PET Study of Repeated ASN51 in Healthy Volunteers

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

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.

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).