Safety, Pharmacokinetics, and Food Effect of PS1 in Subjects

This is a phase I, double-blind, placebo-controlled, randomized, single- and multiple-ascending dose study to evaluate new study intervention, PS1. PS1 is a potential blood glucose control medication, which is developed by Pharmasaga Co. Ltd. planned for treating type II diabetes mellitus (T2DM). This is a first-in-human study to evaluate the safety, tolerability, pharmacokinetics (PK), food effect and potential efficacy of PS1 in subjects.

This first-in-human Phase I study consists of a single ascending-dose (SAD) portion, a food effect (FE) portion, and a multiple ascending-dose (MAD) portion, aiming to evaluate the safety, tolerability, pharmacokinetics, food effect and potential efficacy of PS1 in healthy subjects.

A randomized, double-blinded, placebo-controlled study design will be applied for the SAD portion with three SAD dose cohorts-25 mg (Cohort 1), 50 mg (Cohort 2), and 75 mg (Cohort 3). An eligible subject in this portion will receive a single dose of PS1 or Placebo tablets in a fed condition on Day 1 and be followed for 7 days.

In FE portion, only one cohort (Cohort 4) is assigned. The FE cohort (Cohort 4) will use the same study design as the SAD cohorts. An eligible subject in this portion will receive a single dose of 50 mg PS1 or Placebo tablets in a fasted condition on Day 1 and be followed for 7 days.

Four cohorts are assigned in the MAD portion: 25 mg/day (Cohort 5 \& 7) and 50 mg/day (Cohort 6 \& 8) in healthy volunteers and participants respectively. Only the dose level of MAD lower than the maximum tolerated dose (MTD) of SAD portion can be activated (If 50 mg was determined as the MTD of SAD, only cohort 5 \& 7 could be activated). An eligible subject will receive PS1 or Placebo tablets once daily in a fed condition for 14 days \& 28 days in healthy volunteers and participants respectively and be followed for additional 7 days.

Eligibility Criteria:
Inclusion Criteria:

For all cohorts, a subject is eligible for the study if all of the following apply:

1. Both genders aged 18 to 80 years, inclusive at screening
2. Body mass index (BMI) between 18.5 and 40.0 kg/m2
3. Negative test for hepatitis B surface antigen (HBsAg), Anti-HCV antibody, and human immunodeficiency virus (HIV) at screening
4. Is willing to follow the trial life style instruction and protocol procedure
5. Able to understand and sign the informed consent form.

   Inclusion criteria applied for healthy subjects (Cohorts 1\~6)
6. Overtly healthy subject, who is considered to be generally healthy based on medical history, vital signs, laboratory tests, 12-lead EKG, and physical examination, as judged by the investigator
7. With HbA1c value of \< 6.5% and fasting plasma glucose \< 110 mg/dL at Screening
8. With estimated glomerular filtration rate (eGFR) \> 80 ml/min

   Inclusion criteria applied for T2DM patients (Cohort 7 and 8)
9. Diagnosis of T2DM
10. T2DM treated with diet and exercise alone currently, for at least 2 weeks prior to Screening
11. With HbA1c level between 6.5% to 9.0% and fasting plasma glucose level between 130 mg/dL to 250 mg/dL at Screening
12. With estimated glomerular filtration rate (eGFR) \> 60 ml/min
13. For patients taking medication for other chronic disease, the medication should be on a stable dose for at least 4 weeks prior to Screening, and should not be a strong CYP enzyme inhibitor or inducer

Exclusion Criteria:

For all cohorts, a subject meeting any of the following exclusion criteria will be excluded from study participation.

1. History of Type I diabetes mellitus
2. Under the systemic treatment of any prescription medication or over-the-counter (OTC) medication that may interfere with the safety or PK assessment judged by the investigator within 7 days before Screening
3. Received strong CYP enzyme inhibitor or inducer within 14 days before Screening
4. Received any vaccination within 14 days before Screening
5. Has required insulin therapy within the past 12 weeks
6. Known hypersensitivity to any of the components of PS1 tablet
7. History of major clinically significant hematological, renal, respiratory, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, musculoskeletal, immune, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing) within 3 months of Screening that may significantly alter the biomarker panel, require receiving any systemic medications, or interfere with the interpretation of data, as judged by the investigator
8. History of pancreatitis
9. Serum amylase \> 1.5 × Upper Limit of Normal (ULN) or lipase \> 1.5 × ULN
10. Clinically significant ECG abnormality at Screening
11. History of cancer (malignancy) or have ever received any anti-cancer therapy
12. Regular smoker Regular smoker is defined as who smokes every day (≥ 1 cigarette/day in average in the past 8 weeks of Screening)
13. Consumed greater than 3 units of alcoholic beverages per day in average for the past 4 weeks before Screening One unit is equivalent to one can of beer (20% alcohol; about 45 mL)
14. Received any investigational therapy from another clinical study or underwent any major surgeries within the last 12 weeks prior to Screening.
15. Took glucose-lowering medications within the last 2 weeks prior to Screening
16. Received any systemic steroids (inhaled and intranasal steroids are permitted) or other immunosuppressive medications within 4 weeks prior to Screening
17. Have ever received cell therapy or organ transplantation
18. Other conditions not suitable for participating in this study as judged by the investigator
19. Any conditions that forbid the completion of study procedures due to the local regulatory restrictions
20. Female subject of childbearing potential who:

    * Is lactating; or
    * Has a positive pregnancy test result at Screening; or
    * Refuses to adopt at least one form of birth control (refer to Section 5.3) from signing informed consent to the end of the study.
21. Male subject with a female spouse/partner who is of childbearing potential refuses to adopt at least one form of birth control (refer to Section 5.3) from signing informed consent to the end of the study.

    Exclusion criteria applied for healthy subjects (Cohorts 1\~6):
22. History of type II diabetes mellitus