Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (PEG)-BHD1028

A Randomized, Double-Blinded, Placebo-Controlled, Single and Multiple Ascending Dose Study in Overweight/Obese Subjects to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (PEG)-BHD1028

Adiponectin has been known to play critical roles in various physio-regulatory processes, and adiponectin deficiency may contribute to insulin resistance. (PEG)-BHD1028 was developed as an agonist of adiponectin receptors.

This first-in-human study evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of (PEG)-BHD1028 in healthy overweight/obese subjects with insulin resistance.

(PEG)-BHD1028 is a peptide agonist to adiponectin receptors, AdipoR1 and R2, designed based on the active site of the hormone and receptor binding configurations. Various scientific and clinical research revealed that adiponectin deficiency is positively associated with pathophysiological conditions, including insulin resistance and inflammation. Despite the beneficial effects of adiponectin, the hormone could not be developed into a therapeutic agent because of the complications in controlling post-transcriptional modifications.

This study investigates the safety and tolerability of (PEG)-BHD1028 after a single ascending dose (SAD) of a placebo, 4, 8, 16, 32, and 64 μg/Kg and multiple ascending doses (MAD) of a placebo, 8, 16, and 32 μg/Kg for 28 days following Q.D. injection subcutaneously in the healthy obese/overweight subjects. The pharmacokinetics (PK) and pharmacodynamics (PD) are also evaluated following single and multiple doses and multiple doses, respectively. The changes in the inflammatory biomarkers are explored during the 28 days as a part of the MAD portion study.

Inclusion Criteria:

• HbA1c < 6.5 % by local laboratory analysis (one retest is permitted)
• Body Mass Index (BMI) ≥ 27 kg/m2
• HOMA-IR ≥ 1.8
• Female subjects must be non-pregnant and non-lactating, and females of childbearing potential must have used a stable regimen of highly effective contraceptive methods (for at least 2 months prior to the Screening) that they were willing to continue for at least 30 days after the last dose of the study drug.
• Male subjects must be surgically sterile, abstinent or, if engaged in sexual relations with a woman of childbearing potential, the subject and his partner must use an acceptable method of contraception for at least 90 days after the last dose of the study drug.
• Ability and willingness to comply with all protocol procedures
• Ability to provide written informed consent

Exclusion Criteria:

• History of type 1 or 2 diabetes mellitus (T1DM, T2DM)
• Systolic blood pressure > 159 mm Hg or diastolic blood pressure > 99 mmHg at ----Screening (reading may be repeated on a different day)
• Treatment with antihypertensive medication or statins if the medication was not stable during the 2 months prior to Screening
• Treatment with thyroid hormones was not stable during the 3 months prior to Screening
• History of any weight control treatment, including over-the-counter and herbal medication and supplements, or any medication with a labeled indication for weight loss or weight gain within 30 days prior to Screening
• History of gastrointestinal surgery for obesity that may induce malabsorption, or any malabsorption disorder, or clinically significant (C.S.) ongoing gastrointestinal disorders (including gastroparesis, peptic ulcers, and severe gastrointestinal reflux disease)
• History of symptomatic heart failure (New York Heart Association class II, III, or IV), myocardial infarction, unstable angina, transient ischemic attack, cerebral infarct, cerebral hemorrhage, or invasive cardiovascular procedure (including coronary artery bypass grafting [CABG] and percutaneous coronary intervention [PCI]) within 6 months of Screening
• Presence of CS ECG findings (including corrected Q.T. interval using Fridericia's formula [QTcF] > 450 msec for males, QTcF > 470 msec for females, left bundle branch block [LBBB]) at Screening, or cardiac arrhythmia requiring medical or surgical treatment within 6 months prior to Screening
• Presence of any C.S. physical, laboratory, ECG finding, or medical condition (including moderate to severe osteoarthritis or other C.S. rheumatological disease), that (in the opinion of an Investigator) may interfere with any aspect of the study conduct or interpretation of results
• Estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2 at Screening (using the Modification of Diet in Renal Disease [MDRD] equation)
• Clinically significant disease (within the last five years) of the gastrointestinal, cardiovascular, hepatic, neurological, renal, pancreatic, immunological, dermatological, endocrine, genitourinary or hematological system
• Chronic liver disease, HIV, HBV- or active HCV infection, or a positive test at Screening
• History of mental handicap, major depression, suicidal behavior or attempts, or other psychiatric disorders requiring medical treatment (within 2 years of Screening), including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antipsychotics, lithium, or other psychiatric disorders including eating disorders and seizures
• Fasting triglycerides > 500 mg/dL or alanine aminotransferase (ALT) and/or (aspartate aminotransferase ) AST d> 2 x upper limit of normal (ULN) (a single retest of triglycerides, ALT, or AST was allowed)
• Use of any drugs that were known to interfere with glucose or insulin metabolism, including oral corticosteroids, glucagon-like peptide-1 (GLP-1) receptor agonists, monoamine oxidase (MAO) inhibitors, and growth hormone, or use of non-prescription drugs within 7 days of first dosing
• Administration of vaccines/immunizations within 14 days prior to the initiation of dosing
• Major surgery within 8 weeks prior to Screening
• History of, or suspected allergy or hypersensitivity to the investigational product (I.P.) components
• History of any active infection within 14 days prior to Screening
• Participation in any other clinical interventional study receiving active treatment within 30 days or 5 half-lives prior to Screening, whichever was longer
• History of alcohol or illicit drug abuse, including marijuana, or a positive drug test at Screening
• History of alcohol abuse within approximately 1 year, or average daily alcohol intake >2 drinks for men and > 1 drink of alcoholic beverages for women, or positive alcohol breath test at Screening
• Daily use of more than 15 cigarettes/week or equivalent use of any tobacco product within 6 weeks prior to Screening, or inability to abstain from smoking during the study
• Existence of any surgical or medical condition that, in the judgment of an Investigator, might interfere with the absorption, distribution, metabolism, or excretion of the IP
• A history of fainting from blood collections or vasovagal syncope
• Any anticipated procedures that might have interfered with compliance or completion of the study
• Donation or loss of > 500 mL of blood or blood product within 56 days prior to Screening