Safety, Tolerability, and Dose Response of VNA-318 in Healthy Males

A Phase 1, Randomized, Double-blind, Placebo-controlled Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Doses of VNA-318 in Healthy Male Subjects

This is a phase 1, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses (SAD) and multiple ascending doses (MAD) of VNA-318 in healthy male subjects.

The First-in-Human phase I, single center study investigating VNA-318, administered orally, will consist of 2 parts:

• Part 1 SAD, conducted in 5 to 8 cohorts of 8 healthy male subjects per dose level, including one optional exploratory cohort with cerebrospinal fluid (CSF) sampling
• Part 2 MAD, conducted in 3 to 4 cohorts of 12 healthy male subjects per dose level Subjects will be included in either Part 1 or 2.

A Study Safety Committee is involved and will make recommendations on the study advancement, i.e. the dose for the next planned cohort.

The doses of the MAD part will be selected by this Study Safety Committee and will be based upon safety and tolerability assessments, the observed PK and, if available and applicable, PD data from SAD.

Inclusion Criteria:

1. Subjects able and willing to provide written informed consent prior any other clinical study procedures.

2. Subjects able and willing to comply with the clinical study protocol (hospitalization periods, scheduled visits, IMP administration, clinical laboratory tests, and other study procedures including lifestyle considerations) according to International Council of Harmonization (ICH) and local regulations.

   Demography

3. Healthy male.

4. Aged 18-65 years (inclusive) on the day of signing the informed consent form (ICF). - Aged 18-45 years (inclusive) for the SAD optional exploratory cohort with CSF sampling

5. Have a body mass index (BMI) between 18.5-30.0 kg/m2 (inclusive) at screening and D 1.

   Health Status

6. Have normal physical examination and vital signs (VS) results within normal ranges at screening and D˗1. If outside normal ranges, it must be considered by the Investigator without clinically significant abnormal findings.

7. Have a clinical laboratory of blood and urine within normal ranges at screening and D-1. If outside normal ranges, it must be considered by the Investigator without clinically significant abnormal findings.

8. Have 12-lead ECG results without clinically significant abnormal findings confirmed by the Investigator at screening and D-1.

9. Non-smoker (and no other nicotine use) as determined by history (no nicotine use over the past 6 months) and by urine cotinine concentration (< 200 ng/mL) at screening and D-1.

   Contraception

10. If sexually active and not sterile, with a woman of childbearing potential, the subject and his partner must commit to using a highly effective method of birth control starting at screening and throughout the entire study and for 90 days after last dose of IMP administration:

    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, started at least 4 weeks prior to the dosing (D1) and use of condom for the male partner.
    • Progestogen-only hormonal contraception associated with inhibition of ovulation, started at least 4 weeks prior to the dosing (D1) and use of condom for the male partner.
    • Intrauterine device placed at least 4 weeks prior to the dosing (D1), and use of condom for the male partner.
    • Intrauterine hormone-releasing system placed at least 4 weeks prior to the dosing (D1), and use of condom for the male partner.
    • Simultaneous use of a diaphragm or cervical cap with intravaginally applied spermicide and, for the male partner, a male condom.
    • Sexual abstinence (when in line with the preferred and usual subject's lifestyle).
    • Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable.

    Or subject with a male partner.

11. Male subjects must agree to abstain from sperm donation starting at screening and throughout the study and for 90 days following their last dose of IMP administration.

    Regulations

12. Covered by a health insurance system where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research.

13. Have competence in speaking, writing, and comprehending the local language(s) where the study is conducted.

Exclusion Criteria:

Medical History

1. Any condition or disease detected during the medical interview/physical examination that could relapse during or immediately after the study, or would render the subject unsuitable for the study, place the subject at undue risk, or interfere with the ability of the subject to complete the clinical study, as determined by the Investigator.

2. Have a history of and/or current clinically significant disease/disorder determined by the Investigator: gastrointestinal, endocrine, renal, hepatic, immunological, cardiovascular, hematological, respiratory, neurologic, metabolic, urologic, dermatologic, psychiatric disorder, or allergic disease, hypersensitivity, or allergic reactions excluding mild asymptomatic seasonal allergies (either spontaneous or following drug administration), or malignancy (including lymphoma, leukemia, and skin cancer) unless remission over 10 years.

3. Have a personal or family history of prolonged QT interval syndrome or Torsade de Pointes, or family history of sudden death.

4. Have current presence of an illness, such as a common cold, isolated headache, diarrhea, etc., within 14 days prior to D1 that is categorized as clinically significant by the Investigator.

5. History or presence of regular use of recreational or illicit drugs within 1 year before study D1.

6. Donation of blood or blood loss (i.e., > 450 ml) within 90 days, or donated plasma within 7 days prior to D-1.

7. Known significant hypersensitivity or other contraindication to any of the components of the study drug.

8. History of suicidal behavior or any risk of suicidal behavior in the opinion of a certified clinician or as evidenced by a "yes" to any questions of Columbia-Suicide Severity Rating Scale (C-SSRS) taken at screening (MAD part only).

9. Confirmed coronavirus disease 2019 (COVID-19) infection within 90 days of screening or contact with an individual with COVID-19 infection in the past 14 days at D-1.

   Physical and Laboratory Findings

10. Have a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus 1 and/or 2 antibodies (anti-HIV1 and anti HIV2 Ab) at screening.

11. Positive findings of urine drug screen (methadone, barbiturates, morphine, amphetamines, methamphetamines, opiates (including morphine), cannabinoids, cocaine, benzodiazepines, tricyclic antidepressants (TCA), 3,4-methylenedioxy-methamphetamine [MDMA; ecstasy]).

12. Have a positive alcohol breath test result at screening or D-1.

    Lifestyle restrictions

13. Have regular consumption of grapefruit juice and any xanthine-containing products (e.g., coffee, tea, chocolate, or Coca-Cola like drinks) more than 6 cups per day (or equivalent), or consumption of any alcoholic beverages within 48 h before prior dosing (D1) until final discharge day inclusive.

14. Have regular consumption of alcoholic beverages that exceeds 21 units per week (1 unit = 10 g of pure alcohol).

    Prior/Concurrent Clinical Study Experience

15. Participation in any another interventional study within ≤90 days prior to Screening provided that the clinical study did not entail administration of a biological compound with a long terminal phase half-life (t½), or in the exclusion period of a previous trial or participation in more than 3 clinical studies within the last 12 months.

    Prohibited Treatments

16. Use of any prescribed or non-prescribed drugs (including vitamins, herbal and dietary supplements, e.g., St. John's Wort) within 2 weeks or 5 half-lives, whichever is longer, prior to study drug administration, except for the occasional use of acetaminophen (up to 3 g/day).

    Other Exclusions

17. Subjects who, in the opinion of the Investigator, are not likely to complete the study for whatever reason.

18. Subject is employed by Sponsor, the CRO, or study site (permanent, temporary contract worker, or designee responsible for the conduct of the study) or is immediate family (i.e., a spouse, parent, sibling, or child, whether biological or legally adopted) of Sponsor, CRO, or study site employee.

19. Prisoners or subjects who are legally institutionalized and with right's restrictions.

20. For Part 1 SAD optional exploratory cohort with CSF sampling only:

    • Platelets and coagulation results within normal ranges.
    • Any medical history that could contraindicate a lumbar puncture [such as spinal trauma, scoliosis, regular headaches (non-exhaustive list)].
    • Use of aspirin or any anticoagulant medication within 3 weeks prior to CSF sampling