A Study Assessing the Safety of Oral ATH-399A in Healthy Adult Participants

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability and pharmacokinetics of single and multiple doses of ATH-399A in healthy adults and also evaluate the effect of food on ATH-399A in order to develop mechanism-based and/or disease-modifying treatments for Parkinson Disease.

Official Title
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A Randomized, Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics of Single and Multiple Doses as Well as the Food Effect of Orally Administered ATH-399A in Healthy Adult Participants

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: ATH-399A
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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. Population Part 1a and 1b: Men and women, age 18-55 years inclusive at date of screening. Part 2: Men and women aged 18-55 years inclusive at date of screening. Additional cohort: Participants of the additional cohort will be of approximately equal numbers of male and post-menopausal or surgically sterile females, with a minimum of 2 of each gender, aged >55-80 years, inclusive. Women of childbearing potential (WOCBP) must be non-pregnant and non-lactating. Postmenopausal women must have had ≥12 months of spontaneous amenorrhea (with follicle-stimulating hormone [FSH] ≥40 milli-international units per milliliter (mIU/mL)). Surgically sterile women are defined as those who have had a hysterectomy and/or bilateral oophorectomy. Women who are surgically sterile must provide verbal confirmation. Male participants who are sexually active with WOCBP must: Agree to use condoms to protect their partners from becoming pregnant during the study (including washout periods) and not to donate sperm for at least 90 days after the last dose of study drug, and Agree to ensure that they and their partners are routinely using a medically approved contraceptive method. It is important that male participants not impregnate others while in the study. Body weight ≥50.0 kilogram (kg) for men and ≥45.0 kg for women and body mass index within the range of 18.0-30.0 kilogram/square meter (kg/m^2) (inclusive). Participants participating in Part 1b must be willing and able to consume the entire high-fat, high-calorie breakfast in the designated timeframe. Participants must understand the nature of the study, must be willing to participate in 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 English or French. 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. Exclusion Criteria: A positive urine cotinine, drug screen, or alcohol breath 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 that requires current treatment with psychiatric medications. Participants with mild anxiety or depression which is stable for >6 months are permitted. History of drug abuse within 1 year prior to screening or recreational use of soft drugs (such as marijuana) within 1 month or hard drugs (such as cocaine, phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine derivatives) within 3 months prior to screening. A diagnosis of intellectual disability (intellectual developmental disorder) or mental retardation. A serious mental illness, dementia, or other neuropsychiatric disorder that would interfere with participation in the trial, or ability to provide informed consent in the opinion of the Investigator. Any active suicidal ideation as indicated by the C-SSRS (score of ≥4) or history of suicidal behaviour within the 12 months prior to screening. A positive Hepatitis B surface antigen or positive Hepatitis C antibody result at screening. A positive test at screening for human immunodeficiency virus (HIV) antigen or antibody or a history of positive test. Alanine aminotransferase or aspartate aminotransferase levels greater than 1.2 times the ULN at screening or Day -1. 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 30 days prior to first dose administration. History of alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to screening that exceeds 10 units for women or 15 units for men of alcohol per week (1 unit = 340 mL of beer 5%, 140 mL of wine 12%, or 45 mL of distilled alcohol 40%). Regularly consumed (e.g., more days than not) excessive quantities of xanthine-containing beverages (e.g., more than 2 cups of coffee or the equivalent per day) within 1 week prior to screening or between screening and first dose administration, or unwillingness to refrain from xanthine-containing beverages during the in-clinic stay. Received or used an investigational product (including placebo) or device within the following time period prior to the first dosing day in the current study: 30 days or 5 half-lives (whichever is longer). For biological products, administration of a biological product within 90 days prior to the first dosing, or concomitant participation in an investigational study involving no drug or device administration. Other than those medications outlined in the protocol body and those allowed in the MAD additional cohort, use of prescription or non-prescription drugs, 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 first dose administration, 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 drugs, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation. Donation of plasma within 7 days prior to the first dosing or donation or loss of 500 mL or more of whole blood within 8 weeks prior to the first dosing. A positive 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. Participants with fully resolved childhood asthma with no hospitalizations or recurrence in adulthood are permitted to enroll. For the additional cohort in Part 2, any of the above are acceptable where the condition is stable for >6 months and, in the opinion of the Investigator, it does not impact participant safety. A clinically significant abnormality on physical examination, neurological examination, electrocardiogram (ECG), or laboratory evaluations at screening and Day -1. A QT interval measurement corrected according to the Fridericia rule (QTcF) > 450 millisecond (msec) during controlled rest at screening and Day -1, 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. A clinically significant vital sign abnormality at screening or between screening and first dose administration. Significant (> 10%) weight loss or gain within 30 days prior to screening or between screening and first dose administration. A history of seizures. Occurrence of a single febrile seizure is not exclusionary. A history of head trauma, including closed head injury with loss of consciousness. Concussions which did not lead to hospitalization or loss of consciousness, and for which there are no ongoing issues, are not exclusionary. A history of symptomatic orthostatic hypotension (i.e., postural syncope). A history of neuroleptic malignant syndrome. A history of chronic urinary tract infections (≥2 times per year). 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 NurrOn Pharmaceuticals, Inc., HanAll Biopharma Co. Ltd., or HanAll Pharmaceutical Inc, or by a clinical trial site participating in this study, or a first-degree relative of an NurrOn Pharmaceuticals, Inc. or HanAll Pharmaceutical Inc., or HanAll Biopharma Co. Ltd. employee or of an employee at a participating clinical trial site. Unsatisfactory venous access. Unable to swallow oral capsules. Positive result to a Corona Virus disease (COVID-19) Polymerase chain reaction (PCR) test. COVID-19 or flu vaccination within 30 days prior to study drug administration or any other vaccination which is judged by the investigator to potentially affect eligibility. Presence of fever (body temperature >37.5°C) (e.g., a fever associated with a symptomatic viral or bacterial infection) within 2 weeks prior to first dosing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a (Single Ascending Doses (SAD)): ATH-399A<br>Participants will receive single oral dose of ATH-399A capsule in up to 5 ascending dose levels (5mg, 10mg, 20mg, 40mg, 80mg). | Drug: ATH-399A<br>* Orally administered drug in capsule form.<br>* Other names: ATH-399A, HL192;|
| Placebo Comparator: Part 1a (SAD): Placebo<br>Participants will receive single oral dose of placebo-matched to ATH-399A capsule. | Drug: Placebo<br>* Orally administered drug in capsule form.<br>|
| Experimental: Part 1b (High calorie): ATH-399A<br>Participants will receive single oral dose of ATH-399A capsule after high-calorie, high-fat breakfast and then will cross over to receive single oral dose of ATH-399A capsule after fasting. | Drug: ATH-399A<br>* Orally administered drug in capsule form.<br>* Other names: ATH-399A, HL192;|
| Experimental: Part 1b (Fasting): ATH-399A<br>Participants will receive single oral dose of ATH-399A capsule after fasting and then will cross over to receive single oral dose of ATH-399A capsule after high-calorie, high-fat breakfast. | Drug: ATH-399A<br>* Orally administered drug in capsule form.<br>* Other names: ATH-399A, HL192;|
| Experimental: Part 2 (Multiple Ascending doses (MAD)): ATH-399A<br>Participants will receive once daily (QD) dose of ATH-399A capsules from Day 1 to Day 12 in fasted state. | Drug: ATH-399A<br>* Orally administered drug in capsule form.<br>* Other names: ATH-399A, HL192;|
| Placebo Comparator: Part 2 (MAD): Placebo<br>Participants will receive QD dose of placebo-matched to ATH-399A capsules from Day 1 to Day 12 in fasted state. | Drug: Placebo<br>* Orally administered drug in capsule form.<br>|
| Experimental: Additional Cohort (Ages 56-80 years old): ATH-399A<br>Participants will receive QD dose of ATH-399A capsules from Day 1 to Day 12 in fasted state following MAD dosing. | Drug: ATH-399A<br>* Orally administered drug in capsule form.<br>* Other names: ATH-399A, HL192;|
| Placebo Comparator: Additional Cohort: (Ages 56-80 years old) Placebo<br>Participants will receive QD dose of placebo-matched to ATH-399A capsules from Day 1 to Day 12 in fasted state following MAD dosing. | Drug: Placebo<br>* Orally administered drug in capsule form.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse events (AEs) and serious adverse events (SAEs) for Part 1a, Part 1b and Part 2 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. AEs were considered SAEs if the AE resulted in death, was life-threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, or birth defect or required inpatient hospitalization or led to prolongation of hospitalization or as deemed by the medical or scientific judgement of the Investigator is deemed serious in other situations such as important medical events. | From time of informed consent up to follow-up visit [Day 8-11 (Part 1a), Day 16-19 (Part 1b), Day 13 (Part 2)] | 
| Columbia Suicidality Severity Rating Scale (C-SSRS) for Part 1a, Part 1b and Part 2 | C-SSRS is a participant rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses), and intensity of ideation (rated 1=low severity to 5=high severity). | Baseline and Day 8-11 (Part 1a), Day 16-19 (Part 1b), Day 13 (Part 2) | 
| Changes in Vital Signs | Vital signs include temperature, blood pressure, pulse rate, and respiratory rate | Baseline and up to follow-up visit [Day 8-11 (Part 1a), Day 16-19 (Part 1b), Day 13 (Part 2)] | 
| Changes in ECGs | The ECG will electronically measure and calculate ventricular heart rate and the PR, RR, QRS, QT, and QTcF intervals. The QTcF interval will be used for clinical evaluations. | Baseline and up to follow-up visit [Day 8-11 (Part 1a), Day 16-19 (Part 1b), Day 13 (Part 2)] | 
| Changes in clinical laboratory tests | Hematology, Clinical Chemistry, HbA1c, and Urinalysis, Thyroid Panel, Coagulation Tests | Part 1a, 1b, 2: Hematology, Clinical Chemistry, HbA1c, and Urinalysis baseline and up to follow-up visit; Thyroid Panel at baseline, discharge and follow-up; Coagulation tests at baseline and discharge | 
| Changes in telemetry | 12-Lead continuous telemetry for evaluation of cardiac arrhythmias | Part 1a, 1b: Day 1 approximately 1-2 hours pre-dose and continued to approximately 48 hours post-dose; Part 2: Day 1 and Day 12 approximately 1-2 hours pre-dose and continued to approximately 24 hours post dose | 
| Changes in physical examination and neurological examination | Assessments of the following: head, eyes, ears, nose, throat (HEENT), neck, chest, lungs, abdomen, musculoskeletal, dermatological, cardiovascular/peripheral vascular, and general neurological examination | Part 1a, 1b, 2: baseline and at discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t | Plasma Pharmacokinetic (PK) parameter: Area Under the Concentration-Time Curve from Time Zero Until the Last Observed Concentration (AUC0-t) for Part 1a, Part 1b and Part 2 | pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 & for Part 1 only: 48 hours post-dose | 
| AUC0-inf | PK parameter: Area Under The Concentration-Time Curve From Time Zero To Infinity (Extrapolated) (AUC0-inf) for Part 1a, Part 1b and Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 & for Part 1 only: 48 hours post-dose | 
| Cmax | PK parameter: Maximal Observed Concentration (Cmax) for Part 1a, Part 1b and Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 & for Part 1 only: 48 hours post-dose | 
| Tmax | PK parameter: Time When The Maximal Concentration Is Observed (Tmax) for Part 1a, Part 1b and Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 & for Part 1 only: 48 hours post-dose | 
| λz | PK parameter: Individual Estimate Of The Terminal Elimination Rate Constant (λz) for Part 1a, Part 1b and Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 & for Part 1 only: 48 hours post-dose | 
| t½ el | PK parameter: Terminal Elimination Half-Life (t½ el) for Part 1a, Part 1b and Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 & for Part 1 only: 48 hours post-dose | 
| Cmax, ss | PK parameter: Maximal Observed Concentration at steady state (Cmax, ss) for Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post-dose | 
| Cmin | PK parameter: Minimal Observed Concentration (Cmin) for Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post-dose | 
| Cavg | PK parameter: Average Plasma Concentration (Cavg) for Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post-dose | 
| Tmax, ss | PK parameter: Time When The Maximal Concentration Is Observed at Steady State (Tmax, ss) for Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post-dose | 
| (AUC0-τ) Day 12 (AUC0-24) for Part 2 | PK parameter: Area Under The Concentration-Time Curve For One Dosing Interval (Τ) (AUC0-τ) Day 12 (AUC0-24) for Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post-dose | 
| AUC0-24 for Part 2 | PK parameter: Area Under The Concentration-Time Curve From Time Zero To 24 hours (AUC0-24) for Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post-dose | 
| AR | PK parameter: Accumulation Ratio (AR) for Part 2 | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post-dose | 
| Concentrations of ATH-399A and metabolites in blood for Part 1a | Concentrations of ATH-399A and metabolites in blood for Part 1a | Pre-dose (within 2 hours of dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post-dose | 
| Concentrations of ATH-399A and metabolites in urine for Part 1a | Concentrations of ATH-399A and metabolites in urine for Part 1a | Day 1 pre-dose and 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATH399A, HL192, Parkinson's Disease