PET Study of Repeated ASN51 in Healthy Volunteers

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: ASN51

Registration Number: NCT05725005

Lead Sponsor: Asceneuron S.A.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Normotensive male volunteer (PET participants).
Male or female volunteer of non-childbearing potential (PBMC-only participants).
Deemed healthy on the basis of a clinical history, physical and neurological examination, electrocardiogram (ECG), vital signs, and laboratory tests of blood and urine.
Agree to follow the contraception requirements of the trial.
Able to give fully informed written consent.

Exclusion Criteria

Significant (> 10%) recent weight change.
Positive tests for hepatitis B and hepatitis C, human immunodeficiency virus (HIV).
Severe adverse reaction to any drug.
Sensitivity to trial medication.
Drug or alcohol abuse.
Regular consumption of xanthine-containing products.
Frequent use of nicotine-containing products.
Severe adverse reaction to any drug.
Sensitivity to trial medication (all participants) or PET imaging radioligand (PET participants).
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).
Received vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 2 weeks of screening.
Participation in other clinical trials of unlicensed medicines.
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).
Clinically relevant abnormal findings at the screening assessment, including ECG abnormalities (all participants) or those identified by MRI scan (PET participants only).
Acute or chronic illness.
Clinically relevant abnormal history of or concurrent medical (including neurological or psychiatric) condition.
Positive columbia-suicide severity rating scale (C-SSRS) result.
Vegan.
Possibility that volunteer will not cooperate.
Unsatisfactory venous access.
Objection by general practitioner (GP).
PET participants only: significant exposure to research related radiation (more than 10 millisievert [mSv]) within the previous 12 months.
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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Group 1: ASN51 Low Dose	ASN51	Participants received low dose of ASN51, orally, once-daily (QD) for 14 days in fasted or fed state.
Group 2: ASN51 High Dose	ASN51	Participants received high dose of ASN51, orally, QD for 14 days in fasted or fed state.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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.