Classic Galactosemia
Conditions
Keywords
Classic Galactosemia, Aldose Reductase Inhibition, Galactose, Galactitol
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).
Interventions
DRUGAT-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.
DRUGPlacebo
Matching placebo will be administered once in the morning before breakfast
Sponsors
Applied Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events | Events after 1 day of administration. | To evaluate the safety and tolerability of AT-007 after administration to healthy subjects, including clinically-significant changes in clinical laboratory test results, physical examination findings, vital sign evaluations, and electrocardiogram results. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 Concentration in Plasma | Part D: Day 32. Part D Extension: Days 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 |
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg Baseline characteristics of the healthy adult subjects enrolled in Part A were well-balanced between active and placebo across all dosing cohorts. | 6 |
| Part A Cohort 2: AT-007 5mg/kg Baseline characteristics of the healthy adult subjects enrolled in Part A were well-balanced between active and placebo across all dosing cohorts. | 6 |
| Part A Cohort 3: AT-007 10mg/kg Baseline characteristics of the healthy adult subjects enrolled in Part A were well-balanced between active and placebo across all dosing cohorts. | 6 |
| Part A Cohort 4: AT-007 20mg/kg Baseline characteristics of the healthy adult subjects enrolled in Part A were well-balanced between active and placebo across all dosing cohorts. | 6 |
| Part A Cohort 5: AT-007 40mg/kg Baseline characteristics of the healthy adult subjects enrolled in Part A were well-balanced between active and placebo across all dosing cohorts. | 6 |
| Part A Placebo Comparator Baseline characteristics of the healthy adult subjects enrolled in Part A were well-balanced between active and placebo across all dosing cohorts. | 10 |
| Part B & C AT-007 5mg/kg Cohort Baseline characteristics of the healthy adult subjects enrolled in Part B & C were well-balanced between active and placebo across all dosing cohorts. | 6 |
| Part B & C AT-007 10mg/kg Cohort Baseline characteristics of the healthy adult subjects enrolled in Part B & C were well-balanced between active and placebo across all dosing cohorts. | 8 |
| Part B & C AT-007 20mg/kg Cohort Baseline characteristics of the healthy adult subjects enrolled in Part B & C were well-balanced between active and placebo across all dosing cohorts. | 10 |
| Part B & C AT-007 40mg/kg Cohort Baseline characteristics of the healthy adult subjects enrolled in Part B & C were well-balanced between active and placebo across all dosing cohorts. | 9 |
| Part B & C Placebo Comparator Baseline characteristics of the healthy adult subjects enrolled in Part B & C were well-balanced between active and placebo across all dosing cohorts. | 8 |
| Part D Cohort 1: AT-007 5mg/kg Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D were well-balanced between active and placebo across all dosing cohorts. | 3 |
| Part D Cohort 1 (Placebo) Then Cohort 2 (AT-007 20mg/kg) Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D were well-balanced between active and placebo across all dosing cohorts. | 1 |
| Part D Cohort 1 (AT-007 5mg/kg) Then Cohort 3 (AT-007 40mg/kg) Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D were well-balanced between active and placebo across all dosing cohorts. | 1 |
| Part D Cohort 1 (Placebo) Then Cohort 3 (AT-007 40mg/kg) Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D were well-balanced between active and placebo across all dosing cohorts. | 1 |
| Part D Cohort 2: AT-007 20mg/kg Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D were well-balanced between active and placebo across all dosing cohorts. | 2 |
| Part D Cohort 2 (AT-007 20mg/kg) Then Chort 3 (AT-007 40mg/kg) Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D were well-balanced between active and placebo across all dosing cohorts. | 1 |
| Part D Cohort 3: AT-007 40mg/kg Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D were well-balanced between active and placebo across all dosing cohorts. | 1 |
| Part D Placebo Comparator Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D were well-balanced between active and placebo across all dosing cohorts. | 4 |
| Part D Extension Placebo Comparator Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D Extension were well-balanced between active and placebo across all dosing cohorts. | 4 |
| Part D Extension Cohort 1: AT-007 20mg/kg Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D Extension were well-balanced between active and placebo across all dosing cohorts. | 9 |
| Part D Extension Cohort 2: AT-007 40mg/kg Baseline characteristics of the adult subjects with Classic Galactosemia enrolled in Part D Extension were well-balanced between active and placebo across all dosing cohorts. | 2 |
| Total | 110 |
Baseline characteristics
| Characteristic | Part B & C Placebo Comparator | Part B & C AT-007 40mg/kg Cohort | Part B & C AT-007 20mg/kg Cohort | Part B & C AT-007 10mg/kg Cohort | Part B & C AT-007 5mg/kg Cohort | Part A Placebo Comparator | Part A Cohort 5: AT-007 40mg/kg | Part A Cohort 4: AT-007 20mg/kg | Part A Cohort 3: AT-007 10mg/kg | Part A Cohort 2: AT-007 5mg/kg | Part A Cohort 1: AT-007 0.5mg/kg | Part D Cohort 1: AT-007 5mg/kg | Part D Cohort 1 (Placebo) Then Cohort 2 (AT-007 20mg/kg) | Part D Cohort 1 (AT-007 5mg/kg) Then Cohort 3 (AT-007 40mg/kg) | Part D Cohort 1 (Placebo) Then Cohort 3 (AT-007 40mg/kg) | Part D Cohort 2: AT-007 20mg/kg | Part D Cohort 2 (AT-007 20mg/kg) Then Chort 3 (AT-007 40mg/kg) | Part D Cohort 3: AT-007 40mg/kg | Part D Placebo Comparator | Part D Extension Placebo Comparator | Part D Extension Cohort 1: AT-007 20mg/kg | Part D Extension Cohort 2: AT-007 40mg/kg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 37 years | 27.0 years | 35.0 years | 35.5 years | 32.5 years | 54.5 years | 31.5 years | 44.0 years | 35.0 years | 54.0 years | 42.5 years | 19.5 years | 37 years | 50 years | 19 years | 20.5 years | 28 years | 43 years | 32 years | 29.5 years | 22.0 years | 36.0 years | NA years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 6 Participants | 3 Participants | 4 Participants | 9 Participants | 3 Participants | 2 Participants | 2 Participants | 5 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 4 Participants | 4 Participants | 5 Participants | 2 Participants | 1 Participants | 3 Participants | 4 Participants | 4 Participants | 1 Participants | 5 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 4 Participants | 9 Participants | 2 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Galactitol | — | — | — | — | — | — | — | — | — | — | — | 2490 ng/mL | 2380 ng/mL | 2140 ng/mL | 2360 ng/mL | 2170 ng/mL | 2340 ng/mL | 2810 ng/mL | 2480 ng/mL | 2612.5 ng/mL | 2300 ng/mL | NA ng/mL | 2434.4 ng/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 3 Participants | 4 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 7 Participants | 6 Participants | 4 Participants | 5 Participants | 9 Participants | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 4 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 4 Participants | 9 Participants | 2 Participants | 82 Participants |
| Region of Enrollment United States | 8 participants | 9 participants | 10 participants | 8 participants | 6 participants | 10 participants | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 3 participants | 1 participants | 1 participants | 1 participants | 2 participants | 1 participants | 1 participants | 4 participants | 4 participants | 9 participants | 2 participants | 110 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 4 Participants | 3 Participants | 5 Participants | 8 Participants | 4 Participants | 4 Participants | 2 Participants | 5 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 3 Participants | 0 Participants | 56 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 6 Participants | 5 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 4 Participants | 1 Participants | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 6 Participants | 2 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 | 0 / 6 | 0 / 8 | 0 / 10 | 0 / 9 | 0 / 8 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 6 | 0 / 9 | 0 / 2 | 0 / 4 |
| other Total, other adverse events | 1 / 6 | 0 / 6 | 0 / 6 | 2 / 6 | 1 / 6 | 2 / 10 | 1 / 6 | 2 / 8 | 3 / 10 | 1 / 9 | 2 / 8 | 3 / 4 | 1 / 4 | 2 / 4 | 2 / 6 | 7 / 9 | 1 / 2 | 2 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 | 0 / 6 | 0 / 8 | 0 / 10 | 0 / 9 | 0 / 8 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 6 | 1 / 9 | 0 / 2 | 0 / 4 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events
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.
Time frame: 90 Days after Dosing
Population: All subjects dosed were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | Number of Participants With Treatment-emergent Adverse Events | 7 Participants |
| Part A Cohort 2: AT-007 5mg/kg | Number of Participants With Treatment-emergent Adverse Events | 1 Participants |
| Part A Cohort 3: AT-007 10mg/kg | Number of Participants With Treatment-emergent Adverse Events | 2 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events
To evaluate the safety and tolerability of AT-007 after multiple ascending doses are administered to healthy subjects, including clinically-significant changes in clinical laboratory test results, physical examination findings, vital sign evaluations, and electrocardiogram results. Part B and Part C are combined.
Time frame: 7 Days after Dosing
Population: All subjects dosed were analyzed
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | Number of Participants With Treatment-emergent Adverse Events | 1 Participants |
| Part A Cohort 2: AT-007 5mg/kg | Number of Participants With Treatment-emergent Adverse Events | 2 Participants |
| Part A Cohort 3: AT-007 10mg/kg | Number of Participants With Treatment-emergent Adverse Events | 3 Participants |
| Part A Cohort 4: AT-007 20mg/kg | Number of Participants With Treatment-emergent Adverse Events | 1 Participants |
| Part A Cohort 5: AT-007 40mg/kg | Number of Participants With Treatment-emergent Adverse Events | 2 Participants |
Primary
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.
Time frame: 28 Days of Dosing
Population: All subjects dosed were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | Number of Participants With Treatment-emergent Adverse Events | 3 Participants |
| Part A Cohort 2: AT-007 5mg/kg | Number of Participants With Treatment-emergent Adverse Events | 1 Participants |
| Part A Cohort 3: AT-007 10mg/kg | Number of Participants With Treatment-emergent Adverse Events | 2 Participants |
| Part A Cohort 4: AT-007 20mg/kg | Number of Participants With Treatment-emergent Adverse Events | 2 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events
To evaluate the safety and tolerability of AT-007 after administration to healthy subjects, including clinically-significant changes in clinical laboratory test results, physical examination findings, vital sign evaluations, and electrocardiogram results.
Time frame: Events after 1 day of administration.
Population: All subjects dosed were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | Number of Participants With Treatment-emergent Adverse Events | 1 Participants |
| Part A Cohort 2: AT-007 5mg/kg | Number of Participants With Treatment-emergent Adverse Events | 0 Participants |
| Part A Cohort 3: AT-007 10mg/kg | Number of Participants With Treatment-emergent Adverse Events | 0 Participants |
| Part A Cohort 4: AT-007 20mg/kg | Number of Participants With Treatment-emergent Adverse Events | 2 Participants |
| Part A Cohort 5: AT-007 40mg/kg | Number of Participants With Treatment-emergent Adverse Events | 1 Participants |
| Part A: Placebo Comparator | Number of Participants With Treatment-emergent Adverse Events | 2 Participants |
Secondary
AUCinf of AT-007
Area under the plasma concentration-time curve from time zero extrapolated to infinity
Time frame: 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.
Population: AUCinf was only calculated for all cohorts of Part A and on Day 1 of Part D. It was not calculated for Parts B, C, or D Extension so those cohorts are not presented.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | AUCinf of AT-007 | 14.3 microgram*hour/mL | Geometric Coefficient of Variation 43.7 |
| Part A Cohort 2: AT-007 5mg/kg | AUCinf of AT-007 | 81.8 microgram*hour/mL | Geometric Coefficient of Variation 15.1 |
| Part A Cohort 3: AT-007 10mg/kg | AUCinf of AT-007 | 169 microgram*hour/mL | Geometric Coefficient of Variation 35.3 |
| Part A Cohort 4: AT-007 20mg/kg | AUCinf of AT-007 | 163 microgram*hour/mL | — |
| Part A Cohort 5: AT-007 40mg/kg | AUCinf of AT-007 | 655 microgram*hour/mL | Geometric Coefficient of Variation 0.45 |
| Part A: Placebo Comparator | AUCinf of AT-007 | 109 microgram*hour/mL | Geometric Coefficient of Variation 28.2 |
| Part B & C Cohort 2: AT-007 10mg/kg | AUCinf of AT-007 | 518 microgram*hour/mL | Geometric Coefficient of Variation 65.2 |
| Part B & C Cohort 3: AT-007 20mg/kg | AUCinf of AT-007 | 1327 microgram*hour/mL | Geometric Coefficient of Variation 17.2 |
Secondary
AUClast of AT-007
Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration
Time frame: 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.
Population: For Part D Extension, AUClast was not performed so these cohorts are not presented.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | AUClast of AT-007 | 12.6 microgram*hour/mL | Geometric Coefficient of Variation 44.7 |
| Part A Cohort 2: AT-007 5mg/kg | AUClast of AT-007 | 89.0 microgram*hour/mL | Geometric Coefficient of Variation 18.5 |
| Part A Cohort 3: AT-007 10mg/kg | AUClast of AT-007 | 158 microgram*hour/mL | Geometric Coefficient of Variation 35 |
| Part A Cohort 4: AT-007 20mg/kg | AUClast of AT-007 | 352 microgram*hour/mL | Geometric Coefficient of Variation 75 |
| Part A Cohort 5: AT-007 40mg/kg | AUClast of AT-007 | 624 microgram*hour/mL | Geometric Coefficient of Variation 28 |
| Part A: Placebo Comparator | AUClast of AT-007 | 181 microgram*hour/mL | Geometric Coefficient of Variation 44.3 |
| Part B & C Cohort 2: AT-007 10mg/kg | AUClast of AT-007 | 311 microgram*hour/mL | Geometric Coefficient of Variation 47.4 |
| Part B & C Cohort 3: AT-007 20mg/kg | AUClast of AT-007 | 592 microgram*hour/mL | Geometric Coefficient of Variation 26.9 |
| Part B & C Cohort 4: AT-007 40mg/kg | AUClast of AT-007 | 1110 microgram*hour/mL | Geometric Coefficient of Variation 50.2 |
| Part D Cohort 1: AT-007 5mg/kg | AUClast of AT-007 | 172 microgram*hour/mL | Geometric Coefficient of Variation 25.3 |
| Part D Cohort 2: AT-007 20mg/kg | AUClast of AT-007 | 698 microgram*hour/mL | Geometric Coefficient of Variation 21.8 |
| Part D Cohort 3: AT-007 40mg/kg | AUClast of AT-007 | 1006 microgram*hour/mL | Geometric Coefficient of Variation 62.3 |
Secondary
Cmax of AT-007
Maximum (peak) plasma drug concentration
Time frame: 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
Population: Part D Extension Cohort 2 40mg/kg ended early at Day 30 as recommended by Monitoring Committee. As such, only 1 subject has D30 data available; the other subject did not have enough blood samples to calculate.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | Cmax of AT-007 | 1.53 microgram/mL | Geometric Coefficient of Variation 55.2 |
| Part A Cohort 2: AT-007 5mg/kg | Cmax of AT-007 | 8.92 microgram/mL | Geometric Coefficient of Variation 31.4 |
| Part A Cohort 3: AT-007 10mg/kg | Cmax of AT-007 | 15.2 microgram/mL | Geometric Coefficient of Variation 49.5 |
| Part A Cohort 4: AT-007 20mg/kg | Cmax of AT-007 | 27 microgram/mL | Geometric Coefficient of Variation 103 |
| Part A Cohort 5: AT-007 40mg/kg | Cmax of AT-007 | 57.4 microgram/mL | Geometric Coefficient of Variation 23.2 |
| Part A: Placebo Comparator | Cmax of AT-007 | 15.2 microgram/mL | Geometric Coefficient of Variation 45 |
| Part B & C Cohort 2: AT-007 10mg/kg | Cmax of AT-007 | 23.0 microgram/mL | Geometric Coefficient of Variation 39 |
| Part B & C Cohort 3: AT-007 20mg/kg | Cmax of AT-007 | 47.8 microgram/mL | Geometric Coefficient of Variation 35.4 |
| Part B & C Cohort 4: AT-007 40mg/kg | Cmax of AT-007 | 72.8 microgram/mL | Geometric Coefficient of Variation 44.9 |
| Part D Cohort 1: AT-007 5mg/kg | Cmax of AT-007 | 13.7 microgram/mL | Geometric Coefficient of Variation 34 |
| Part D Cohort 2: AT-007 20mg/kg | Cmax of AT-007 | 39.9 microgram/mL | Geometric Coefficient of Variation 70.8 |
| Part D Cohort 3: AT-007 40mg/kg | Cmax of AT-007 | 67.9 microgram/mL | Geometric Coefficient of Variation 68 |
| Part D Extension Cohort 1: AT-007 20mg/kg DAY 30 | Cmax of AT-007 | 48.6 microgram/mL | Geometric Coefficient of Variation 21.8 |
| Part D Extension Cohort 1: AT-007 20mg/kg DAY 60 | Cmax of AT-007 | 48.0 microgram/mL | Geometric Coefficient of Variation 24.4 |
| Part D Extension Cohort 1: AT-007 20mg/kg DAY 90 | Cmax of AT-007 | 44.1 microgram/mL | Geometric Coefficient of Variation 36.5 |
| Part D Extension Cohort 2: AT-007 40mg/kg DAY 30 | Cmax of AT-007 | 70.8 microgram/mL | — |
Secondary
Galactose-1-Phosphate (Gal-1p) Concentration in Plasma
Disease-Specific Biomarker in Classic Galactosemia Patients
Time frame: Part D: Day 32. Part D Extension: Days 30, 60, & 90.
Population: Part D Extension Cohort 2 40mg/kg ended early at Day 30 as recommended by Monitoring Committee. As such, there are no results for this outcome measure for the Part D Extension Cohort 2 40mg/kg. Part D Extension Cohort 1 of AT-007 20mg/kg is presented for Days 30, 60, and 90.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 5.71 percent change from baseline | Standard Deviation 15.7 |
| Part A Cohort 2: AT-007 5mg/kg | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 31.5 percent change from baseline | Standard Deviation 6.78 |
| Part A Cohort 3: AT-007 10mg/kg | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 7.86 percent change from baseline | Standard Deviation 21 |
| Part A Cohort 4: AT-007 20mg/kg | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 25.2 percent change from baseline | Standard Deviation 8.74 |
| Part A Cohort 5: AT-007 40mg/kg | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 33.1 percent change from baseline | Standard Deviation 51.123 |
| Part A: Placebo Comparator | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 16.04 percent change from baseline | Standard Deviation 43.218 |
| Part B & C Cohort 2: AT-007 10mg/kg | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 4.87 percent change from baseline | Standard Deviation 24.917 |
| Part B & C Cohort 3: AT-007 20mg/kg | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 8.63 percent change from baseline | Standard Deviation 24.473 |
| Part B & C Cohort 4: AT-007 40mg/kg | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 14.03 percent change from baseline | Standard Deviation 13.181 |
| Part D Cohort 1: AT-007 5mg/kg | Galactose-1-Phosphate (Gal-1p) Concentration in Plasma | 11.97 percent change from baseline | Standard Deviation 21.511 |
Secondary
Galactose Concentration in Plasma
Disease-Specific Biomarker in Classic Galactosemia Patients
Time frame: Part D: Day 32. Part D Extension: Days 30, 60, & 90.
Population: Part D Extension Cohort 2 40mg/kg ended early at Day 30 as recommended by Monitoring Committee. As such, there are no results for this outcome measure for the Part D Extension Cohort 2 40mg/kg. Part D Extension Cohort 1 of AT-007 20mg/kg is presented for Days 30, 60, and 90.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | Galactose Concentration in Plasma | 8.94 percent change from baseline | Standard Deviation 8.71 |
| Part A Cohort 2: AT-007 5mg/kg | Galactose Concentration in Plasma | -27.8 percent change from baseline | Standard Deviation 29.3 |
| Part A Cohort 3: AT-007 10mg/kg | Galactose Concentration in Plasma | 25.4 percent change from baseline | Standard Deviation 69.5 |
| Part A Cohort 4: AT-007 20mg/kg | Galactose Concentration in Plasma | 39.8 percent change from baseline | Standard Deviation 62.7 |
| Part A Cohort 5: AT-007 40mg/kg | Galactose Concentration in Plasma | -153.78 percent change from baseline | Standard Deviation 381.475 |
| Part A: Placebo Comparator | Galactose Concentration in Plasma | 52.29 percent change from baseline | Standard Deviation 170.753 |
| Part B & C Cohort 2: AT-007 10mg/kg | Galactose Concentration in Plasma | 30.42 percent change from baseline | Standard Deviation 102.15 |
| Part B & C Cohort 3: AT-007 20mg/kg | Galactose Concentration in Plasma | 139.75 percent change from baseline | Standard Deviation 273.418 |
| Part B & C Cohort 4: AT-007 40mg/kg | Galactose Concentration in Plasma | 98.67 percent change from baseline | Standard Deviation 132.115 |
| Part D Cohort 1: AT-007 5mg/kg | Galactose Concentration in Plasma | 130.00 percent change from baseline | Standard Deviation 101.059 |
Secondary
Maximal Galactitol Reduction in Plasma
Disease-Specific Biomarker in Classic Galactosemia Patients
Time frame: 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.
Population: Part D Extension Cohort 2 40mg/kg ended early at Day 30 as recommended by Monitoring Committee. As such, there are no results for this outcome measure for the Part D Extension Cohort 2 40mg/kg.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | Maximal Galactitol Reduction in Plasma | -475 maximal change from baseline in ng/mL | Standard Deviation 305 |
| Part A Cohort 2: AT-007 5mg/kg | Maximal Galactitol Reduction in Plasma | -1175 maximal change from baseline in ng/mL | Standard Deviation 239 |
| Part A Cohort 3: AT-007 10mg/kg | Maximal Galactitol Reduction in Plasma | -1259 maximal change from baseline in ng/mL | Standard Deviation 220 |
| Part A Cohort 4: AT-007 20mg/kg | Maximal Galactitol Reduction in Plasma | -393 maximal change from baseline in ng/mL | Standard Deviation 239 |
| Part A Cohort 5: AT-007 40mg/kg | Maximal Galactitol Reduction in Plasma | -974.4 maximal change from baseline in ng/mL | Standard Deviation 322.42 |
| Part A: Placebo Comparator | Maximal Galactitol Reduction in Plasma | -344.0 maximal change from baseline in ng/mL | Standard Deviation 449.67 |
Secondary
t1/2 of AT-007
Terminal elimination half life
Time frame: 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.
Population: For Part D Extension, t1/2 was not performed so these cohorts are not presented.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | t1/2 of AT-007 | 13.7 hours | Geometric Coefficient of Variation 45.3 |
| Part A Cohort 2: AT-007 5mg/kg | t1/2 of AT-007 | 22.0 hours | Geometric Coefficient of Variation 92.6 |
| Part A Cohort 3: AT-007 10mg/kg | t1/2 of AT-007 | 10.3 hours | Geometric Coefficient of Variation 31.7 |
| Part A Cohort 4: AT-007 20mg/kg | t1/2 of AT-007 | 8.42 hours | — |
| Part A Cohort 5: AT-007 40mg/kg | t1/2 of AT-007 | 8.2 hours | Geometric Coefficient of Variation 7.55 |
| Part A: Placebo Comparator | t1/2 of AT-007 | 13.1 hours | Geometric Coefficient of Variation 39.5 |
| Part B & C Cohort 2: AT-007 10mg/kg | t1/2 of AT-007 | 15.7 hours | Geometric Coefficient of Variation 79.9 |
| Part B & C Cohort 3: AT-007 20mg/kg | t1/2 of AT-007 | 9.76 hours | Geometric Coefficient of Variation 22.4 |
| Part B & C Cohort 4: AT-007 40mg/kg | t1/2 of AT-007 | 9.96 hours | Geometric Coefficient of Variation 27.4 |
| Part D Cohort 1: AT-007 5mg/kg | t1/2 of AT-007 | 13.9 hours | Geometric Coefficient of Variation 11 |
| Part D Cohort 2: AT-007 20mg/kg | t1/2 of AT-007 | 16.8 hours | Geometric Coefficient of Variation 56.6 |
| Part D Cohort 3: AT-007 40mg/kg | t1/2 of AT-007 | 16.1 hours | Geometric Coefficient of Variation 21.1 |
Secondary
Tmax of AT-007
Time to reach maximum (peak) plasma drug concentration
Time frame: 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
Population: Part D Extension Cohort 2 40mg/kg ended early at Day 30 as recommended by Monitoring Committee. As such, only 1 subject has D30 data available; the other subject did not have enough blood samples to calculate.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1: AT-007 0.5mg/kg | Tmax of AT-007 | 4.00 hours |
| Part A Cohort 2: AT-007 5mg/kg | Tmax of AT-007 | 4.00 hours |
| Part A Cohort 3: AT-007 10mg/kg | Tmax of AT-007 | 4.00 hours |
| Part A Cohort 4: AT-007 20mg/kg | Tmax of AT-007 | 4.00 hours |
| Part A Cohort 5: AT-007 40mg/kg | Tmax of AT-007 | 4.00 hours |
| Part A: Placebo Comparator | Tmax of AT-007 | 4.00 hours |
| Part B & C Cohort 2: AT-007 10mg/kg | Tmax of AT-007 | 3.96 hours |
| Part B & C Cohort 3: AT-007 20mg/kg | Tmax of AT-007 | 4.00 hours |
| Part B & C Cohort 4: AT-007 40mg/kg | Tmax of AT-007 | 4.00 hours |
| Part D Cohort 1: AT-007 5mg/kg | Tmax of AT-007 | 4.00 hours |
| Part D Cohort 2: AT-007 20mg/kg | Tmax of AT-007 | 4.96 hours |
| Part D Cohort 3: AT-007 40mg/kg | Tmax of AT-007 | 4.00 hours |
| Part D Extension Cohort 1: AT-007 20mg/kg DAY 30 | Tmax of AT-007 | 4.03 hours |
| Part D Extension Cohort 1: AT-007 20mg/kg DAY 60 | Tmax of AT-007 | 4.01 hours |
| Part D Extension Cohort 1: AT-007 20mg/kg DAY 90 | Tmax of AT-007 | 4.00 hours |
| Part D Extension Cohort 2: AT-007 40mg/kg DAY 30 | Tmax of AT-007 | 4.17 hours |