PET Study of Repeated ASN51 in Healthy Volunteers

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Healthy

Intervention / Treatment
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* Drug: ASN51


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 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. Enrolment of up to 12 healthy subjects is planned, in up to 2 groups (Groups 1 and 2). Each group will consist of up to 6 subjects.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Group 1 will receive 10 mg once-daily (QD) doses of ASN51, by mouth, for 14 days. | Drug: ASN51<br>* ASN51 formulation for oral capsule<br>|
| Experimental: Group 2<br>Group 2 will receive 20 mg once-daily (QD) doses of ASN51, by mouth, for 14 days. | Drug: ASN51<br>* ASN51 formulation for oral capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic (PD) change in peripheral blood mononuclear cell (PBMC) O-GlcNAcylation |  | Baseline up to Day 20 | 
| PD change in percentage of O-GlcNAcase (OGA) enzyme occupancy |  | Baseline up to Day 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Up to 45 days | 
| Pharmacokinetic (PK) parameter: Cmax | Maximum observed concentration of ASN51 at steady state in plasma | Up to Day 20 | 
| Pharmacokinetic (PK) parameter: Cmax/Dose | Data contains Dose normalized Cmax (normalized to total body dose) (Cmax/Dose) of ASN51 | Up to Day 20 | 
| Pharmacokinetic (PK) parameter: Tmax | Data indicates Time to Cmax (Tmax) of ASN51 | Up to Day 20 | 
| Pharmacokinetic (PK) parameter: t1/2 | Data contains Terminal half-life (t1/2) of ASN51 | Up to Day 20 | 
| Pharmacokinetic (PK) Parameter: λz | Data contains Terminal elimination rate constant (λz) of ASN51 | Up to Day 20 | 
| Pharmacokinetic (PK) Parameter: AUC tau | Area under the plasma concentration-time curve during a dosing interval (tau) | Up to Day 20 | 
| Pharmacokinetic (PK) Parameters: AUC0-inf and AUC0-last | Data contain Area under the serum concentration-time curve (AUC) from time zero to infinity (AUC0-inf) and Area under the serum concentration-time curve from time zero to the last quantifiable concentration (AUC0-last) of ASN51 | Up to Day 20 | 
| Pharmacokinetic (PK) Parameters: AUC0-inf/Dose | Data contain Dose normalized AUC0-inf (AUC0-inf/Dose) | Up to Day 20 | 
| Pharmacokinetic (PK) Parameter: %AUCextrap | Data contains Percentage of AUC0-inf obtained by extrapolation (%AUCext) of ASN51 | Up to Day 20 | 
| Pharmacokinetic (PK) Parameter: CLss/F | Data contains apparent total clearance from plasma after non-intravenous administration calculated at steady state | Up to Day 20 | 
| Pharmacokinetic (PK) Parameter: VZ/F | Data contains apparent volume of distribution after non-intravenous administration calculated at steady state | Up to Day 20 | 
| Pharmacokinetic (PK) Parameter: Ctrough | Trough plasma concentration (measured concentration at the end of a dosing interval at a steady state [taken directly before next administration]) obtained direction from the concentration-time data. | Up to Day 20 | 
| Pharmacokinetic (PK) Parameter: Rac(Cmax) | Accumulation ratio for Cmax calculated from Cmax at steady state and Cmax after a single dose | Up to Day 20 | 
| Pharmacokinetic (PK) Parameter: Rac(AUC) | Accumulation ratio for AUC calculated from AUCtau at steady state and AUCtau after a single dose | Up to Day 20 | 
| Pharmacodynamic (PD) Parameter: Trough [18F]-IMA601 VT | Lowest concentration of [18F]-IMA601 based on the regional total volume of distribution at each brain scan | Up to 23 days |