A Phase 1, Open-label, Positron Emission Tomography Study in Healthy Subjects to Determine the Relationship Between Plasma Concentration and Target Occupancy of ASN51 Following Repeated Oral Doses
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Other
- Masking
- None
Eligibility Criteria
- Ages
- 22 Years to 55 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
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.
- •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).
Arms & Interventions
Group 1: ASN51 Low Dose
Participants received low dose of ASN51, orally, once-daily (QD) for 14 days in fasted or fed state.
Intervention: ASN51 (Drug)
Group 2: ASN51 High Dose
Participants received high dose of ASN51, orally, QD for 14 days in fasted or fed state.
Intervention: ASN51 (Drug)
Outcomes
Primary Outcomes
Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs)
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
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
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 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
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 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
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 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
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 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
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 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
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 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
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 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 Outcomes
- Accumulation Ratio for Cmax (Rac[Cmax]) of ASN51(Pre-dose up to Day 14)
- 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)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs(Up to 4.5 months)
- Number of Participants With Clinically Significant Abnormalities in Vital Signs(Up to 4.5 months)
- Number of Participants With Clinically Significant Abnormal 12-lead Safety Electrocardiogram (ECG) Findings(Up to 4.5 months)
- Number of Participants With Clinically Significant Abnormal Physical Examinations(Up to 4.5 months)
- Number of Participants With Clinically Significant Abnormal Neurological Examinations Findings(Up to 4.5 months)
- Number of Participants With Clinically Significant Changes in Laboratory Parameters(Up to 4.5 months)
- Number of Participants With Suicidal Ideation According to Columbia - Suicide Severity Rating Scale (C-SSRS) Ideation(Up to 4.5 months)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Accumulation Ratio for AUC (Rac[AUC]) of ASN51(Pre-dose up to Day 14)
- 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)
- 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))
- 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))
- 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)