Clinical trial NCT05725005: PET Study of Repeated ASN51 in Healthy Volunteers
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Asceneuron S.A.
Sponsor class: INDUSTRY
Collaborators: name: Hammersmith Medicines Research
name: Invicro
First posted: 2023-02-13
Enrollment: 12
Sex: ALL
Minimum age (years): 22
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Mean Protein O-GlcNAcylation in Peripheral Blood Mononuclear Cells (PBMCs)
timeFrame: 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
measure: Regional Total Volume of Distribution (VT) of [18F]-IMA601 in Frontal Lobe at Each Brain Scan
timeFrame: 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
measure: Regional VT of [18F]-IMA601 in Anterior Cingulate at Each Brain Scan
timeFrame: 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
measure: Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan
timeFrame: 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
measure: Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan
timeFrame: 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
measure: Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan
timeFrame: 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
measure: Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan
timeFrame: 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
measure: Regional VT of [18F]-IMA601 in Cerebral White Matter at Each Brain Scan
timeFrame: 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
Secondary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Up to 4.5 months
measure: Number of Participants With Clinically Significant Abnormalities in Vital Signs
timeFrame: Up to 4.5 months
measure: Number of Participants With Clinically Significant Abnormal 12-lead Safety Electrocardiogram (ECG) Findings
timeFrame: Up to 4.5 months
measure: Number of Participants With Clinically Significant Abnormal Physical Examinations
timeFrame: Up to 4.5 months
measure: Number of Participants With Clinically Significant Abnormal Neurological Examinations Findings
timeFrame: Up to 4.5 months
measure: Number of Participants With Clinically Significant Changes in Laboratory Parameters
timeFrame: Up to 4.5 months
measure: Number of Participants With Suicidal Ideation According to Columbia - Suicide Severity Rating Scale (C-SSRS) Ideation
timeFrame: Up to 4.5 months
measure: Plasma Concentration of ASN51 at Each Post-dose PET Scan
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of ASN51
timeFrame: 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
measure: Dose-normalised Cmax (Cmax/Dose) of ASN51
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of ASN51
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of ASN51
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
measure: Dose-normalised AUC Infinity (AUCinf /D) of ASN51
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) of ASN51
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
measure: Area Under the Plasma Concentration-time Curve During a Dosing Interval (AUCtau) of ASN51
timeFrame: 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
measure: Terminal Half-life (t1/2) of ASN51
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
measure: Terminal Rate Constant (λz) of ASN51
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
measure: Apparent Total Clearance From Plasma After Oral Administration (CLss/F) of ASN51 at Steady State
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
measure: Apparent Volume of Distribution After Oral Administration (VZ/F) of ASN51
timeFrame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, and 12 hours post-dose on Day 14
measure: Trough Plasma Concentration (Ctrough) of ASN51
timeFrame: 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
measure: Accumulation Ratio for AUC (Rac[AUC]) of ASN51
timeFrame: Pre-dose up to Day 14
measure: Accumulation Ratio for Cmax (Rac[Cmax]) of ASN51
timeFrame: Pre-dose up to Day 14
measure: Effect of Food on PBMC Protein O-GlcNAcylation Levels During Repeated Dosing of ASN51
timeFrame: Predose and 8 hours post-dose on Days 11 and 14
measure: Group 1: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and Time
timeFrame: 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)
measure: Group 2: Estimated O-GlcNAcase RO by Plasma Concentration of ASN51 and Time
timeFrame: 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)
measure: Trough of [18F]-IMA601
timeFrame: Day 1 up to Day 10
measure: Receptor Occupancy as Assessed by Plasma Concentration That Corresponds to 50% Occupancy (EC50)
timeFrame: Up to 220.5 hours post-dose on Day 1
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Hammersmith
Study officials:
affiliation: Hammersmith Medicines Research
name: Adeep Puri, MD
role: PRINCIPAL_INVESTIGATOR
References: