A FIH Study to Investigate the Safety, Tolerability and PK of P218

A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile and Food Effect of P218 in Healthy Adult Volunteers

The First in Human (FIH) study is separated into two parts:

• The first part is a Single Ascending Dose (SAD), double-blinded, randomized and placebo-controlled, including 8 cohorts of 8 subjects (2 placebo and 6 on active drug).
• The second part is a food effect cohort with an open-labelled, randomized fed/fasted cross-over design.

The main objectives of the study are to confirm safety, tolerability and Pharmacokinetics (PK) of P218 in healthy volunteers.

The study is divided into two parts:

Part A

This is a double-blind randomised, placebo-controlled, parallel group, ascending dose study and will comprise up to eight fasted cohorts (8 volunteers in each) that will receive a single ascending dose (SAD) of P218 to assess its safety, tolerability and pharmacokinetic profile. Each subject will participate in only one dose group and will receive only one dose of study drug. In each cohort, 2 and 6 subjects will be randomized to placebo and P218, respectively. The data obtained from each cohort will undergo a formal review by the Safety Review Team (SRT). SRT will confirm that it is safe to proceed with the next dose/cohort.

Part B

This is the pilot food effect evaluation. Once predicted human efficacious concentrations of P218 and a safe exposure window (at least 3-fold above the targeted therapeutic exposure in order to account for a possible increase in exposure with food) has been achieved in Part A, a new cohort of 8 subjects (all receiving active drug) will be evaluated for food effect in an open-label, randomized fed/fasted crossover design. Subjects participating in this food effect cohort will be randomized to two single dose sessions (fed/fasted). The second dose will be administered after a washout period of at least 5x observed human half-life (T1/2), to be confirmed once PK data are available from the relevant doses from Part A.

Primary objectives:

• To investigate the safety and tolerability of single escalating oral doses of P218 when administered to healthy volunteers (men and Women of Non Child Bearing Potential (WNCBP)) under fasted conditions.

Secondary objectives:

• To describe the pharmacokinetics of P218 and its major glucuronide metabolite (P218 acyl glucuronide) in healthy volunteers (men and WNCBP) after administration of single escalating oral doses
• To investigate the effect of a high fat meal on the pharmacokinetics and safety/tolerability of P218.

This study incorporates the use of an adaptive design. All anticipated dosing levels can be adjusted in accordance with PK, safety and tolerability data collected up to the decision making time-point.

Inclusion Criteria:

1. Subject is a healthy male or female (of non-childbearing potential), aged 18 to 45 years, inclusive.

2. Satisfactory medical assessment with no clinically significant or relevant abnormalities as determined by medical history, physical examination, vital signs, 12-lead electrocardiograms (ECG), and clinical laboratory evaluation (haematology, biochemistry, coagulation, and urinalysis) that is reasonably likely to interfere with the subject's participation in or ability to complete the study as assessed by the Investigator.

3. Subject has a body weight of at least 50 kg and a Body Mass Index (BMI) of 18-25 Kg/m2, inclusive.

4. Female subjects must be of non-childbearing potential:

   1. Natural (spontaneous) post-menopausal defined as being amenorrheic for at least 12 months without an alternative medical cause with a screening follicle stimulating hormone level > 25 IU/L (or at the local laboratory levels for post-menopause).
   2. Premenopausal with irreversible surgical sterilization by hysterectomy and/or bilateral oophorectomy or salpingectomy at least 6 months before screening (as determined by subject medical history).

5. Heterosexually active male subjects with a female spouse/partner of childbearing potential must agree to use barrier contraception (male condom), even with documented medical assessment of surgical success of a vasectomy, if your partner could become pregnant from the time of the first administration of P218 and for 100 days following this. Your partner must also use a method of highly effective contraception including:

   • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:

     • Oral
     • Intravaginal
     • Transdermal

   • Progestogen-only hormonal contraception associated with inhibition of ovulation:

     • Oral
     • Injectable
     • Implantable

   • Intrauterine device

   • Intrauterine hormone-releasing system

   • Bilateral tubal occlusion

6. Subjects are non-smokers or ex-smokers for more than 90 days prior to screening or smoke no more than 5 cigarettes per day. If users of nicotine products (i.e. spray, patch, e-cigarette, etc.) no more than 5 cigarettes per day is allowed. Subjects must agree to abstain from smoking while in the unit.

7. Ability to swallow multiple capsules at a time or (consecutively) 1 capsule at a time.

8. Subjects must be capable of fully understanding and complying with the requirements of the study and must have signed the informed consent form prior to undergoing any study-related procedures.

9. Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Male subjects with a female partner(s) who is (are) pregnant or lactating from the time of the administration of study medication.

2. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means.

3. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal (including gallbladder), cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug or food allergies, anaphylaxis or other severe allergic reactions but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).

4. Current or relevant history of physical or psychiatric illness that may require treatment or make the subject unlikely to fully comply with the requirements or complete the study, or any condition that presents undue risk from the investigational product or study procedures.

5. Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel disease, etc.), distribution, metabolism or excretion.

6. Any history of gallbladder disease, including cholecystitis and/or cholelithiasis.

7. Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of the participation in the study may influence the result of the study, or the subject's ability to participate in the study.

8. History of photosensitivity.

9. History of megaloblastic anaemia or folate deficiency.

10. History or clinical evidence of substance and/or alcohol abuse within the 12 months before screening. Alcohol abuse is defined as regular weekly intake of more than 21 units for males and 14 units for females (using alcohol tracker http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx).

11. Treatment with an investigational drug within 90 days or 5 half-lives preceding the first dose of study medication (or as determined by the local requirement, whichever is the longer).

12. Donation of blood or blood products (excluding plasma) within 90 days prior to study medication administration.

13. Use of moderate/strong inhibitors or inducers of Cytochromes P450 (CYP450) or transporters within 30 days or 5 half-lives (whichever is the longer) prior to the first dose of study medication.

14. Consumption of grapefruit, grapefruit juice or grapefruit-related citrus fruits (e.g. Seville oranges, pomelos) within 30 days prior to the first dose of study medication.

15. Ingestion of any poppy seeds within the 24 hours prior to screening.

16. Use of prescription or non-prescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is the longer) prior to the first dose of study medication. With the exception of paracetamol, which may be used incidentally or for a short-term treatment at a maximum dose of 1 gr. per day.

17. Use of herbal supplements at least 30 days prior to the first dose of study medication.

18. Any clinically significant abnormal laboratory, vital signs or other safety findings as determined by medical history, physical examination or other evaluations conducted at screening or on admission.

19. The history or presence of any of the following cardiac conditions: known structural cardiac abnormalities; family history of long QT syndrome; cardiac syncope or recurrent, idiopathic syncope; exercise related clinically significant cardiac events.

    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of corrected QT interval (QTc) changes. This includes subjects with any of the following (at screening):
    • Sinus node dysfunction.
    • Clinically significant interval prolongation of the interval from the beginning of the P wave to the beginning of the three distinct waves created by the passage of the cardiac electrical impulse through the ventricles (QRS complex) on an electrocardiogram (PR).
    • Intermittent second or third degree atrioventricular (AV) block.
    • Incomplete or complete bundle branch block.
    • Abnormal T wave morphology.
    • Prolonged QT intervals calculated using Bazett's formula (QTcB) >450 ms or shortened QTcB < 350 ms. Any other ECG abnormalities in the standard 12-lead ECG and 24-hour 12 lead Holter ECG or an equivalent assessment which in the opinion of the Investigator will interfere with the ECG analysis.

    Subjects with borderline abnormalities may be included if the deviations do not pose a safety risk, and if agreed between the appointed Cardiologist and the PI.

20. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines, cocaine, cannabinoids, opiates, barbiturates, and methadone) or from the alcohol breath test at screening or on admission.

21. A positive human immunodeficiency virus (HIV) I and II antibodies, hepatitis B surface antigen (HBsAg), anti Hepatitis core antibody (anti hepatitis B core antigen (HBc) immunoglobulin G (IgG) [and anti HBc Immunoglobulin M (IgM) if IgG is positive]), or hepatitis C virus (HCV) antibody at screening.

22. Subjects have veins unsuitable for intravenous puncture or cannulation on either arm (e.g. veins that are difficult to locate access or puncture veins with a tendency to rupture during or after puncture).

23. Any conditions which in the opinion of the investigator would make the subject unsuitable for enrollment or could interfere with the subjects' participation in or completion of the study.