PET Study of Repeated ASN51 in Healthy Volunteers

Protein O-GlcNAcylation in PBMCs at different time-point is reported.

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 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 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 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 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 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 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.

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.

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.

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.

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.

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.

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.

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.

Cmax was obtained directly from the concentration-time data.

Calculated as Cmax /Dose administered.

The tmax was obtained directly from the concentration-time data.

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.

Calculated as AUCinf /Dose administered. Here, the unit of measure is represented as hours*nanograms per milliliters per milligram (h*ng/mL/mg).

AUClast was calculated using the trapezoidal method.

AUCtau was calculated using the trapezoidal method.

The t1/2 was calculated from the terminal slope of the log concentration-time curve as follows: t1/2 = loge 2 / lambda(λ)z.

Terminal rate constant was estimated by linear regression of logarithmically transformed concentration versus time data.

Calculated using the formula as follows: CLss/F = Dose/ AUCtau.

Calculated using the formula as follows: VZ/F = Dose/λz *AUCtau.

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 was calculated from area under the plasma concentration-time curve during a dosing interval at steady state, and after single dose of ASN51.

Rac(Cmax) was calculated from Cmax at steady state and Cmax after single dose.

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.

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.

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.

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.