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.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance
• Intervention / Treatment: Other: Placebo; Drug: (PEG)-BHD1028 Single Ascending Dose; Drug: (PEG)-BHD1028 Multiple Ascending Dose

Detailed Description

(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.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Overland Park, Kansas, United States, 66212
      • Altasciences Clinical

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo_Single Ascending Dose; Participants received a single SC dose of placebo on Day 1	Other: Placebo; Diluent
Experimental: Experimental (PEG)-BHD1028_Single Ascending Dose; Participants received a single escalated SC dose of (PEG)-BHD1028 on Day 1	Drug: (PEG)-BHD1028 Single Ascending Dose; 4, 8, 16, 32, and 64 μg/Kg; Other Names: adiponectin receptor agonist
Placebo Comparator: Placebo_Multiple Ascending Dose; Participants received SC doses of placebo once a day for 28 days	Other: Placebo; Diluent
Experimental: Experimental (PEG)-BHD1028_Multiple Ascending Dose; Participants received SC doses of (PEG)-BHD1028 once a day for 28 days	Drug: (PEG)-BHD1028 Multiple Ascending Dose; 8, 16, and 32 μg/Kg; Other Names: adiponectin receptor agonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of (PEG)-BHD1028 -Single ascending dose as measured by TEAEs	Treatment emergent adverse events (including clinical AEs and Lab AEs) after a single dose of (PEG)-BHD1028 (including clinical AEs and Lab AEs) of (PEG)-BHD1028	Baseline to Day 3
Safety and tolerability of (PEG)-BHD1028 -Multiple ascending dose as measured by TEAEs	Treatment emergent adverse events (including clinical AEs and Lab AEs) after multiple doses of (PEG)-BHD1028	Baseline to Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of (PEG)-BHD1028 after a single dose, Cmax	Maximum plasma concentration of (PEG)-BHD1028	pre-dose, and at 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr after the single dose
Pharmacokinetics of (PEG)-BHD1028 after a single dose, Tmax	Time to reach Maximum plasma concentration of (PEG)-BHD1028	pre-dose, and at 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr after the single dose
Pharmacokinetics of (PEG)-BHD1028 after a single dose, t1/2	Time to reach apparent (PEG)-BHD1028 apparent terminal half life	pre-dose, and at 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr after the single dose
Pharmacokinetics of (PEG)-BHD1028 after a single dose, AUClast	Area under the (PEG)-BHD1028 concentration -time curve up to the last measurable concentration in serum	pre-dose, and at 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr after the single dose
Pharmacokinetics of (PEG)-BHD1028 after a single dose, AUCinf	AUCinf Area under the (PEG)-BHD1028 concentration -time curve up extrapolated to infinity	pre-dose, and at 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr after the single dose
Pharmacokinetics of (PEG)-BHD1028 after a single dose, CL/F	CL/F Apparent clearance of the drug calculated as dose of drug divided by the AUC	pre-dose, and at 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr after the single dose
Pharmacokinetics of (PEG)-BHD1028 after a single dose, Vd/F	Apparent Volume of distribution calculated as Total administered dose/initial plasma concentration	pre-dose, and at 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr after the single dose
Pharmacokinetics of (PEG)-BHD1028 after multiple doses, Cmax	Maximum plasma concentration of (PEG)-BHD1028	pre-dose, and post dose on Day 1, Day 14 and Day 28
Pharmacokinetics of (PEG)-BHD1028 after multiple doses, Tmax	Time to reach Maximum plasma concentration of (PEG)-BHD1028	pre-dose, and post dose on Day 1, Day 14 and Day 28
Pharmacokinetics of (PEG)-BHD1028 after multiple doses, Cav,ss	Average plasma concentrate at steady state	pre-dose, and post dose on Day 1, Day 14 and Day 28
Pharmacokinetics of (PEG)-BHD1028 after multiple doses, AUCtau	Area under the (PEG)-BHD1028 concentration -time curve up to the last dose	pre-dose, and post dose on Day 1, Day 14 and Day 28
Pharmacokinetics of (PEG)-BHD1028 after multiple doses, t1/2	Time to reach (PEG)-BHD1028 apparent terminal half life	pre-dose, and post dose on Day 1, Day 14 and Day 28
Pharmacokinetics of (PEG)-BHD1028 after multiple doses, CLss/F	Apparent plasma clearance of drug after extravascular administration at steady state	pre-dose, and post dose on Day 1, Day 14 and Day 28
Pharmacokinetics of (PEG)-BHD1028 after multiple doses, Vd/F	Apparent volume of distribution after extravascular administration	pre-dose, and post dose on Day 1, Day 14 and Day 28
Pharmacokinetics of (PEG)-BHD1028 after multiple doses, Rac(Cmax)	Accumulation ratio calculated as Cmax (day 28)/ Cmax (day 1)	post dose on Day 1 and Day 28
Pharmacokinetics of (PEG)-BHD1028 after multiple doses, Rac(AUC)	Accumulation ratio calculated as AUC0-t (day 28)/ AUC0-t (day 1)	post dose on Day 1 and Day 28
Pharmacodynamics of (PEG)-BHD 1028 after multiple doses as measured by Insulin C -peptide	Insulin c-peptide as assessed by the net AUC at baseline and the percentage change from baseline. Responders defined as subjects which exhibited a reduction in insulin c-peptide AUC during the Mixed Meal Tolerance Test (MMTT) of at least 15% from Day -1 to Day 28.	Day -1 and Day 28
Pharmacodynamics of (PEG)-BHD 1028 after multiple doses as measured by insulin	Insulin AUC as assessed by the net AUC at baseline and the percentage change from baseline during the Mixed Meal Tolerance Test (MMTT).	Day -1 and Day 28
Pharmacodynamics of (PEG)-BHD 1028 after multiple doses as measured by glucose	Fasting plasma glucose (FPG), Post-prandial glucose (PPG), and glucose AUC assessed during the Mixed Meal Tolerance Test (MMTT).	Day -1 and Day 28

Collaborators and Investigators

• Sponsor: EncuraGen, Inc
• Investigators: Principal Investigator: Martin Kankam, MD, Altasciences Clinical

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2022
• Primary Completion (Actual): April 23, 2024
• Study Completion (Actual): June 23, 2024

Study Registration Dates

• First Submitted: July 26, 2024
• First Submitted That Met QC Criteria: August 17, 2024
• First Posted (Actual): August 20, 2024

Study Record Updates

• Last Update Posted (Actual): August 20, 2024
• Last Update Submitted That Met QC Criteria: August 17, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: ECN1028-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No