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

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Classic Galactosemia

Intervention / Treatment
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* Drug: AT-007
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AT-007<br> | Drug: AT-007<br>* 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.<br>|
| Placebo Comparator: Placebo Comparator<br> | Drug: placebo<br>* Matching placebo will be administered once in the morning before breakfast<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Classic Galactosemia, Aldose Reductase Inhibition, Galactose, Galactitol