A First-In-Human Study of Single and Multiple Ascending Doses of Oral SUL-238 in Healthy Subjects

A Randomized, Double-blind, Placebo-controlled Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics of Single and Multiple Ascending Oral Doses of SUL-238 in Healthy Subjects

The goal of this randomized, double-blind, placebo-controlled, single-center study is to evaluate the safety, tolerability, pharmacokinetics of single and multiple oral doses of SUL-238 in healthy subjects (aged ≥40 years).

This double-blind placebo-controlled study will be completed in 4 parts.

Part 1 will be single ascending dose in which 6 different oral doses (50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg) will be administered to healthy adult male subjects. Each dosing group, including dose escalations, will be performed as described below:

Dose escalation will be performed until suspected adverse events (AEs) are observed. AEs will be evaluated by the blinded investigator, based on clinical signs detailed in the MedDRA criteria. At each dose level, 2 subjects will be administered SUL-238, whereas 1 subject will be administered the placebo. Escalation to the next higher dose level may occur only if no treatment-emergent AEs are observed in the 2 subjects that received SUL-238. If 1 out of 2 subjects experiences a suspected AE, 5 new subjects will be enrolled at the same dose level (4 subjects will receive one SUL-238 tablet and 1 subject will receive one placebo tablet). If no further suspected AEs occur, escalation to the next higher dose level will be performed. If any additional suspected AE is noted, dose escalation is stopped, and the previous dose level is considered the maximum tolerated dose (MTD). If suspected AE are observed in 2 subjects, dose escalation will be stopped and 5 new subjects (4 subjects will receive one SUL-238 tablet and 1 subject will receive one placebo tablet) will be enrolled at the next lower dose level. If no further suspected AE are observed, this dose level is considered the MTD.

Part 2 of the study will be single dose pharmacokinetics study in which 1 dose level below that with suspected AEs will be administered to 10 healthy adult male or female subjects (aged ≥40 years). Five male subjects and 5 female subjects will receive SUL-238. After obtaining the initial PK results from Part 1, at least 3 volunteers who accept to be tapped for Cerebrospinal Fluid (CSF) collection will provide one CSF sample on Day 1, at the time point of 1 hour after reaching Cmax during Part 2 of the study.

Part 2B will be a randomized, single-dose, two-treatment, two-period, crossover study. A total of twenty (20) healthy adults (10 male and 10 female volunteers, aged ≥40 years) will be included. The volunteers will be randomized equally into two treatment groups (each group will have 5 male and 5 female volunteers) in the first period: fasted versus high-fat-fed. All volunteers will receive a single dose of 2000 mg SUL-238 either in a fasted state (at least 10 hours) or after consuming a standardized high-fat meal (30 minutes before the study drug). In the second period, which will be conducted 14 days after the first period (washout period), a crossover will be implemented: volunteers who received SUL-238 in a fasted state in the first period will receive 2000 mg SUL-238 after a high-fat meal in the second period, and vice versa. A high-fat meal will have a total of 800-1000 calories, with ≥50% (500-600 calories) coming from fat. At least three volunteers in each group who accept to be tapped for CSF collection will provide one CSF sample on Day 1, at the time point of 1 hour after reaching Cmax during Part 2B of the study.

Part 3 of the study will be multiple ascending oral doses of SUL-238 or placebo in which 30 healthy elderly subjects (aged ≥40 years) will be included. There will be 2 dosing groups (n=15 for each) once (or twice, or three times a day) daily (5 male subjects and 5 female subjects) in each dosing group for SUL-238, dosing regimen and doses of SUL-238 will be decided after Part 2B. The volunteers will stay at the investigational site for up to 72 hours following the initial dosing (Day 1-4) as well as after the final dosing (Day 14-17). After completion of 72-hour visit, volunteers will be discharged from the clinical unit. The treatment regimen spans a 14-day period, during which participants will undergo continuous monitoring for an additional 14 days. A daily clinic visit will be required from volunteers for the administration of the investigational medicine until day 14. The MTD will be the dose for the first dosing group. The second dosing group will be one below the MTD level (e.g., if MTD is 2000 mg, the second dosing group will receive 1000 mg SUL-238). In the first dosing group three 3 male and 2 female subjects and in the second dosing group 2 male and 3 female subjects will receive placebo. PK parameters as well as renal clearance and percentage of drug excreted in urine and feces will be measured in both dosing groups. At least 3 volunteers who agreed to be tapped for a CSF in both dosing groups receiving SUL-238 will provide one CSF sample on day 14 (post-first dose) 8 or 12 hours post-morning dose in Part 3.

In Part 1, 2 and 2B blood samples will be drawn, before drug administration (0 hours), after 30 minutes and at the following time points: 1, 2, 4, 8, 12, 18, 24, 32, 48 and 72 hours. In Part 3, blood samples will be drawn, before drug administration (0 hours), after 30 minutes and at the following time points: 1, 2, 4, 6, 8, 12, 18, 24, 32, 48 and 72 hours, Days 8 (pre-morning dose), 14 (pre-last dose baseline, post-last dose at 30 minutes, 1, 2, 4, 6, 8, 12 and 18 hours), 15 (post-last dose at 24 and 32 hours), 16 and 17. The subject randomized to placebo arm will provide blood samples as subjects randomized to active drug.

In Part 1 and 2 ambulatory visits will be performed at Day 8, 11, 15, 22 and 29 after dosing on which volunteers will visit the clinical investigational site. In Part 2B ambulatory visits will be performed at Day 8, 22 and 29 after dosing. The volunteers will be followed up until Day 29. In Part 3, ambulatory visits will be performed at Day 22, and 29 after dosing on which volunteers will visit the clinical investigational site.

Inclusion Criteria:

1. Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, neurological examination, laboratory tests and cardiac monitoring.
2. Men and women aged≥40 years at Screening.
3. Subject must understand the nature of the study and provide signed and dated written informed consent in accordance with local regulations before the conduct of any study-related procedures.
4. Able to complete all study related testing and evaluations.
5. Women and men of child-bearing potential with partners of child-bearing potential must agree to use highly effective contraception. For male subjects, contraception should continue for 90 days after the last dose of investigational medicinal product (IMP, one spermatic cycle).
6. Women of non-childbearing potential must be post-menopausal (the last menstrual period was at least 12 months ago, and follicle-stimulating hormone [FSH] at Screening confirms post-menopausal status), or have no uterus, ovaries, or fallopian tubes (or have their fallopian tubes tied). All women must have a negative pregnancy test result before administration of test article. Women who are surgically sterile must provide documentation of the procedure by an operative report or by ultrasound.
7. Body weight > 50 kg for men and > 50 kg for women and Body Mass Index (BMI) within the range 18.5-30.0 kg/m2, inclusive.
8. Subject 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.

Exclusion Criteria:

1. A positive urine drug screen/alcohol breath test at Screening or Day -1.
2. Any history of intellectual disability or psychiatric disorders, including substance use disorders, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, except a history of mild depression/anxiety that has been resolved for at least the past 12 months.
3. A positive Hepatitis B surface antigen, Hepatitis C antibody, or Human Immunodeficiency Virus (HIV) antibody test at Screening.
4. 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 administration.
5. History of regular alcohol consumption within the last 12 months, defined as an average weekly intake of >21 alcoholic drinks/week for men or >14 alcoholic drinks/week for women.
6. 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 Day -1.
7. Received or used an investigational product (including placebo) or device within the following time period prior to Day -1 in the current study: 90 days, 5 half-lives, or twice the duration of the biological effect of the investigational product (whichever is longer).
8. Use of prescription or non-prescription drugs, vitamins, herbal, and dietary supplements within 7 days (or 28 days if the drug is a potential hepatic enzyme inducer) or 5 half-lives (whichever is longer) prior to Day -1.
9. 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.
10. A positive serum pregnancy test or lactation.
11. A history or presence of any disease, condition, or surgery likely to affect drug absorption, distribution, metabolism, or excretion. Subjects with a history of cholecystectomy should be excluded.
12. A history or presence of a clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, pulmonary, ophthalmologic, immunologic, hematologic, dermatologic, or neurologic abnormality.
13. 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.
14. A clinically significant vital signs abnormality at Screening or Day -1 This includes, but is not limited to, the following, in the sitting position (3 measurements, each 5 minutes apart): (a) systolic blood pressure < 90 or >140 mmHg, (b) diastolic blood pressure < 50 or > 95 mmHg, or (c) heart rate < 45 or > 100 beats per minute.
15. Subjects who have previously been enrolled in this study.
16. The subject is, in the opinion of the Investigator or Medical Monitor, unlikely to comply with the protocol or is unsuitable for any reason, e.g., known issues with ability to swallow tablets.