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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
12
Oral capsule
Hammersmith
London, United Kingdom
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
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
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
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
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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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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)
Trough of [18F]-IMA601
Time frame: Day 1 up to Day 10
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