A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GLWL-01

Study Overview
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Brief Summary
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This 3-part study will explore the safety and tolerability of GLWL-01 in overweight/obese healthy participants after single doses (in Part A), and in participants with type 2 diabetes mellitus after multiple doses during a 28-day period (Parts B and C).

Official Title
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A 3-Part, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose, and Proof of Concept Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GLWL-01

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: GLWL-01, Part A
* Drug: Placebo, Part A
* Drug: GLWL-01, Part B
* Drug: Placebo, Part B
* Drug: GLWL-01, Part C
* Drug: Placebo, Part C


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PARTS A-C: Non-vasectomized males (or those vasectomized less than 4 months prior to study start) must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study drug Males agree to not donate sperm from dosing until 90 days after dosing Laboratory test results within normal range or acceptable deviation, and Aspartate Aminotransferase (AST) / Alanine Aminotransferase (ALT) / Gamma Glutamyl Transferase (GGT) / Alkaline Phosphatase (ALP) to be less than or equal to (≤)1.5 x upper limit of normal (ULN), and total bilirubin has to be within normal limit Estimated glomerular filtration rate (eGFR) greater than or equal to (≥) 60 milliliter (mL)/minute/1.73m2 No evidence of weight excursion beyond 5% of baseline weight within 3 months of screening PART A Only: Overtly healthy males or females, as determined by medical history and physical examination Males must be 18 to 65 years old; females must be 40 to 65 years old Female participants must be: Women with prior history of hysterectomy who are at least 45 years of age and with follicle-stimulating hormone (FSH) greater than (>) 40 milli-international units per milliliter (mIU/mL), or Menopausal women with either: spontaneous amenorrhea for at least 12 months (not induced by a medical condition or medications); or spontaneous amenorrhea for 6 to 12 months and a FSH > 40 mIU/mL Body mass index (BMI) of 28 to 35 kilograms divided by height in meters squared (kg/m2) Normotensive (supine systolic blood pressure (BP) less than (<) 140 millimeter of mercury (mmHg) and diastolic BP <90 mmHg No evidence of weight excursion beyond 5% of baseline weight within 3 months of screening PARTS B and C: Must have Type 2 Diabetes Mellitus Be 18 to 70 years old Have BMI of 28 to 42 kg/m2 Female participants must be of non-childbearing potential, and must have undergone one of the following sterilization procedures at least 6 months prior to first dose: hysteroscopic sterilization, bilateral tubal ligation or bilateral salpingectomy, hysterectomy, or bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and with FSH serum levels consistent with postmenopausal status Normotensive (supine systolic BP) < 150 mmHg and diastolic BP <95 mmHg or well-controlled hypertension while on a stable hypertensive Exclusion Criteria: PARTS A-C: Currently enrolled in a clinical trial or any other medical research judged to be not compatible with the study, or have participated in the last 30 days prior to dosing in a clinical trial involving an investigational product or non-approved use of a drug with short half-life, or within 5 half-lives of an investigational product with a half-life longer than 6 days Abnormality in the 12-lead electrocardiogram (ECG) including corrected QT (QTc) interval with Bazett's correction >450 milliseconds (msec) for men and >470 msec for women, or an abnormality that, in the opinion of the Investigator, increases the risks associated with participating in the study Significant cardiovascular disease or other disorders Evidence of human immunodeficiency virus (HIV) infection, hepatitis B, hepatitis C, or other chronic liver or biliary disease Average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females), or is unwilling to stop use of Cytochrome P450 (CYP3A) inhibitors/inducers (St. John's Wort) or alcohol consumption for the study, or regular use of known drugs of abuse or positive finding on urinary drug screen, use of cigarettes or nicotine products within last 3 months, or blood donation or loss within 56 days prior to the study Neuropsychiatric disease or pharmacological therapy for such conditions within 1 year of dosing, or antidepressants or antipsychotics within 3 months of dosing, or surgery within last 60 days Eating disorder or weight loss medications within 4 months of dosing, or bariatric surgery Unsuitable for inclusion in the study in the opinion of the investigator or sponsor PART A Only: History of hypertension (or on treatment with any antihypertensives) Endocrine illness such as diabetes, growth hormone insufficiency / acromegaly, adrenal gland or thyroid illness PARTS B and C: Currently taking simvastatin > 10 mg per day, or atorvastatin > 20 mg per day, or lovastatin >20 mg per day, or history of statin-induced myopathy / rhabdomyolysis. Participants taking any dose of simvastatin will be excluded from some cohorts Allergic to the components of the Mixed Meal Tolerance Test

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GLWL-01, Part A<br>Escalating dose in at least 2 of 3 periods, starting at 10 milligrams (mg) | Drug: GLWL-01, Part A<br>* Capsules administered orally, in 2 out of 3 periods<br>|
| Placebo Comparator: Placebo, Part A<br>Escalating dose of placebo to match GLWL-01, in 1 period | Drug: Placebo, Part A<br>* Capsules administered orally in 1 out of 3 periods<br>|
| Experimental: GLWL-01, Part B<br>Multiple ascending daily doses of GLWL-01 at up to six dose levels, based on Part A | Drug: GLWL-01, Part B<br>* Capsules administered orally either once or twice daily for 27 days, with a single dose on Day 28<br>|
| Placebo Comparator: Placebo, Part B<br>Multiple daily doses of placebo to match GLWL-01 | Drug: Placebo, Part B<br>* Capsules administered orally either once or twice daily for 27 days with a single dose on Day 28<br>|
| Experimental: GLWL-01, Part C<br>Multiple daily doses of GLWL-01 at level based upon Part B | Drug: GLWL-01, Part C<br>* Capsules administered orally either once or twice daily for 27 days with a single dose on Day 28<br>|
| Placebo Comparator: Placebo, Part C<br>Multiple daily doses of placebo to match GLWL-01 | Drug: Placebo, Part C<br>* Capsules administered orally either once or twice daily for 27 days with a single dose on Day 28<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With One or More Treatment Emergent Adverse Events (Part A) | Treatment Emergent Adverse Event defined as an adverse event that started or worsened in severity at the time of, or after treatment | Baseline to 7 weeks | 
| Number of Participants With One or More Treatment Emergent Adverse Events (Parts B) | Treatment Emergent Adverse Event defined as an adverse event that started or worsened in severity at the time of, or after treatment | Baseline to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Non-Zero Concentration (AUC0-t) (Part A) |  | Pre-dose, 0.5, 1, 2, 4.5, 6, 8.5, 12.5, 24, 28.5, 48, 96 and 144 hours post-dose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Non-Zero Concentration (AUC0-t) (Part B) |  | Predose, 0.5, 1, 2, 4.5, 6, 8.5, 12, 13, 14, 16, 24, 48, 168, and 336 hours post dose starting on Day 28 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24-hour Post-Dose (AUC0-24) (Part A) |  | Predose, 0.5, 1, 2, 4.5, 6, 8.5, 12, 13, 14, 16, 24 hours post-dose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24-hour Post-Dose (AUC0-24) (Parts B) |  | Predose, 0.5, 1, 2, 4.5, 6, 8.5, 12, 13, 14, 16, 24 hours post dose starting on Day 28 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) (Part A) |  | Pre-dose, 0.5, 1, 2, 4.5, 6, 8.5, 12.5, 24, 28.5, 48, 96 and 144 hours post-dose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) (Part B) |  | Predose, 0.5, 1, 2, 4.5, 6, 8.5, 12, 13, 14, 16, 24, 48, 168, and 336 hours post dose starting Day 1 | 
| Maximum Observed Drug Concentration (Cmax) (Part A) |  | Pre-dose, 0.5, 1, 2, 4.5, 6, 8.5, 12.5, 24, 28.5, 48, 96 and 144 hours post-dose | 
| Maximum Observed Drug Concentration (Cmax) (Part B) |  | Predose, 0.5, 1, 2, 4.5, 6, 8.5, 12, 13, 14, 16, 24, 48, 168, and 336 hours post dose starting on Day 28 | 
| Time to Observed Cmax (Tmax) (Part A) |  | Pre-dose, 0.5, 1, 2, 4.5, 6, 8.5, 12.5, 24, 28.5, 48, 96 and 144 hours post-dose | 
| Time to Observed Cmax (Tmax) (Part B) |  | Predose, 0.5, 1, 2, 4.5, 6, 8.5, 12, 13, 14, 16, 24, 48, 168, and 336 hours post dose starting on Day 28 | 
| Elimination Half-Life (T1/2) (Part A) |  | Pre-dose, 0.5, 1, 2, 4.5, 6, 8.5, 12.5, 24, 28.5, 48, 96 and 144 hours post-dose | 
| Elimination Half-Life (T1/2) (Part B) |  | Predose, 0.5, 1, 2, 4.5, 6, 8.5, 12, 13, 14, 16, 24, 48, 168, and 336 hours post dose starting on Day 28 | 
| Apparent Clearance of Drug (CL/F) (Part A) |  | Pre-dose, 0.5, 1, 2, 4.5, 6, 8.5, 12.5, 24, 28.5, 48, 96 and 144 hours post-dose | 
| Apparent Clearance of Drug (CL/F) (Part B) |  | Predose, 0.5, 1, 2, 4.5, 6, 8.5, 12, 13, 14, 16, 24, 48, 168, and 336 hours post dose starting on Day 28 | 
| Apparent Total Volume of Distribution (VZ/F) (Part A) |  | Pre-dose, 0.5, 1, 2, 4.5, 6, 8.5, 12.5, 24, 28.5, 48, 96 and 144 hours post-dose | 
| Apparent Total Volume of Distribution (VZ/F) (Part B) |  | Predose, 0.5, 1, 2, 4.5, 6, 8.5, 12, 13, 14, 16, 24, 48, 168, and 336 hours post dose starting on Day 28 | 
| Amount of Drug Excreted in Urine (Aet1-t12) (Part A) | Data Not Collected for this Parameter | Pre-Dose and 12 hours Post-Dose | 
| Amount of Drug Excreted in Urine (Aet1-t12) (Part B) | Data Not Collected for this Parameter | Pre-Dose and 12 hours Post-Dose on Day 28 | 
| Amount of Drug Excreted in Urine (Aet0-24) (Part A) |  | Pre-Dose and 24-hours Post-Dose | 
| Amount of Drug Excreted in Urine (Aet0-24) (Part B) |  | Pre-Dose and 24-hours Post-Dose on Day 28 | 
| Fraction of Drug Excreted in the Urine (Fe) (Part A) |  | Pre-Dose and 24-hours Post-Dose | 
| Fraction of Drug Excreted in the Urine (Fe) (Part B) |  | Pre-Dose and 24-hours Post-Dose on Day 28 | 
| Change From Baseline in Average Plasma Glucose Concentration After Multiple Doses (Part B) |  | Baseline to Day 24-26 | 
| Change From Baseline in Postprandial Glucose (Part B) | Mixed Meal Tolerance Test (4.5 hours after a meal on Day 28); Baseline Adjusted. The day 28 values were used for analysis; change from baseline was calculated on Day 28. | Day 28 | 
| Change From Baseline in C-Peptide Concentration (Part B) | Mixed Meal Tolerance Test (4.5 hours after a meal on Day 28); Baseline-Adjusted. The day 28 values were used for analysis; change from baseline was calculated on Day 28. | Day 28 | 
| Change From Baseline in Insulin Concentration (Part B) | 4.5 hours following Mixed Meal Tolerance Test (MMTT) on Day 28; Baseline Adjusted. The day 28 values were used for analysis; change from baseline was calculated on Day 28. | Day 28 | 
| Fasting Glucose Concentration (Part B) | Fasting glucose concentration after 28 day treatment | Baseline to Day 28 | 
| Change From Baseline in Weight (Part B) |  | Baseline to Day 28 | 
| Change From Baseline in Waist Circumference (Part B) |  | Baseline to Day 28 | 
| Change From Baseline in Hip Circumference (Part B) |  | Baseline to Day 28 |