PET Study of Repeated ASN51 in Healthy Volunteers

Healthy Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05725005
• Other study ID #: ASN51-103
• Status: Completed
• Phase: Phase 1
• Start date: January 26, 2023
• Est. completion date: June 8, 2023

Study information

• Verified date: April 2024
• Source: Asceneuron S.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: June 8, 2023
• Est. primary completion date: April 4, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 22 Years to 55 Years

Eligibility

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)

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• ASN51
ASN51 formulation for oral capsule

Locations

Country	Name	City	State
United Kingdom	Hammersmith	London

Sponsors (3)

Lead Sponsor	Collaborator
Asceneuron S.A.	Hammersmith Medicines Research, Invicro

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacodynamic (PD) change in peripheral blood mononuclear cell (PBMC) O-GlcNAcylation		Baseline up to Day 20
Primary	PD change in percentage of O-GlcNAcase (OGA) enzyme occupancy		Baseline up to Day 20
Secondary	Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		Up to 45 days
Secondary	Pharmacokinetic (PK) parameter: Cmax	Maximum observed concentration of ASN51 at steady state in plasma	Up to Day 20
Secondary	Pharmacokinetic (PK) parameter: Cmax/Dose	Data contains Dose normalized Cmax (normalized to total body dose) (Cmax/Dose) of ASN51	Up to Day 20
Secondary	Pharmacokinetic (PK) parameter: Tmax	Data indicates Time to Cmax (Tmax) of ASN51	Up to Day 20
Secondary	Pharmacokinetic (PK) parameter: t1/2	Data contains Terminal half-life (t1/2) of ASN51	Up to Day 20
Secondary	Pharmacokinetic (PK) Parameter: ?z	Data contains Terminal elimination rate constant (?z) of ASN51	Up to Day 20
Secondary	Pharmacokinetic (PK) Parameter: AUC tau	Area under the plasma concentration-time curve during a dosing interval (tau)	Up to Day 20
Secondary	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
Secondary	Pharmacokinetic (PK) Parameters: AUC0-inf/Dose	Data contain Dose normalized AUC0-inf (AUC0-inf/Dose)	Up to Day 20
Secondary	Pharmacokinetic (PK) Parameter: %AUCextrap	Data contains Percentage of AUC0-inf obtained by extrapolation (%AUCext) of ASN51	Up to Day 20
Secondary	Pharmacokinetic (PK) Parameter: CLss/F	Data contains apparent total clearance from plasma after non-intravenous administration calculated at steady state	Up to Day 20
Secondary	Pharmacokinetic (PK) Parameter: VZ/F	Data contains apparent volume of distribution after non-intravenous administration calculated at steady state	Up to Day 20
Secondary	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
Secondary	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
Secondary	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
Secondary	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