Healthy
Conditions
Brief summary
This is a phase 1, open-label, dose escalation, positron emission tomography (PET) study to investigate the brain occupancy of O-GlcNAcase, and the pharmacodynamics (PD) response in peripheral blood mononuclear cells (PBMCs), after repeated doses of ASN51 in healthy participants.
Detailed description
The clinical data from the first-in-human single- and multiple-ascending dose study of ASN51 (ASN51-101), and the adaptive-design PET study of O-GlcNAcase brain ASN51 occupancy after single oral doses (ASN51-102), showed acceptable safety, tolerability and pharmacokinetics (PK). However, to date, no assessment of receptor occupancy (RO) after multiple doses of ASN51 and at plasma concentrations below the EC50 have been done. Hence, the purpose of this study is to assess brain O-GlcNAcase RO using PET following repeated doses of ASN51. The study will also characterise the PBMC response (including the effect of food), and further assess the safety, tolerability, PK, and PK/RO relationship, after repeated ASN51 doses. The results of this study will be used to select doses for subsequent studies in participants.
Interventions
DRUGASN51
Oral capsule
Sponsors
Hammersmith Medicines Research
Invicro
Asceneuron S.A.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
22 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Normotensive male volunteer (PET participants). 2. Male or female volunteer of non-childbearing potential (PBMC-only participants). 3. Deemed healthy on the basis of a clinical history, physical and neurological examination, electrocardiogram (ECG), vital signs, and laboratory tests of blood and urine. 4. Agree to follow the contraception requirements of the trial. 5. Able to give fully informed written consent.
Exclusion criteria
1. Significant (\> 10%) recent weight change. 2. Positive tests for hepatitis B and hepatitis C, human immunodeficiency virus (HIV). 3. Severe adverse reaction to any drug. 4. Sensitivity to trial medication. 5. Drug or alcohol abuse. 6. Regular consumption of xanthine-containing products. 7. Frequent use of nicotine-containing products. 8. Severe adverse reaction to any drug. 9. Sensitivity to trial medication (all participants) or PET imaging radioligand (PET participants). 10. Use of over-the-counter medication (with the exception of paracetamol \[acetaminophen\]) during the 7 days before the first dose of radioligand (PET participants) or trial medication (PBMC participants) (or longer if the medicine is a potential enzyme inducer), or prescribed medication during the 28 days before first dose of radioligand (PET participants) or trial medication (PBMC participants). 11. Received vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 2 weeks of screening. 12. Participation in other clinical trials of unlicensed medicines. 13. Loss of more than 400 milliliters (mL) blood, within the 3 months before the first dose of tracer (PET participants) or trial medication (PBMC participants). 14. Clinically relevant abnormal findings at the screening assessment, including ECG abnormalities (all participants) or those identified by MRI scan (PET participants only). 15. Acute or chronic illness. 16. Clinically relevant abnormal history of or concurrent medical (including neurological or psychiatric) condition. 17. Positive columbia-suicide severity rating scale (C-SSRS) result. 18. Vegan. 19. Possibility that volunteer will not cooperate. 20. Unsatisfactory venous access. 21. Objection by general practitioner (GP). 22. PET participants only: significant exposure to research related radiation (more than 10 millisievert \[mSv\]) within the previous 12 months. 23. Contraindications to arterial cannulation (e.g., allen's test indicates risk) or magnetic resonance imaging (MRI) scanning (e.g., presence of a cardiac pacemaker or other implanted electronic device or a history of claustrophobia).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose on Days 1, 2, 11, and 14; 8 hours post-dose on Day 1, 11 and 14; 12 hours post-dose on Day 1 and 14, 24 hours post-dose on Day 15; 72 hours post-dose on Day 17; 144 hours post-dose on Day 20 | Protein O-GlcNAcylation in PBMCs at different time-point is reported. |
| Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose | Regional VT of \[18F\]-IMA601 in frontal lobe at each brain scan was measured with a PET scan. Participants received an intravenous (IV) dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure. |
| Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose | Regional VT of \[18F\]-IMA601 in anterior cingulate at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure. |
| Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose | Regional VT of \[18F\]-IMA601 in Caudate at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure. |
| Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose | Regional VT of \[18F\]-IMA601 in Putamen at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure. |
| Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose | Regional VT of \[18F\]-IMA601 in Accumbens at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure. |
| Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose | Regional VT of \[18F\]-IMA601 in Amygdala at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure. |
| Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose | Regional VT of \[18F\]-IMA601 in cerebral white matter at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Suicidal Ideation According to Columbia - Suicide Severity Rating Scale (C-SSRS) Ideation | Up to 4.5 months | The C-SSRS is a valid and reliable suicidal scale that includes a seven-item subscale that asks participants to self-report on actual attempts, interrupted attempts, aborted attempts, and preparatory acts or behaviors. The suicidal ideation section is rated on a scale from 1 to 5, with higher score indicating a greater severity of suicidal ideation or risk of suicidal behavior. Participants who respond yes to any question related to suicidal ideation are reported in this outcome measure. |
| Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours; Day 11: 8 hours; Day 14: 0.25, 0.5, 1, 2, 4, 6, 12 hours; Day 15, Day 16, Day 17, Day 18, Day 20, and Day 23 | — |
| Maximum Observed Plasma Concentration (Cmax) of ASN51 | Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1; Pre-dose, and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | Cmax was obtained directly from the concentration-time data. |
| Dose-normalised Cmax (Cmax/Dose) of ASN51 | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1; Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | Calculated as Cmax /Dose administered. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of ASN51 | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1; Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | The tmax was obtained directly from the concentration-time data. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of ASN51 | Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | AUCinf was calculated using the trapezoidal method for the interval 0 to tlast (time tlast is the time at which the last non-zero level was recorded), plus the area under the exponential curve from tlast to infinity. |
| Dose-normalised AUC Infinity (AUCinf /D) of ASN51 | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1, Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | Calculated as AUCinf /Dose administered. Here, the unit of measure is represented as hours\*nanograms per milliliters per milligram (h\*ng/mL/mg). |
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) of ASN51 | Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | AUClast was calculated using the trapezoidal method. |
| Terminal Rate Constant (λz) of ASN51 | Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | Terminal rate constant was estimated by linear regression of logarithmically transformed concentration versus time data. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Up to 4.5 months | An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with that treatment. A TEAE is defined as an AE that emerges during treatment (having been absent before treatment) or that worsens after treatment. Serious TEAE is defined as any adverse event that is fatal, is life-threatening, requires or prolongs in-patient treatment, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. |
| Apparent Volume of Distribution After Oral Administration (VZ/F) of ASN51 | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | Calculated using the formula as follows: VZ/F = Dose/λz \*AUCtau. |
| Trough Plasma Concentration (Ctrough) of ASN51 | Pre-dose on Days 2, 4, 7, 11 and 14; and 8 hours post-dose on Day 11; 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14, and on Day 15 | Trough plasma concentration i.e., measured concentration at the end of a dosing interval at steady state (taken directly before next administration, and at 1 dosing interval after the final dose) was obtained directly from the concentration-time data. |
| Accumulation Ratio for AUC (Rac[AUC]) of ASN51 | Pre-dose up to Day 14 | Accumulation ratio was calculated from area under the plasma concentration-time curve during a dosing interval at steady state, and after single dose of ASN51. |
| Accumulation Ratio for Cmax (Rac[Cmax]) of ASN51 | Pre-dose up to Day 14 | Rac(Cmax) was calculated from Cmax at steady state and Cmax after single dose. |
| Effect of Food on PBMC Protein O-GlcNAcylation Levels During Repeated Dosing of ASN51 | Predose and 8 hours post-dose on Days 11 and 14 | The analysis of the PD response of PBMCs during repeated ASN51 dosing was conducted using ANOVA. Assessments were conducted at pre-dose and 8 hours post-dose on Day 11 (fed state) and Day 14 (fasted state). The ratio of fed to fasted has been reported. |
| Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time | At 5.1, 75.9 hours post-dose on Day 1 (Participant 1); 6.0, 196.9 hours post-dose on Day 1 (Participant 2); 5.2, 79.3 hours post-dose on Day 1 (Participant 3) and 5.5 and 77.0 hours post-dose on Day 1 (Participant 4) | Occupancy estimates were plotted against plasma concentrations of ASN51, corresponding to the start of each post-dose PET scan. Participant wise data was reported for this outcome measure. Row titles include participant number, PET scan session, post-dose time, and plasma concentration. |
| Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time | At 5.5, 75.6 hours post-dose on Day 1 (Participant 5); 5.3, 75.4 hours post-dose on Day 1 (Participant 6); 4.9, 75.9 hours post-dose on Day 1 (Participant 7) and 5.0 and 220.5 hours post-dose on Day 1 (Participant 8) | Occupancy estimates were plotted against plasma concentrations of ASN51, corresponding to the start of each post-dose PET scan. Participant wise data was reported for this outcome measure. Row titles include participant number, PET scan session, post-dose time, and plasma concentration. |
| Trough of [18F]-IMA601 | Day 1 up to Day 10 | — |
| Receptor Occupancy as Assessed by Plasma Concentration That Corresponds to 50% Occupancy (EC50) | Up to 220.5 hours post-dose on Day 1 | Change in VT from baseline to post-dose scans were interpreted as an effect of O-GlcNAcase occupancy by ASN51. Occupancy estimates were plotted against plasma concentrations of ASN51, corresponding to the start of each post-dose PET scan. The following model was fitted to the occupancy data set: Occ=100\*Cp/Cp+EC50. Where Occ was the target occupancy (%), Cp was measured plasma concentration of ASN51 (ng/ml) and EC50 was the plasma concentration of ASN51 that corresponds to 50% occupancy. Summarized data was reported for all participants. |
| Apparent Total Clearance From Plasma After Oral Administration (CLss/F) of ASN51 at Steady State | Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | Calculated using the formula as follows: CLss/F = Dose/ AUCtau. |
| Number of Participants With Clinically Significant Abnormalities in Vital Signs | Up to 4.5 months | Vital signs including blood pressure, pulse rate, tympanic temperature, and respiratory rate were assessed. Number of participants with clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator. |
| Number of Participants With Clinically Significant Abnormal 12-lead Safety Electrocardiogram (ECG) Findings | Up to 4.5 months | ECG parameters including Ventricular rate, QRS complex of the ECG reflects the rapid depolarization of the right and left ventricles (QRS) interval, portion of the ECG between consecutive R waves, representing the ventricular rate (PR) interval, and QTc interval with Fridericia's correction method (QTcF) was measured. Number of participants with clinically significant abnormal ECG findings were reported. Clinical significance was determined by the investigator. |
| Number of Participants With Clinically Significant Abnormal Physical Examinations | Up to 4.5 months | Complete physical examination including general appearance; head, ears, eyes, nose and throat; thyroid; lymph nodes; back and neck; heart; chest; lungs; abdomen; skin; and extremities were performed. Number of participants with clinically significant abnormal physical examinations were reported. Clinical significance was determined by the investigator. |
| Area Under the Plasma Concentration-time Curve During a Dosing Interval (AUCtau) of ASN51 | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1, Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | AUCtau was calculated using the trapezoidal method. |
| Terminal Half-life (t1/2) of ASN51 | Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14 | The t1/2 was calculated from the terminal slope of the log concentration-time curve as follows: t1/2 = loge 2 / lambda(λ)z. |
| Number of Participants With Clinically Significant Abnormal Neurological Examinations Findings | Up to 4.5 months | Complete neurological examinations including motor system, romberg test, coordination, and direct pupillary reflexes were performed. Number of participants with clinically significant abnormal neurological examinations findings were reported. Clinical significance was determined by the investigator. |
| Number of Participants With Clinically Significant Changes in Laboratory Parameters | Up to 4.5 months | Laboratory tests including hematology, clinical chemistry, coagulation, serology, follicle stimulating hormone (FSH) test (only for females), and urinalysis were performed. Number of participants with clinically significant changes in laboratory parameters were reported. Clinical significance was determined by the investigator. |
Countries
United Kingdom
Participant flow
Recruitment details
Participants took part in the study at an investigative site in the United Kingdom from 26 January 2023 to 08 June 2023.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: ASN51 Low Dose Participants received low dose of ASN51, orally, QD for 14 days in fasted or fed state. | 6 |
| Group 2: ASN51 High Dose Participants received high dose of ASN51, orally, QD for 14 days in fasted or fed state. | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Group 2: ASN51 High Dose | Total | Group 1: ASN51 Low Dose |
|---|---|---|---|
| Age, Continuous | 37.3 years STANDARD_DEVIATION 6.12 | 38.8 years STANDARD_DEVIATION 6.78 | 40.2 years STANDARD_DEVIATION 7.68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 12 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 4 / 6 | 3 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs)
Protein O-GlcNAcylation in PBMCs at different time-point is reported.
Time frame: Pre-dose on Days 1, 2, 11, and 14; 8 hours post-dose on Day 1, 11 and 14; 12 hours post-dose on Day 1 and 14, 24 hours post-dose on Day 15; 72 hours post-dose on Day 17; 144 hours post-dose on Day 20
Population: Pharmacodynamics (PD) analysis population included all participants in the safety population for who a PBMC measure is available. Number analyzed is the number of participants evaluated in respective arm at a specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 8 hours post-dose on Day 11 | 302.19 percentage of protein O-GlcNAcylation | Standard Deviation 49.84 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose on Day 1 | 100.0 percentage of protein O-GlcNAcylation | Standard Deviation 0 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 8 hours post-dose on Day 1 | 219.33 percentage of protein O-GlcNAcylation | Standard Deviation 74.728 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 12 hours post-dose on Day 1 | 291.02 percentage of protein O-GlcNAcylation | Standard Deviation 117.673 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose on Day 2 | 183.83 percentage of protein O-GlcNAcylation | Standard Deviation 84.144 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose on Day 11 | 205.70 percentage of protein O-GlcNAcylation | Standard Deviation 19.045 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose on day 14 | 196.42 percentage of protein O-GlcNAcylation | Standard Deviation 99.33 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 8 hours post-dose on Day 14 | 297.01 percentage of protein O-GlcNAcylation | Standard Deviation 119.672 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 12 hours post-dose on Day 14 | 303.24 percentage of protein O-GlcNAcylation | Standard Deviation 147.572 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 24 hours post-dose on Day 15 | 166.19 percentage of protein O-GlcNAcylation | Standard Deviation 62.638 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 72 hours post-dose on Day 17 | 169.66 percentage of protein O-GlcNAcylation | Standard Deviation 45.654 |
| Group 1: ASN51 Low Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 144 hours post-dose on Day 20 | 168.68 percentage of protein O-GlcNAcylation | Standard Deviation 40.767 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 72 hours post-dose on Day 17 | 192.67 percentage of protein O-GlcNAcylation | Standard Deviation 128.801 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose on day 14 | 197.54 percentage of protein O-GlcNAcylation | Standard Deviation 98.51 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose on Day 1 | 100.0 percentage of protein O-GlcNAcylation | Standard Deviation 0 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 24 hours post-dose on Day 15 | 160.38 percentage of protein O-GlcNAcylation | Standard Deviation 58.879 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 8 hours post-dose on Day 1 | 232.79 percentage of protein O-GlcNAcylation | Standard Deviation 94.193 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 8 hours post-dose on Day 14 | 282.51 percentage of protein O-GlcNAcylation | Standard Deviation 151.609 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 12 hours post-dose on Day 1 | 190.48 percentage of protein O-GlcNAcylation | Standard Deviation 56.442 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 144 hours post-dose on Day 20 | 187.14 percentage of protein O-GlcNAcylation | Standard Deviation 126.539 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose on Day 2 | 188.02 percentage of protein O-GlcNAcylation | Standard Deviation 96.636 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 12 hours post-dose on Day 14 | 305.26 percentage of protein O-GlcNAcylation | Standard Deviation 167.261 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose on Day 11 | 188.30 percentage of protein O-GlcNAcylation | Standard Deviation 126.761 |
| Group 2: ASN51 High Dose | Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs) | 8 hours post-dose on Day 11 | 346.01 percentage of protein O-GlcNAcylation | Standard Deviation 233.011 |
Primary
Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan
Regional VT of \[18F\]-IMA601 in frontal lobe at each brain scan was measured with a PET scan. Participants received an intravenous (IV) dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure.
Time frame: PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan. Here, number analyzed signifies specific participant evaluated in respective arm at a specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 11.47 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.97 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 2.68 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 14.81 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.02 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 2, PET Scan 3, Day 9 | 16.81 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 3, PET Scan 1, Baseline | NA milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 2.20 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.77 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 13.62 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 2.07 milliliters/cubic centimeter(mL/cm^3) |
| Group 1: ASN51 Low Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 4, PET Scan 3, Day 4 | 2.84 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 2.11 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 15.91 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 17.34 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.60 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 14.90 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 3.67 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 1.56 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 13.53 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 4, PET Scan 3, Day 10 | 7.72 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.46 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 2, PET Scan 3, Day 4 | 2.91 milliliters/cubic centimeter(mL/cm^3) |
| Group 2: ASN51 High Dose | Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.62 milliliters/cubic centimeter(mL/cm^3) |
Primary
Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan
Regional VT of \[18F\]-IMA601 in Accumbens at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure.
Time frame: PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan. Here, number analyzed signifies specific participant evaluated in respective arm at a specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 13.16 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.73 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 2.51 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 18.94 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.22 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 2, PET Scan 3, Day 9 | 22.18 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 18.57 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 2.14 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.80 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 16.18 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 1.87 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 4, PET Scan 3, Day 4 | 2.62 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 2.64 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 19.29 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 20.52 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.51 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 18.65 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 3.91 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 1.49 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 16.58 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 4, PET Scan 3, Day 10 | 9.09 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.66 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 2, PET Scan 3, Day 4 | 3.29 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.67 mL/cm^3 |
Primary
Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan
Regional VT of \[18F\]-IMA601 in Amygdala at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure.
Time frame: PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan. Here, number analyzed signifies specific participant evaluated in respective arm at a specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 15.00 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 2.13 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 3.13 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 19.84 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.30 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 2, PET Scan 3, Day 9 | 22.25 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 19.37 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 2.32 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 3.11 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 16.77 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 1.89 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 4, PET Scan 3, Day 4 | 2.94 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 2.10 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 18.91 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 22.00 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.54 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 17.57 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 4.42 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 1.76 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 17.77 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 4, PET Scan 3, Day 10 | 9.38 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.50 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 2, PET Scan 3, Day 4 | 3.40 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 3.12 mL/cm^3 |
Primary
Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan
Regional VT of \[18F\]-IMA601 in anterior cingulate at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure.
Time frame: PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan. Here, number analyzed signifies specific participant evaluated in respective arm at a specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 1.94 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 13.57 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.97 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 2.85 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 17.45 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.13 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 2, PET Scan 3, Day 9 | 19.79 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 18.34 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 2.26 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.94 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 15.87 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 4, PET Scan 3, Day 4 | 2.69 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.82 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 4, PET Scan 3, Day 10 | 8.53 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 18.51 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 20.14 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.60 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 17.02 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 3.98 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 1.60 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 16.08 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 2.04 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.56 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan | Participant 2, PET Scan 3, Day 4 | 3.17 mL/cm^3 |
Primary
Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan
Regional VT of \[18F\]-IMA601 in Caudate at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure.
Time frame: PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan. Here, number analyzed signifies specific participant evaluated in respective arm at a specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 8.25 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.21 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 1.76 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 12.89 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 1.74 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 2, PET Scan 3, Day 9 | 14.98 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 13.77 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 1.77 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.27 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 11.50 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 1.66 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 4, PET Scan 3, Day 4 | 2.04 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 1.91 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 13.28 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 13.95 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.23 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 13.44 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 2.97 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 1.17 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 11.43 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 4, PET Scan 3, Day 10 | 6.99 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.32 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 2, PET Scan 3, Day 4 | 2.75 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 1.94 mL/cm^3 |
Primary
Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan
Regional VT of \[18F\]-IMA601 in cerebral white matter at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure.
Time frame: PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan. Here, number analyzed signifies specific participant evaluated in respective arm at a specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 8.39 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.67 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 2.30 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 11.39 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 1.89 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 2, PET Scan 3, Day 9 | 13.25 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 12.39 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 2.03 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.46 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 9.95 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 1.81 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 4, PET Scan 3, Day 4 | 2.34 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 1.78 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 10.72 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 12.86 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.32 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 11.45 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 2.96 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 1.51 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 10.15 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 4, PET Scan 3, Day 10 | 6.34 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.43 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 2, PET Scan 3, Day 4 | 2.96 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.45 mL/cm^3 |
Primary
Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan
Regional VT of \[18F\]-IMA601 in Putamen at each brain scan was measured with a PET scan. Participants received an IV dose of the radiolabelled tracer, \[18F\]-IMA601, at the start of each PET scan. Participant wise data was reported for this outcome measure.
Time frame: PET Scan 1 (Baseline), PET Scan 2 (post-dose on Day 1), PET Scan 3 (Day 4 [for participants 1, 2 (Group 2 only) 3, and 4 (Group 1 only)] and Day 9 [for participant 2 in Group 1 only] and Day 10 [for participant 4 in Group 2 only]) after final ASN51 dose
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan. Here, number analyzed signifies specific participant evaluated in respective arm at a specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 12.74 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 2.03 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 2.86 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 17.46 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.32 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 2, PET Scan 3, Day 9 | 20.27 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 16.76 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 2.31 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.87 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 14.88 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 2.02 mL/cm^3 |
| Group 1: ASN51 Low Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 4, PET Scan 3, Day 4 | 2.74 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 4, PET Scan 2, Day 1 | 2.07 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 1, PET Scan 1, Baseline | 17.00 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 3, PET Scan 1, Baseline | 20.70 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 1, PET Scan 2, Day 1 | 1.63 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 4, PET Scan 1, Baseline | 17.00 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 1, PET Scan 3, Day 4 | 3.89 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 3, PET Scan 2, Day 1 | 1.78 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 2, PET Scan 1, Baseline | 15.89 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 4, PET Scan 3, Day 10 | 8.50 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 2, PET Scan 2, Day 1 | 2.76 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 2, PET Scan 3, Day 4 | 3.35 mL/cm^3 |
| Group 2: ASN51 High Dose | Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan | Participant 3, PET Scan 3, Day 4 | 2.96 mL/cm^3 |
Secondary
Accumulation Ratio for AUC (Rac[AUC]) of ASN51
Accumulation ratio was calculated from area under the plasma concentration-time curve during a dosing interval at steady state, and after single dose of ASN51.
Time frame: Pre-dose up to Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group 1: ASN51 Low Dose | Accumulation Ratio for AUC (Rac[AUC]) of ASN51 | 2.81 Ratio |
| Group 2: ASN51 High Dose | Accumulation Ratio for AUC (Rac[AUC]) of ASN51 | 2.52 Ratio |
Secondary
Accumulation Ratio for Cmax (Rac[Cmax]) of ASN51
Rac(Cmax) was calculated from Cmax at steady state and Cmax after single dose.
Time frame: Pre-dose up to Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group 1: ASN51 Low Dose | Accumulation Ratio for Cmax (Rac[Cmax]) of ASN51 | 2.55 Ratio |
| Group 2: ASN51 High Dose | Accumulation Ratio for Cmax (Rac[Cmax]) of ASN51 | 1.74 Ratio |
Secondary
Apparent Total Clearance From Plasma After Oral Administration (CLss/F) of ASN51 at Steady State
Calculated using the formula as follows: CLss/F = Dose/ AUCtau.
Time frame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Apparent Total Clearance From Plasma After Oral Administration (CLss/F) of ASN51 at Steady State | 1.42 Liters/hour (L/h) | Standard Deviation 0.174 |
| Group 2: ASN51 High Dose | Apparent Total Clearance From Plasma After Oral Administration (CLss/F) of ASN51 at Steady State | 2.25 Liters/hour (L/h) | Standard Deviation 2.12 |
Secondary
Apparent Volume of Distribution After Oral Administration (VZ/F) of ASN51
Calculated using the formula as follows: VZ/F = Dose/λz \*AUCtau.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Apparent Volume of Distribution After Oral Administration (VZ/F) of ASN51 | 92.1 Liters | Standard Deviation 28.9 |
| Group 2: ASN51 High Dose | Apparent Volume of Distribution After Oral Administration (VZ/F) of ASN51 | 254 Liters | Standard Deviation 340 |
Secondary
Area Under the Plasma Concentration-time Curve During a Dosing Interval (AUCtau) of ASN51
AUCtau was calculated using the trapezoidal method.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1, Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: ASN51 Low Dose | Area Under the Plasma Concentration-time Curve During a Dosing Interval (AUCtau) of ASN51 | Day 1 | 2527 h*ng/mL | Geometric Coefficient of Variation 8.2 |
| Group 1: ASN51 Low Dose | Area Under the Plasma Concentration-time Curve During a Dosing Interval (AUCtau) of ASN51 | Day 14 | 7067 h*ng/mL | Geometric Coefficient of Variation 11.6 |
| Group 2: ASN51 High Dose | Area Under the Plasma Concentration-time Curve During a Dosing Interval (AUCtau) of ASN51 | Day 1 | 4888 h*ng/mL | Geometric Coefficient of Variation 15.1 |
| Group 2: ASN51 High Dose | Area Under the Plasma Concentration-time Curve During a Dosing Interval (AUCtau) of ASN51 | Day 14 | 11237 h*ng/mL | Geometric Coefficient of Variation 73.4 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of ASN51
AUCinf was calculated using the trapezoidal method for the interval 0 to tlast (time tlast is the time at which the last non-zero level was recorded), plus the area under the exponential curve from tlast to infinity.
Time frame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of ASN51 | 20428 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 24.3 |
| Group 2: ASN51 High Dose | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of ASN51 | 40365 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 56.3 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) of ASN51
AUClast was calculated using the trapezoidal method.
Time frame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) of ASN51 | 19655 h*ng/mL | Geometric Coefficient of Variation 21.3 |
| Group 2: ASN51 High Dose | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) of ASN51 | 36574 h*ng/mL | Geometric Coefficient of Variation 60.6 |
Secondary
Dose-normalised AUC Infinity (AUCinf /D) of ASN51
Calculated as AUCinf /Dose administered. Here, the unit of measure is represented as hours\*nanograms per milliliters per milligram (h\*ng/mL/mg).
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1, Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Dose-normalised AUC Infinity (AUCinf /D) of ASN51 | 2043 h*ng/mL/mg | Geometric Coefficient of Variation 24.3 |
| Group 2: ASN51 High Dose | Dose-normalised AUC Infinity (AUCinf /D) of ASN51 | 2018 h*ng/mL/mg | Geometric Coefficient of Variation 56.3 |
Secondary
Dose-normalised Cmax (Cmax/Dose) of ASN51
Calculated as Cmax /Dose administered.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1; Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: ASN51 Low Dose | Dose-normalised Cmax (Cmax/Dose) of ASN51 | Day 1 | 18.3 ng/mL/milligram (mg) | Geometric Coefficient of Variation 14.8 |
| Group 1: ASN51 Low Dose | Dose-normalised Cmax (Cmax/Dose) of ASN51 | Day 14 | 46.2 ng/mL/milligram (mg) | Geometric Coefficient of Variation 20 |
| Group 2: ASN51 High Dose | Dose-normalised Cmax (Cmax/Dose) of ASN51 | Day 1 | 19.3 ng/mL/milligram (mg) | Geometric Coefficient of Variation 30.4 |
| Group 2: ASN51 High Dose | Dose-normalised Cmax (Cmax/Dose) of ASN51 | Day 14 | 31.2 ng/mL/milligram (mg) | Geometric Coefficient of Variation 71.8 |
Secondary
Effect of Food on PBMC Protein O-GlcNAcylation Levels During Repeated Dosing of ASN51
The analysis of the PD response of PBMCs during repeated ASN51 dosing was conducted using ANOVA. Assessments were conducted at pre-dose and 8 hours post-dose on Day 11 (fed state) and Day 14 (fasted state). The ratio of fed to fasted has been reported.
Time frame: Predose and 8 hours post-dose on Days 11 and 14
Population: PD analysis population included all participants in the safety population for who a PBMC measure is available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Effect of Food on PBMC Protein O-GlcNAcylation Levels During Repeated Dosing of ASN51 | Predose | 0.87 Ratios |
| Group 1: ASN51 Low Dose | Effect of Food on PBMC Protein O-GlcNAcylation Levels During Repeated Dosing of ASN51 | 8 hours post-dose | 0.94 Ratios |
| Group 2: ASN51 High Dose | Effect of Food on PBMC Protein O-GlcNAcylation Levels During Repeated Dosing of ASN51 | Predose | 1.05 Ratios |
| Group 2: ASN51 High Dose | Effect of Food on PBMC Protein O-GlcNAcylation Levels During Repeated Dosing of ASN51 | 8 hours post-dose | 0.86 Ratios |
Secondary
Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time
Occupancy estimates were plotted against plasma concentrations of ASN51, corresponding to the start of each post-dose PET scan. Participant wise data was reported for this outcome measure. Row titles include participant number, PET scan session, post-dose time, and plasma concentration.
Time frame: At 5.1, 75.9 hours post-dose on Day 1 (Participant 1); 6.0, 196.9 hours post-dose on Day 1 (Participant 2); 5.2, 79.3 hours post-dose on Day 1 (Participant 3) and 5.5 and 77.0 hours post-dose on Day 1 (Participant 4)
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan. No summary analysis was done due to low number of participants, therefore participant wise data are reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time | Participant 1: PET Scan 2, 5.1 hours at 118.0 ng/mL | 92.0 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time | Participant 1: PET Scan 3, 75.9 hours at 101.0 ng/mL | 84.6 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time | Participant 2: PET Scan 2, 6.0 hours at 118.0 ng/mL | 94.3 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time | Participant 2: PET Scan 3, 196.9 hours at 4.8 ng/mL | -16.0 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time | Participant 3: PET Scan 2, 5.2 hours at 121.0 ng/mL | 95.6 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time | Participant 3: PET Scan 3, 79.3 hours at 127.0 ng/mL | 91.3 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time | Participant 4: PET Scan 2, 5.5 hours at 171.0 ng/mL | 97.8 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time | Participant 4: PET Scan 3, 77.0 hours at 91.4 ng/mL | 91.9 percentage of receptor occupancy |
Secondary
Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time
Occupancy estimates were plotted against plasma concentrations of ASN51, corresponding to the start of each post-dose PET scan. Participant wise data was reported for this outcome measure. Row titles include participant number, PET scan session, post-dose time, and plasma concentration.
Time frame: At 5.5, 75.6 hours post-dose on Day 1 (Participant 5); 5.3, 75.4 hours post-dose on Day 1 (Participant 6); 4.9, 75.9 hours post-dose on Day 1 (Participant 7) and 5.0 and 220.5 hours post-dose on Day 1 (Participant 8)
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan. No summary analysis was done due to low number of participants, therefore participant wise data are reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time | Participant 5: PET Scan 2, 5.5 hours at 232.0 ng/mL | 98.5 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time | Participant 5: PET Scan 3, 75.6 hours at 67.3 ng/mL | 83.4 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time | Participant 6: PET Scan 2, 5.3 hours at 309.0 ng/mL | 98.1 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time | Participant 6: PET Scan 3, 75.4 hours at 152.0 ng/mL | 93.3 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time | Participant 7: PET Scan 2, 4.9 hours at 267.0 ng/mL | 98.1 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time | Participant 7: PET Scan 3, 75.9 hours at 132.0 ng/mL | 91.4 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time | Participant 8: PET Scan 2, 5.0 hours at 304.0 ng/mL | 97.5 percentage of receptor occupancy |
| Group 1: ASN51 Low Dose | Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time | Participant 8: PET Scan 3, 220.5 hours at 21.7ng/mL | 53.9 percentage of receptor occupancy |
Secondary
Maximum Observed Plasma Concentration (Cmax) of ASN51
Cmax was obtained directly from the concentration-time data.
Time frame: Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1; Pre-dose, and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: ASN51 Low Dose | Maximum Observed Plasma Concentration (Cmax) of ASN51 | Day 1 | 183 ng/mL | Geometric Coefficient of Variation 14.8 |
| Group 1: ASN51 Low Dose | Maximum Observed Plasma Concentration (Cmax) of ASN51 | Day 14 | 462 ng/mL | Geometric Coefficient of Variation 20 |
| Group 2: ASN51 High Dose | Maximum Observed Plasma Concentration (Cmax) of ASN51 | Day 1 | 386 ng/mL | Geometric Coefficient of Variation 30.4 |
| Group 2: ASN51 High Dose | Maximum Observed Plasma Concentration (Cmax) of ASN51 | Day 14 | 624 ng/mL | Geometric Coefficient of Variation 71.8 |
Secondary
Number of Participants With Clinically Significant Abnormal 12-lead Safety Electrocardiogram (ECG) Findings
ECG parameters including Ventricular rate, QRS complex of the ECG reflects the rapid depolarization of the right and left ventricles (QRS) interval, portion of the ECG between consecutive R waves, representing the ventricular rate (PR) interval, and QTc interval with Fridericia's correction method (QTcF) was measured. Number of participants with clinically significant abnormal ECG findings were reported. Clinical significance was determined by the investigator.
Time frame: Up to 4.5 months
Population: Safety population included participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: ASN51 Low Dose | Number of Participants With Clinically Significant Abnormal 12-lead Safety Electrocardiogram (ECG) Findings | 0 Participants |
| Group 2: ASN51 High Dose | Number of Participants With Clinically Significant Abnormal 12-lead Safety Electrocardiogram (ECG) Findings | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormalities in Vital Signs
Vital signs including blood pressure, pulse rate, tympanic temperature, and respiratory rate were assessed. Number of participants with clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.
Time frame: Up to 4.5 months
Population: Safety population included participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: ASN51 Low Dose | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| Group 2: ASN51 High Dose | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormal Neurological Examinations Findings
Complete neurological examinations including motor system, romberg test, coordination, and direct pupillary reflexes were performed. Number of participants with clinically significant abnormal neurological examinations findings were reported. Clinical significance was determined by the investigator.
Time frame: Up to 4.5 months
Population: Safety population included participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: ASN51 Low Dose | Number of Participants With Clinically Significant Abnormal Neurological Examinations Findings | 0 Participants |
| Group 2: ASN51 High Dose | Number of Participants With Clinically Significant Abnormal Neurological Examinations Findings | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormal Physical Examinations
Complete physical examination including general appearance; head, ears, eyes, nose and throat; thyroid; lymph nodes; back and neck; heart; chest; lungs; abdomen; skin; and extremities were performed. Number of participants with clinically significant abnormal physical examinations were reported. Clinical significance was determined by the investigator.
Time frame: Up to 4.5 months
Population: Safety population included participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: ASN51 Low Dose | Number of Participants With Clinically Significant Abnormal Physical Examinations | 0 Participants |
| Group 2: ASN51 High Dose | Number of Participants With Clinically Significant Abnormal Physical Examinations | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes in Laboratory Parameters
Laboratory tests including hematology, clinical chemistry, coagulation, serology, follicle stimulating hormone (FSH) test (only for females), and urinalysis were performed. Number of participants with clinically significant changes in laboratory parameters were reported. Clinical significance was determined by the investigator.
Time frame: Up to 4.5 months
Population: Safety population included participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: ASN51 Low Dose | Number of Participants With Clinically Significant Changes in Laboratory Parameters | 0 Participants |
| Group 2: ASN51 High Dose | Number of Participants With Clinically Significant Changes in Laboratory Parameters | 0 Participants |
Secondary
Number of Participants With Suicidal Ideation According to Columbia - Suicide Severity Rating Scale (C-SSRS) Ideation
The C-SSRS is a valid and reliable suicidal scale that includes a seven-item subscale that asks participants to self-report on actual attempts, interrupted attempts, aborted attempts, and preparatory acts or behaviors. The suicidal ideation section is rated on a scale from 1 to 5, with higher score indicating a greater severity of suicidal ideation or risk of suicidal behavior. Participants who respond yes to any question related to suicidal ideation are reported in this outcome measure.
Time frame: Up to 4.5 months
Population: Safety population included participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: ASN51 Low Dose | Number of Participants With Suicidal Ideation According to Columbia - Suicide Severity Rating Scale (C-SSRS) Ideation | 0 Participants |
| Group 2: ASN51 High Dose | Number of Participants With Suicidal Ideation According to Columbia - Suicide Severity Rating Scale (C-SSRS) Ideation | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with that treatment. A TEAE is defined as an AE that emerges during treatment (having been absent before treatment) or that worsens after treatment. Serious TEAE is defined as any adverse event that is fatal, is life-threatening, requires or prolongs in-patient treatment, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect.
Time frame: Up to 4.5 months
Population: Safety population included all participants who received at least one dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 4 Participants |
| Group 1: ASN51 Low Dose | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
| Group 2: ASN51 High Dose | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 3 Participants |
| Group 2: ASN51 High Dose | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
Secondary
Plasma Concentration of ASN51 at Each Post-dose PET Scan
Time frame: Day 1: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours; Day 11: 8 hours; Day 14: 0.25, 0.5, 1, 2, 4, 6, 12 hours; Day 15, Day 16, Day 17, Day 18, Day 20, and Day 23
Population: PK analysis population included the participants who provided evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration. Number analyzed is the number of participants with data available for analysis at a specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 1 hour post-dose | 173.8 nanograms/milliliter (ng/mL) | Standard Deviation 28.174 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 0.5 hour post-dose | 417.8 nanograms/milliliter (ng/mL) | Standard Deviation 130.39 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 6 hours post-dose | 125.7 nanograms/milliliter (ng/mL) | Standard Deviation 11.183 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 1 hour post-dose | 427.8 nanograms/milliliter (ng/mL) | Standard Deviation 54.455 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 2 hours post-dose | 152.5 nanograms/milliliter (ng/mL) | Standard Deviation 13.867 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 2 hours post-dose | 398.8 nanograms/milliliter (ng/mL) | Standard Deviation 46.525 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 8 hours post-dose | 123.8 nanograms/milliliter (ng/mL) | Standard Deviation 7.2503 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 4 hours post-dose | 362.2 nanograms/milliliter (ng/mL) | Standard Deviation 46.357 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 0.5 hour post-dose | 132.9 nanograms/milliliter (ng/mL) | Standard Deviation 65.354 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 6 hours post-dose | 339.2 nanograms/milliliter (ng/mL) | Standard Deviation 28.117 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 12 hours post-dose | 97.30 nanograms/milliliter (ng/mL) | Standard Deviation 8.805 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 12 hours post-dose | 268.0 nanograms/milliliter (ng/mL) | Standard Deviation 28.39 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 3 hours post-dose | 155.2 nanograms/milliliter (ng/mL) | Standard Deviation 11.476 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 15 | 242.3 nanograms/milliliter (ng/mL) | Standard Deviation 33.279 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 16 hours post-dose | 82.98 nanograms/milliliter (ng/mL) | Standard Deviation 4.2687 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 16 | 150.2 nanograms/milliliter (ng/mL) | Standard Deviation 26.347 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 1.5 hours post-dose | 155.2 nanograms/milliliter (ng/mL) | Standard Deviation 11.089 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 17 | 97.23 nanograms/milliliter (ng/mL) | Standard Deviation 17.151 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 11: 8 hours post-dose | 326.0 nanograms/milliliter (ng/mL) | Standard Deviation 43.253 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 18 | 63.52 nanograms/milliliter (ng/mL) | Standard Deviation 22.281 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 4 hours post-dose | 140.3 nanograms/milliliter (ng/mL) | Standard Deviation 21.63 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 20 | 29.38 nanograms/milliliter (ng/mL) | Standard Deviation 15.536 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 0.25 hour post-dose | 264.2 nanograms/milliliter (ng/mL) | Standard Deviation 55.333 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 23 | 11.01 nanograms/milliliter (ng/mL) | Standard Deviation 11.685 |
| Group 1: ASN51 Low Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 0.25 hour post-dose | 4.833 nanograms/milliliter (ng/mL) | Standard Deviation 11.839 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 23 | 35.24 nanograms/milliliter (ng/mL) | Standard Deviation 33.575 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 0.25 hour post-dose | 20.18 nanograms/milliliter (ng/mL) | Standard Deviation 31.68 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 0.5 hour post-dose | 232.7 nanograms/milliliter (ng/mL) | Standard Deviation 228.23 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 1 hour post-dose | 355.3 nanograms/milliliter (ng/mL) | Standard Deviation 66.704 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 1.5 hours post-dose | 311.3 nanograms/milliliter (ng/mL) | Standard Deviation 40.934 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 2 hours post-dose | 310.3 nanograms/milliliter (ng/mL) | Standard Deviation 45.559 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 3 hours post-dose | 277.3 nanograms/milliliter (ng/mL) | Standard Deviation 40.143 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 4 hours post-dose | 281.8 nanograms/milliliter (ng/mL) | Standard Deviation 34.032 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 6 hours post-dose | 254.7 nanograms/milliliter (ng/mL) | Standard Deviation 38.568 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 8 hours post-dose | 244.0 nanograms/milliliter (ng/mL) | Standard Deviation 28.071 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 12 hours post-dose | 199.2 nanograms/milliliter (ng/mL) | Standard Deviation 31.212 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 1: 16 hours post-dose | 154.3 nanograms/milliliter (ng/mL) | Standard Deviation 23.036 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 11: 8 hours post-dose | 567.3 nanograms/milliliter (ng/mL) | Standard Deviation 228.33 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 0.25 hour post-dose | 416.2 nanograms/milliliter (ng/mL) | Standard Deviation 175.02 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 0.5 hour post-dose | 541.7 nanograms/milliliter (ng/mL) | Standard Deviation 224.05 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 1 hour post-dose | 682.5 nanograms/milliliter (ng/mL) | Standard Deviation 280.47 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 2 hours post-dose | 695.3 nanograms/milliliter (ng/mL) | Standard Deviation 285.19 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 4 hours post-dose | 640.2 nanograms/milliliter (ng/mL) | Standard Deviation 258.28 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 6 hours post-dose | 599.0 nanograms/milliliter (ng/mL) | Standard Deviation 255.59 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 14: 12 hours post-dose | 499.2 nanograms/milliliter (ng/mL) | Standard Deviation 214.34 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 15 | 455.8 nanograms/milliliter (ng/mL) | Standard Deviation 180.41 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 16 | 295.4 nanograms/milliliter (ng/mL) | Standard Deviation 134.63 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 17 | 105.8 nanograms/milliliter (ng/mL) | Standard Deviation 40.751 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 18 | 141.0 nanograms/milliliter (ng/mL) | Standard Deviation 69.51 |
| Group 2: ASN51 High Dose | Plasma Concentration of ASN51 at Each Post-dose PET Scan | Day 20 | 78.52 nanograms/milliliter (ng/mL) | Standard Deviation 45.813 |
Secondary
Receptor Occupancy as Assessed by Plasma Concentration That Corresponds to 50% Occupancy (EC50)
Change in VT from baseline to post-dose scans were interpreted as an effect of O-GlcNAcase occupancy by ASN51. Occupancy estimates were plotted against plasma concentrations of ASN51, corresponding to the start of each post-dose PET scan. The following model was fitted to the occupancy data set: Occ=100\*Cp/Cp+EC50. Where Occ was the target occupancy (%), Cp was measured plasma concentration of ASN51 (ng/ml) and EC50 was the plasma concentration of ASN51 that corresponds to 50% occupancy. Summarized data was reported for all participants.
Time frame: Up to 220.5 hours post-dose on Day 1
Population: PET population included all participants in the safety population who had a baseline PET scan, at least 1 post-baseline PET scan, and a PK result immediately preceding a PET scan.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group 1: ASN51 Low Dose | Receptor Occupancy as Assessed by Plasma Concentration That Corresponds to 50% Occupancy (EC50) | 17.6 ng/mL |
Secondary
Terminal Half-life (t1/2) of ASN51
The t1/2 was calculated from the terminal slope of the log concentration-time curve as follows: t1/2 = loge 2 / lambda(λ)z.
Time frame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Terminal Half-life (t1/2) of ASN51 | 45.1 hours | Standard Deviation 13.9 |
| Group 2: ASN51 High Dose | Terminal Half-life (t1/2) of ASN51 | 66.0 hours | Standard Deviation 25.8 |
Secondary
Terminal Rate Constant (λz) of ASN51
Terminal rate constant was estimated by linear regression of logarithmically transformed concentration versus time data.
Time frame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Terminal Rate Constant (λz) of ASN51 | 0.0163 1 per hour (1/h) | Standard Deviation 0.00392 |
| Group 2: ASN51 High Dose | Terminal Rate Constant (λz) of ASN51 | 0.0119 1 per hour (1/h) | Standard Deviation 0.00444 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of ASN51
The tmax was obtained directly from the concentration-time data.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1; Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Time to Reach Maximum Observed Plasma Concentration (Tmax) of ASN51 | Day 1 | 1.00 hours |
| Group 1: ASN51 Low Dose | Time to Reach Maximum Observed Plasma Concentration (Tmax) of ASN51 | Day 14 | 0.767 hours |
| Group 2: ASN51 High Dose | Time to Reach Maximum Observed Plasma Concentration (Tmax) of ASN51 | Day 1 | 1.00 hours |
| Group 2: ASN51 High Dose | Time to Reach Maximum Observed Plasma Concentration (Tmax) of ASN51 | Day 14 | 2.00 hours |
Secondary
Trough of [18F]-IMA601
Time frame: Day 1 up to Day 10
Population: Data for trough volume of distribution of \[18F\]-IMA601 was not collected and analyzed because steady state was not achieved due to non-periodic administration before the imaging sessions.
Secondary
Trough Plasma Concentration (Ctrough) of ASN51
Trough plasma concentration i.e., measured concentration at the end of a dosing interval at steady state (taken directly before next administration, and at 1 dosing interval after the final dose) was obtained directly from the concentration-time data.
Time frame: Pre-dose on Days 2, 4, 7, 11 and 14; and 8 hours post-dose on Day 11; 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14, and on Day 15
Population: PK analysis population included participants who had evaluable data for the comparisons of interest. These participants had at least one quantifiable plasma concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1: ASN51 Low Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 2 | 82.4 ng/mL |
| Group 1: ASN51 Low Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 4 | 173 ng/mL |
| Group 1: ASN51 Low Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 7 | 227 ng/mL |
| Group 1: ASN51 Low Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 11 | 238 ng/mL |
| Group 1: ASN51 Low Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 14 | 236 ng/mL |
| Group 1: ASN51 Low Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 15 | 240 ng/mL |
| Group 2: ASN51 High Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 14 | 377 ng/mL |
| Group 2: ASN51 High Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 2 | 149 ng/mL |
| Group 2: ASN51 High Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 11 | 431 ng/mL |
| Group 2: ASN51 High Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 4 | 316 ng/mL |
| Group 2: ASN51 High Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 15 | 405 ng/mL |
| Group 2: ASN51 High Dose | Trough Plasma Concentration (Ctrough) of ASN51 | Day 7 | 444 ng/mL |