baseline in Total SMOC2 Levels
Change from Baseline in circulating total SMOC2 levels following administration of MTX-439 Unit of Measure: Nanograms per milliliter (ng/mL)
Time frame: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Change From Baseline in Free SMOC2 Levels
Change from Baseline in circulating free SMOC2 levels following administration of MTX-439. Unit of Measure: Nanograms per milliliter (ng/mL)
Time frame: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts