PET Study of Repeated ASN51 in Healthy Volunteers

This is a phase 1, open-label, dose escalation, PET study to investigate the brain occupancy of O-GlcNAcase, and the PD response in PBMCs, after repeated doses of ASN51 in healthy subjects.

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 PK. However, to date, no assessment of 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 patients.

Eligibility Criteria:
Inclusion Criteria:

* Normotensive male volunteer (PET subjects)
* Male or female volunteer of non-childbearing potential (PBMC-only subjects)
* Deemed healthy on the basis of a clinical history, physical and neurological examination, 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 \& C, 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 subjects) or PET imaging radioligand (PET subjects)
* Use of over-the-counter medication (with the exception of paracetamol \[acetaminophen\]) during the 7 days before the first dose of radioligand (PET subjects) or trial medication (PBMC subjects) (or longer if the medicine is a potential enzyme inducer), or prescribed medication during the 28 days before first dose of radioligand (PET subjects) or trial medication (PBMC subjects)
* 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 mL blood, within the 3 months before the first dose of tracer (PET subjects) or trial medication (PBMC subjects)
* Clinically relevant abnormal findings at the screening assessment, including ECG abnormalities (all subjects) or those identified by MRI scan (PET subjects only)
* Acute or chronic illness
* Clinically relevant abnormal history of or concurrent medical (including neurological or psychiatric) condition
* Positive C-SSRS result
* Vegan
* Possibility that volunteer will not cooperate
* Unsatisfactory venous access
* Objection by General Practitioner (GP)
* PET subjects only: significant exposure to research related radiation (more than 10 mSv) within the previous 12 months
* Contraindications to arterial cannulation (eg Allen's test indicates risk) or MRI scanning (eg presence of a cardiac pacemaker or other implanted electronic device or a history of claustrophobia)