Clinical trial NCT06390098: Positron Emission Tomography Study in Healthy Subjects to Determine the Relationship Between Plasma Concentration and Brain Target Occupancy of ASN51
Official title: A Phase 1, Open-Label, Positron Emission Tomography Study in Healthy Adult Subjects to Determine the Relationship Between Plasma Concentration and Brain Target Occupancy of ASN51 Following a Single Oral Dose
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Participants
Lead sponsor: Asceneuron S.A.
Sponsor class: INDUSTRY
Collaborators: name: Hammersmith Medicines Research Invicro
First posted: 2024-04-30
Enrollment: 3
Sex: ALL
Minimum age (years): 25
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a phase 1, open-label, positron emission tomography (PET) study in healthy adult participants to determine the relationship between plasma concentration and brain target occupancy of ASN51 following a single oral dose.


Eligibility criteria: Inclusion Criteria:

* Healthy as determined by the Investigator, based on a medical evaluation including medical history physical examination, neurological examination, laboratory tests and cardiac monitoring. A participant with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if, in the opinion of the Investigator, the finding is (a) unlikely to introduce additional risk to the participant, (b) will not interfere with study procedures or confound study results, and (c) is not otherwise exclusionary
* Men or women aged 25-55 years, inclusive (age range was selected on grounds of radiation burden).
* Women of child-bearing potential (WOCBP) with partners of child-bearing potential must agree to use highly effective contraception from at least 28 days before first tracer dosing through 30 days after last dose of study medication. All WOCBP must have a negative pregnancy test result before administration of test article. Vasectomized partner is also an accepted a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success.
* WOCBP must be postmenopausal (the last menstrual period was at least 12 months ago, and follicle-stimulating hormone at screening confirms postmenopausal status, or have no uterus, ovaries, or fallopian tubes). Women who are surgically sterile must provide documentation of the procedure by an operative report or by ultrasound.
* Non-sterilized male participants who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide from 1 day prior to the first tracer administration throughout the total duration of the treatment period and 90 days after the last dose of study drug. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male participants should refrain from sperm donation throughout this period.
* Body weight \> 50.0 kilograms (kg) for men and \> 45.0 kg for women and Body Mass Index within the range 18.5-30.0 kilograms per square meter (kg/m\^2) (inclusive).
* Participants must understand the nature of the study and must provide signed and dated written informed consent in accordance with local regulations before the conduct of any study-related procedures.
* Participants must be, in the opinion of the Investigator, able to participate in all scheduled evaluations, likely to complete all required tests, and likely to be compliant.
* Participants must be fluent in the local language.
* Participants must agree not to post any personal medical data related to the study or information related to the study on any website or social media site (e.g., Facebook, Twitter, etc.) until the trial has completed.

Exclusion Criteria:

* A positive urine drug screen/alcohol test at Screening or Day -1.
* Any history of psychiatric disorders, including substance use disorders, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.
* A diagnosis of intellectual disability (intellectual developmental disorder) or mental retardation.
* Significant suicide risk as assessed by the Columbia Suicide severity Rating Scale (C-SSRS)
* A positive Hepatitis B surface antigen or positive Hepatitis C antibody result at Screening.
* A positive test for human immunodeficiency virus (HIV) antibody at Screening.
* Alanine aminotransferase or aspartate aminotransferase levels greater than 1.5 times the upper limit of normal (ULN) at Screening or between Screening and first dose of tracer.
* Frequently used any tobacco-containing (e.g., cigar, cigarette, or snuff) or nicotine-containing product (e.g., nicotine chewing gum, nicotine plasters, or other product used for smoking cessation) within 3 months prior to first dose of tracer. Frequent use is defined as 3 or more days per week. Use of any tobacco- or nicotine-containing product is prohibited within 1 week of first dose of tracer.
* History of regular alcohol consumption within 12 months of the study defined as an average weekly intake of \>21 alcoholic units/week for men or \>14 alcoholic units/week for women.
* Regularly consumed (e.g., more days than not) excessive quantities of xanthine-containing beverages (e.g., more than five cups of coffee or the equivalent per day) within 30 days prior to Screening or between Screening and first dose of tracer.
* Received or used an investigational product (including placebo) or device within the following time period prior to the first tracer dosing day in the current study: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Use of prescription or non-prescription drugs, vitamins, herbal, and dietary supplements (including St John's Wort) within 7 days (or 28 days if the drug is a potential hepatic enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study tracer medication, unless in the opinion of the Investigator and Medical Monitor, the medication will not interfere with the study procedures or compromise Participant safety.
* History of clinically significant sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
* Loss of more than 400 milliliters (mL) of blood within 3 months prior to first dose of tracer, i.e., blood donor.
* A positive serum pregnancy test or lactation.
* A history or presence of any disease, condition, or surgery likely to affect drug absorption, distribution, metabolism, or excretion. Participants with a history of cholecystectomy should be excluded.
* A history or presence of a clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, pulmonary, ophthalmologic, immunologic, hematologic, dermatologic, or neurologic abnormality.
* A clinically significant abnormality on physical examination, neurological examination, electrocardiogram (ECG), or laboratory evaluations at screen or between screen and first tracer dose administration.
* A corrected QT(total time from ventricular depolarization to complete repolarization) interval measurement corrected according to the Fridericia rule (QTcF) \> 450 milliseconds (msec) for males and 470 msec for females during controlled rest at screen or between screen and first tracer dose administration, or family history of long QT syndrome.
* Any clinically significant abnormalities in rhythm, conduction, or morphology of the resting ECG and any abnormalities in the 12-lead ECG that, in the judgement of the Investigator or Medical Monitor, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy.
* PR (PQ) interval shortening \< 120 msec (PR \< 120 msec but \> 110 msec is acceptable if there is no evidence of ventricular pre-excitation).
* PR (PQ) interval prolongation (\>220 msec), intermittent second- (Wenckebach block while asleep or in deep rest is not exclusionary) or third-degree AV block.
* Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS \> 120 msec.
* A clinically significant vital signs abnormality at screening This includes, but is not limited to, 3 measurements (each 5 minutes apart) in the seated position: (a) systolic blood pressure \< 90 or \>140 millimeters of mercury (mmHg), (b) diastolic blood pressure \<50 or \> 95 mmHg, or (c) heart rate \< 45 or \>100 beats per minute. The average of the 3 measurements should be used to assess eligibility at screening.
* Significant (\> 10%) weight loss or gain within 30 days prior to Screening and first tracer dose administration.
* A history of seizure. History of a single benign febrile convulsion of childhood is permitted.
* A history of head trauma, including closed head injury with loss of consciousness.
* A history of symptomatic orthostatic hypotension (i.e., postural syncope).
* A history of neuroleptic malignant syndrome.
* A history of chronic urinary tract infections.
* The participant is, in the opinion of the Investigator or Medical Monitor, unlikely to comply with the protocol or is unsuitable for any reason.
* Currently employed by Asceneuron SA or by a clinical trial site participating in this study, or a first-degree relative of an Asceneuron SA employee or of an employee at a participating clinical trial site.
* Unsatisfactory venous access
* Significant exposure to ionizing radiation as part of research within the previous 12 months prior to first tracer dose administration.
* Unsuitable or unwilling to undergo the imaging procedures, as determined by an magnetic resonance imaging (MRI) safety questionnaire. Reasons for exclusion include but are not limited to presence of a cardiac pacemaker or other implanted electronic device; ferromagnetic metal foreign bodies, intracranial aneurysm clips or other metallic objects; non-MRI compatible heart valves; inner ear implants; or a history of claustrophobia.
* Significant structural brain abnormality, as determined by MRI.
* Contraindication for arterial cannulation: Allen's test indicating potential risk in placement of the arterial cannula.
* Participants with a COVID-19 vaccination within two weeks of screening or due to receive second dose of COVID-19 vaccine while participating in the study.

Primary outcomes:
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 (6 hours post-dose [for participant 1] and 31 hours post-dose for [participants 2 and 3] on Day 1), PET Scan 3 (48 hours post-dose on Day 1) 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 (6 hours post-dose [for participant 1] and 31 hours post-dose for [participants 2 and 3] on Day 1), PET Scan 3 (48 hours post-dose on Day 1) after final ASN51 dose
measure: Regional VT of [18F]-IMA601 in Caudate at Each Brain Scan
timeFrame: PET Scan 1 (Baseline), PET Scan 2 (6 hours post-dose [for participant 1] and 31 hours post-dose for [participants 2 and 3] on Day 1), PET Scan 3 (48 hours post-dose on Day 1) after final ASN51 dose
measure: Regional VT of [18F]-IMA601 in Putamen at Each Brain Scan
timeFrame: PET Scan 1 (Baseline), PET Scan 2 (6 hours post-dose [for participant 1] and 31 hours post-dose for [participants 2 and 3] on Day 1), PET Scan 3 (48 hours post-dose on Day 1) after final ASN51 dose
measure: Regional VT of [18F]-IMA601 in Accumbens at Each Brain Scan
timeFrame: PET Scan 1 (Baseline), PET Scan 2 (6 hours post-dose [for participant 1] and 31 hours post-dose for [participants 2 and 3] on Day 1), PET Scan 3 (48 hours post-dose on Day 1) after final ASN51 dose
measure: Regional VT of [18F]-IMA601 in Amygdala at Each Brain Scan
timeFrame: PET Scan 1 (Baseline), PET Scan 2 (6 hours post-dose [for participant 1] and 31 hours post-dose for [participants 2 and 3] on Day 1), PET Scan 3 (48 hours post-dose on Day 1) 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 (6 hours post-dose [for participant 1] and 31 hours post-dose for [participants 2 and 3] on Day 1), PET Scan 3 (48 hours post-dose on Day 1) after final ASN51 dose
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Up to approximately 2.1 months
measure: Number of Participants With Serious TEAEs up to 4 Weeks After Last Administration
timeFrame: Up to 4 weeks
measure: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
timeFrame: Up to approximately 2.1 months
measure: Number of Participants With Clinically Significant Changes in Vital Signs
timeFrame: Up to approximately 2.1 months
measure: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to approximately 2.1 months
measure: Number of Participants With Clinically Significant Abnormal Physical Examinations
timeFrame: Up to approximately 2.1 months
measure: Plasma Concentration of ASN51 at Each Post-dose PET Scan
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3 and 72 hours post-dose on Day 4
measure: Estimated O-GlcNAcase Receptor Occupancy (RO) by Plasma Concentration of ASN51 and PET Scan
timeFrame: At 6 hours post-dose on Day 1 (for participant 1) and 31 hours post-dose on Day 1 (for participants 2 and 3), and at 48 hours post-dose on Day 1 (all participants)
measure: Receptor Occupancy as Assessed by Plasma Concentration That Corresponds to 50% Occupancy (EC50)
timeFrame: At 6, 31 and at 48 hours post-dose on Day 1
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Hammersmith
Study officials:
References: