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

Phase 1

Completed

• Conditions: Classic Galactosemia
• Interventions: Drug: Placebo; Drug: AT-007

• Registration Number: NCT04117711
• Lead Sponsor: Applied Therapeutics, Inc.

Brief Summary

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.

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 Timeline

• Study Start: 2019-06-21
• Study First Submitted: 2019-08-23
• Study First Submitted QC: 2019-10-03
• Study First Posted: 2019-10-07
• Primary Completion: 2021-12-14
• Study Completion: 2021-12-14
• Results First Submitted: 2023-07-25
• Status Verified: 2024-05
• Results First Submitted QC: 2024-05-29
• Last Update Submitted: 2024-05-29
• Results First Posted: 2024-05-30
• Last Update Posted: 2024-05-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 114

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Comparator	Placebo	Placebo is used as a comparator to the experimental arm.
AT-007	AT-007	AT-007 is a CNS and retina penetrant aldose reductase inhibitor.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-emergent Adverse Events	90 Days after Dosing	To evaluate the safety and tolerability of AT-007 administered to Classic Galactosemia Patients, including clinically-significant changes in clinical laboratory test results, physical examination findings, vital sign evaluations, and electrocardiogram results.

Secondary Outcome Measures

Name	Time	Method
Maximal Galactitol Reduction in Plasma	Part D: Samples at predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours on days 1, 12, 32. Part D Extension: Samples at predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours on days 1, 30, 60, & 90.	Disease-Specific Biomarker in Classic Galactosemia Patients
Galactose-1-Phosphate (Gal-1p) Concentration in Plasma	Part D: Day 32. Part D Extension: Days 30, 60, & 90.	Disease-Specific Biomarker in Classic Galactosemia Patients
Cmax of AT-007	Part A: Sampling- predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 48 hrs Parts B, C, D: Day of Last Dose for each Part- predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 48 hrs D Extension: Day 30, 60, 90- predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 48 hrs	Maximum (peak) plasma drug concentration
Tmax of AT-007	Part A: Sampling- predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 48 hrs Parts B, C, D: Day of Last Dose for each Part- predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 48 hrs D Extension: Day 30, 60, 90- predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 48 hrs	Time to reach maximum (peak) plasma drug concentration
t1/2 of AT-007	Part A: Sequential sampling at predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours. Parts B, C, D: Determined using Day of Last Dose for the respective Part; predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours.	Terminal elimination half life
AUClast of AT-007	Part A: Sequential sampling at predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours. Parts B, C, D: Determined using Day of Last Dose for the respective Part at predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours.	Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration
AUCinf of AT-007	Part A: Sequential sampling at predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours. Part D: Determined using Day 1 with sampling at predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours.	Area under the plasma concentration-time curve from time zero extrapolated to infinity
Galactose Concentration in Plasma	Part D: Day 32. Part D Extension: Days 30, 60, & 90.	Disease-Specific Biomarker in Classic Galactosemia Patients

Trial Locations

Locations (4)

Anaheim Clinical Trials, LLC; 🇺🇸 Anaheim, California, United States

Atlanta Center for Medical Research; 🇺🇸 Atlanta, Georgia, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

ICON Clinical Research; 🇺🇸 San Antonio, Texas, United States