Safety, Pharmacokinetics, and Food Effect 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 for healthy subjects with three SAD dose cohorts-25 mg (Cohort 1), 50 mg (Cohort 2), and 75 mg (Cohort 3). An eligible subject will receive a single dose of PS1 or Placebo tablets (8 subjects in each cohort, 6 PS1 + 2 Placebo) 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 (randomized, double-blinded, placebo-controlled, 6 PS1 + 2 Placebo) as the SAD cohorts. An eligible subject 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.

SAD portion for T2DM patients: An open-labeled study design will be applied for the SAD portion for T2DM patients with two SAD dose cohorts-25 mg (Cohort A) and 50 mg (Cohort B). An eligible T2DM patients will receive a single dose of PS1 tablets (6 subjects in each cohort) in a fed condition on Day 1 and be followed for 14 days. Subjects in this portion will have safety and PK observation but will not be evaluated for DLT.

MAD portion for T2DM patients: After confirming the safety and pharmacokinetics of all SAD cohorts (Cohorts 1, 2, 3, A, and B) and the FE cohort (Cohort 4) by iSMC and approved by the authority, a randomized, double-blinded, placebo-controlled study design will be applied for the MAD portion for T2DM patients with two MAD dose cohorts-25 mg/day (Cohort 7) and 50 mg/day (Cohort 8). An eligible subject will receive PS1 or Placebo (8 subjects in each cohort, in a 6:2 ratio of PS1: Placebo) tablets once daily in a fed condition. The treatment period is 28±1 days. All subjects will be followed for additional 7 days.

Inclusion criteria

A subject is eligible for the study if all of the following apply:

• Both genders aged 18 to 80 years, inclusive at screening
• Body mass index (BMI) between 18.5 and 40.0 kg/m2
• Negative test for hepatitis B surface antigen (HBsAg), Anti-HCV antibody, and human immunodeficiency virus (HIV) at screening. Subjects with positive anti-HCV may be enrolled only if they have a negative HCV RNA result during the screening period.
• Is willing to follow the trial life style instruction and protocol procedure
• Able to understand and sign the informed consent form

Inclusion criteria

applied for healthy subjects (Cohorts 1~4)

• 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
• With HbA1c value of < 6.5% and fasting plasma glucose < 110 mg/dL at Screening
• With estimated glomerular filtration rate (eGFR) > 80 ml/min/1.73m2

Inclusion criteria

applied for T2DM patients (Cohorts A, B, 7, and 8)

• Diagnosis of T2DM
• T2DM treated with diet and exercise alone currently, for at least 2 weeks prior to Screening
• With HbA1c level between 5.7% to 9.0% or fasting plasma glucose level between 100 mg/dL to 250 mg/dL at Screening
• With estimated glomerular filtration rate (eGFR) > 60 ml/min /1.73m2
• Patients taking medications for T2DM comorbidities, i.e., hypertriglyceridemia, hyperlipidemia, and hypertension, should be on a stable dose of their medication for at least 3 months prior to Screening. Any other chronic medications should be on a stable dose for at least 4 weeks prior to Screening.

Exclusion criteria

Any subject meeting any of the following exclusion criteria will be excluded from study participation.

• History of Type I diabetes mellitus
• 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
• Received strong CYP enzyme inhibitor or inducer within 14 days before Screening
• Received any vaccination within 14 days before Screening
• Has required insulin therapy within the past 12 weeks
• Known hypersensitivity to any of the components of PS1 tablet
• 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-other than T2DM and its comorbidities (i.e., hypertriglyceridemia, hyperlipidemia, and hypertension)
• History of pancreatitis
• Serum amylase > 1.5 × Upper Limit of Normal (ULN) or lipase > 1.5 × ULN
• Clinically significant ECG abnormality at Screening
• History of cancer (malignancy) or have ever received any anti-cancer therapy
• Regular smoker Regular smoker is defined as who smokes every day (≥ 1 cigarette/day in average in the past 8 weeks of Screening)
• 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 (<10% alcohol; about 330 mL), one glass of wine (10~20% alcohol; about 150 mL), or one shot of distilled spirits (>20% alcohol; about 45 mL)
• Received any investigational therapy from another clinical study or underwent any major surgeries within the last 12 weeks prior to Screening
• Took glucose-lowering medications within the last 2 weeks prior to Screening
• Received any systemic steroids (inhaled and intranasal steroids are permitted) or other immunosuppressive medications within 4 weeks prior to Screening
• Have ever received cell therapy or organ transplantation
• Other conditions not suitable for participating in this study as judged by the investigator
• Any conditions that forbid the completion of study procedures due to the local regulatory restrictions
• Female subject of childbearing potential who:

• Is lactating; or
• Has a positive pregnancy test result at Screening; or
• Refuses abstinence or to adopt at least two forms of highly effective contraception from signing informed consent to the end of the study.
• Male subject with a female spouse/partner who is of childbearing potential refuses abstinence or to adopt at least two forms of highly effective contraception from signing informed consent to the end of the study.

Exclusion criteria

applied for healthy subjects (Cohorts 1~4):

• History of type II diabetes mellitus

Exclusion criteria

applied for T2DM patients (Cohorts 7 and 8):

• Triglyceride >300 mg/dL (fasting lipid profile) or cholesterol > 1.5 × ULN (fasting lipid profile)
• Received beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNI; e.g., Entresto (sacubitril/valsartan)), or renin inhibitors (e.g., Rasilez (aliskiren)) medications within 3 months prior to Screening