A Study to Assess Safety, Tolerability and Exposure of 4ET1103 in Healthy Human Volunteers

A First in Human Randomized, Double-Blind, Placebo Controlled Single Ascending Dose (SAD) Phase 1 Study to Determine Safety, Tolerability, and Pharmacokinetics of 4ET1103 in Healthy Volunteers

This study will dose healthy human volunteers with either active drug (4ET1103) or placebo. Each study subject will receive a single dose of either active drug or placebo, and will then be monitored for safety, tolerability and exposure of active drug.

This is a randomized, double-blind, placebo-controlled, SAD study conducted in approximately 40 healthy male and female volunteers. The study drug (4ET1103 or placebo) will be administered orally under fasting condition. 40 subjects (8 subjects/cohort) will participate in this study in up to 5 dose cohorts (45, 135, 270, 450 and 720 mg of 4ET1103.

Inclusion Criteria:

• Healthy males and females (sex at birth) between 18 and 65 years of age; inclusive based on the date of Screening.

• Body mass index (BMI) between 18 and 32 kg/m2 (inclusive) and weigh at least 50 kg at Screening and Day -1.

• Provision of signed and dated, written informed consent prior to any study-specific procedures

• Female subjects have a negative serum pregnancy test result at Screening and negative urine pregnancy test result at Day -1.

• Female subjects with male partners must meet one of the following criteria:

  1. Using a medically acceptable form of birth control for at least 30 days prior to Screening (60 days on oral contraceptives) until 3 months following the last dose of study drug [e.g., hormonal contraceptives (oral, patch, injectable or vaginal ring), implantable device (implantable rod or intrauterine device), bilateral tubal ligation/tubal occlusion or a double barrier (e.g., diaphragm, cervical cap, condom in conjunction with spermicide or sponge)]. For female subjects using hormonal contraceptives, it is also required to use at least one additional form of contraception, i.e., implantable device (implantable rod or intrauterine device), or a double barrier method (e.g., diaphragm, cervical cap, or condom in conjunction with spermicide or sponge).
  2. Surgically sterile for at least 3 months prior to Screening by one of the following means:

• Bilateral salpingectomy (with or without oophorectomy)

• Surgical hysterectomy

• Bilateral oophorectomy (with or without hysterectomy) c. Postmenopausal, defined as the following:

• Female subjects with 12 months consecutive amenorrhea and follicle-stimulating hormone (FSH) levels greater than 40 international units per liter (IU/L) at Screening.

  d. Female subjects of reproductive potential who are abstinent of heterosexual activity (when in line with the preferred and usual lifestyle of the subject), are acceptable provided they agree to a double barrier method for at least 3 months after their last dose of the study drug should they become sexually active with a male partner.

  e. Females must agree to avoid egg donation throughout the study and for at least 3 months after last dose of study drug.

• Male subjects with female partners have history of vasectomy or must agree to utilize a highly effective method of contraception (condom with spermicide) during heterosexual intercourse from clinic admission until at least 3 months following the last dose of the study drug and must refrain from donating sperm for this same period.

• Considered healthy by the Investigator, based on subject's reported medical history, full physical examination, clinical laboratory tests, 12-lead ECG, and vital signs at Screening and Day -1.

• Willing and able to adhere to study restrictions and to be confined at the clinical research center

• Subjects willing to defer receiving any vaccines (e.g. influenza or coronavirus or pneumococcal vaccines) within 30 days prior to the first dose of study drug (Day 1) and throughout the study.

• Nicotine-free (cigarettes, pipe, cigar, chewing tobacco, nicotine patches, vapes, etc.) for at least 3 months before Screening and a negative urine cotinine test at Screening and Day -1.

Exclusion Criteria:

1. History or presence of any illness, condition, or finding that in the opinion of the Principal Investigator (PI) or designee would put the subject or study conduct at risk, or have the potential to confound the results of the study, if the subject were to participate in the study.

2. History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, bleeding disorder or psychiatric disease or drug hypersensitivity as determined by the Investigator

3. Any surgical or medical condition that could interfere with the absorption, distribution, metabolism, or excretion of the drug. Cholecystectomies will be exclusionary and uncomplicated appendectomies will not be exclusionary

4. In opinion of the Investigator, the subject has history of any true drug allergy; excluding histories limited to mild to moderate gastrointestinal distress (nausea, anorexia, diarrhea, infrequent vomiting).

5. History of alcohol abuse (drinking 14 units of alcohol per week: 1 unit = 360 mL of beer, or 37 mL of spirits, or 120 mL of wine) within 3 months prior to Screening, or positive urine alcohol test at Screening or Day -1. Subjects must agree to abstain from alcohol intake from 72 hours before study drug administration through discharge from the CRU.

6. History of prescription drug abuse, or marijuana or cannabis product use or illicit drug use within 6 months prior to Screening, or positive findings on the urine drug screen at Screening or Day -1.

7. History of organ transplant, including history of bone marrow transplant.

8. Use of any prescription (excluding contraceptives) medication, over the counter (OTC) medication or herbal supplements within 7 days or 5 half-lives, whichever is longer prior to Day 1.

9. Evidence of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) infection or oral temperature >38°C at Day -1. During the study, if subjects have infections, the subjects may continue the study at the discretion of the Investigator. In the case of COVID-19 infection, subject will be withdrawn.

10. Subjects who have received any vaccines within 30 days prior to Day 1

11. Donated or lost blood >500 ml within 60 days prior to Screening

12. Acute illness within 14 days of study Day 1; acute illness occurring before this must show complete recovery at least 14 days prior to Day 1.

13. Regular consumption of > 3caffeine - or xanthine-containing products in 2 weeks before Screening and unwilling to consume <3 caffeine - or xanthine-containing products while confined at the CRU.

14. Positive serologic findings for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody (Ab), and/or Human immunodeficiency virus (HIV) Ab at Screening.

15. Positive Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening

16. Surgery within the past 90 days prior to Day 1 as determined by the Investigator to be clinically relevant.

17. Seated systolic blood pressure (SBP) not within the range of 90 mmHg to 140 mmHg and diastolic blood pressure (DBP) not within the range of 50 mmHg to 90 mmHg at Screening or Day 1.

    Note: If a subject fails to meet SBP and/or DBP criteria, optional repeat visits/measurements can, at the discretion of the Investigator, to be completed. For those subjects who have a repeat blood pressure measurement, the repeat value will be used to determine eligibility.

18. Heart rate <40 bpm or >99 bpm at Screening or Day -1. Note: If a subject fails to meet heart rate criteria, optional repeat visits/measurements can, at the discretion of the Investigator, to be completed. For those subjects who have a repeat blood pressure measurement, the repeat value will be used to determine eligibility.

19. Any clinically significant ECG abnormality at Screening (as deemed by the Investigator).

    NOTE: The following (a-d) are considered not clinically significant without consulting Sponsor's Medical Monitor:

    1. Mild first-degree A-V block (P-R interval <0.23 sec)
    2. Right or left axis deviation
    3. Incomplete right bundle branch block
    4. Isolated left anterior fascicular block (left anterior hemiblock)

20. QTcF interval >450 msec for male and >470 msec for female (the average value for the triplicate ECG at Screening and Day -1), or history of prolonged QT syndrome.

21. Subject with abnormal liver function test (LFT) at Screening or Day -1.

22. Subjects with estimated glomerular filtration rate (eGFR) < or = 75 mL/min/1.73m2 using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 2021 at Screening or Day -1.

23. Receipt of an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to dosing on Day 1.

24. Subjects who have taken a special diet (including dragon fruit, mango, grapefruit or grapefruit juice and other known inhibitors of CYP) or strenuous exercise, or other factors affecting drug absorption, distribution, metabolism, and excretion within 5 days before Day 1.

25. Subjects with hypersensitivity to any excipients present in study drug (excipients listed in Investigator's Brochure).