Safety and Pharmacokinetics of AT-007 in Healthy Subjects and in Adult Subjects With Classic Galactosemia

A Phase 1-2, Dose-Escalating, 4-Part Study to Evaluate the Safety and Pharmacokinetics of Single and Multiple Doses of AT-007 in Healthy Adult Subjects and Adult Subjects With Classic Galactosemia

This study is a first-in-human, randomized, placebo-controlled, 4-Part, single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adult subjects and adult subjects with Classic Galactosemia.

Study Overview

• Status: Completed
• Conditions: Classic Galactosemia
• Intervention / Treatment: Drug: AT-007; Drug: placebo

Detailed Description

The study is designed to assess the safety and PK of AT-007 in healthy subjects and subjects with Classic Galactosemia as well as the effect of AT-007 on biomarkers of galactose metabolism (galactose, galactitol, and other galactose metabolites) in subjects with Classic Galactosemia.

This study consists of 4 parts:

• Part A (SAD) in 32 healthy subjects. Once daily oral escalating dose (6 active, 2 placebo).
• Part B and C (MAD for 7 days) in 36 healthy subjects. Once daily multiple daily dosing (8 active, 2 placebo per each dose cohort).
• Part D (SAD followed by MAD for 27 days) in 18 subjects with Classic Galactosemia. Once daily followed by multiple daily oral dosing (6 active, 2 placebo for each dose cohort).

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Anaheim, California, United States, 92801
      • Anaheim Clinical Trials, LLC
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • Atlanta Center for Medical Research
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Texas
    • San Antonio, Texas, United States, 78209
      • ICON Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of Classic Galactosemia confirmed by evidence of absent or significantly decreased (<1%) GALT activity in red blood cells and by GALT gene analysis
• Urine galactitol >100 mmol/mol creatinine
• Galactose-restricted diet

Exclusion Criteria:

• Complications of CG resulting in disability that, in the opinion of the Investigator, may prevent the subject from completing all study requirements (e.g., severe neurological deficits, severe cognitive impairment, or severe language difficulty).
• Renal disease (eGFR < 90 mL/min/1.73 m2 or albuminuria).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Comparator	Drug: placebo; Matching placebo will be administered once in the morning before breakfast
Experimental: AT-007	Drug: AT-007; AT-007 will be administered once daily before breakfast. Up to 4 different dose cohorts in part A; up to 4 dose cohorts in part B, up to 2 dose cohorts for part C, and up to 3 dose cohorts for part D will be enrolled in the study. The starting dose in Part A will be 0.5 mg/kg as a single dose. Subsequent doses in Part A and all doses in Parts B, C, and D will be based on the results of previous cohorts and/or previous parts of the study. Part B will start after all subjects in Part A have completed the study. Cohort C1 will be conducted simultaneously with Cohort B3 and using the same dose as Cohort B2. The dose for Cohort D1 will not be higher than the dose for Cohort B2. The second and third cohorts in Part D (D2 and D3) will not start until after all subjects in Cohorts B3 and B4, respectively, have completed the study and the dose levels will not be higher than those for Cohorts B3 and B4, respectively.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-emergent adverse events	To evaluate the safety and tolerability of AT-007 after a single dose administered to healthy subjects, including clinically-significant changes in clinical laboratory test results, physical examination findings, vital sign evaluations, and electrocardiogram results.	1 Day after Dosing
Number of participants with treatment-emergent adverse events	To evaluate the safety and tolerability of AT-007 after multiple doses administered to healthy subjects, including clinically-significant changes in clinical laboratory test results, physical examination findings, vital sign evaluations, and electrocardiogram results.	7 Days after Dosing
Number of participants with treatment-emergent adverse events	To evaluate the safety and tolerability of AT-007 after multiple doses administered to Classic Galactosemia Patients, including clinically-significant changes in clinical laboratory test results, physical examination findings, vital sign evaluations, and electrocardiogram results.	28 Days after Dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of AT-007	Maximum (peak) plasma drug concentration	Sequential sampling up to 48 hours following drug administration
Tmax of AT-007	Time to reach maximum (peak) plasma drug concentration	Sequential sampling up to 48 hours following drug administration
t1/2 of AT-007	Terminal Elimination Half-life	Sequential sampling up to 48 hours following drug administration
AUClast of AT-007	Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration	Sequential sampling up to 48 hours following drug administration
AUCinf of AT-007	Area under the plasma concentration-time curve from time zero extrapolated to infinity	Sequential sampling up to 48 hours following drug administration
Galactose Concentration in Plasma	Disease-Specific Biomarker in Classic Galactosemia Patients	Sequential sampling for 28 days following drug administration
Galactose Concentration in Urine	Disease-Specific Biomarker in Classic Galactosemia Patients	Sequential sampling for 28 days following drug administration
Galactitol Concentration in Plasma	Disease Specific Biomarker in Classic Galactosemia Patients	Sequential sampling for 28 days following drug administration
Galactitol Concentration in Urine	Disease Specific Biomarker in Classic Galactosemia Patients	Sequential sampling for 28 days following drug administration
Galactose-1-P Concentration in Erythrocytes	Disease-Specific Biomarker in Classic Galactosemia Patients	Sequential sampling for 28 days following drug administration

Collaborators and Investigators

• Sponsor: Applied Therapeutics, Inc.
• Investigators: Principal Investigator: Robert Green, MD, MPH, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2019
• Primary Completion (Actual): December 14, 2021
• Study Completion (Actual): December 14, 2021

Study Registration Dates

• First Submitted: August 23, 2019
• First Submitted That Met QC Criteria: October 3, 2019
• First Posted (Actual): October 7, 2019

Study Record Updates

• Last Update Posted (Actual): June 3, 2022
• Last Update Submitted That Met QC Criteria: June 2, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Classic Galactosemia; Aldose Reductase Inhibition; Galactose, Galactitol
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Galactosemias
• Other Study ID Numbers: AT-007-1001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No