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.

Start Date18 Apr 2022

Sponsor / Collaborator

EncuraGen Co., Ltd.

100 Clinical Results associated with BHD-1028

100 Translational Medicine associated with BHD-1028

100 Patents (Medical) associated with BHD-1028

Literatures (Medical) associated with BHD-1028

International Journal of Molecular SciencesQ2 · BIOLOGY

PEG-BHD1028 Peptide Regulates Insulin Resistance and Fatty Acid β-Oxidation, and Mitochondrial Biogenesis by Binding to Two Heterogeneous Binding Sites of Adiponectin Receptors, AdipoR1 and AdipoR2

Q2 · BIOLOGY

ArticleOA

Author: Kim, Brian B. ; Kim, Gyuyoup ; Kim, Do-Hwi ; Lee, In Kyung

Adiponectin plays multiple critical roles in modulating various physiological processes by binding to its receptors. The functions of PEG-BHD1028, a potent novel peptide agonist to AdipoRs, was evaluated using in vitro and in vivo models based on the reported action spectrum of adiponectin. To confirm the design concept of PEG-BHD1028, the binding sites and their affinities were analyzed using the SPR (Surface Plasmon Resonance) assay. The results revealed that PEG-BHD1028 was bound to two heterogeneous binding sites of AdipoR1 and AdipoR2 with a relatively high affinity. In C2C12 cells, PEG-BHD1028 significantly activated AMPK and subsequent pathways and enhanced fatty acid β-oxidation and mitochondrial biogenesis. Furthermore, it also facilitated glucose uptake by lowering insulin resistance in insulin-resistant C2C12 cells. PEG-BHD1028 significantly reduced the fasting plasma glucose level in db/db mice following a single s.c. injection of 50, 100, and 200 μg/Kg and glucose tolerance at a dose of 50 μg/Kg with significantly decreased insulin production. The animals received 5, 25, and 50 μg/Kg of PEG-BHD1028 for 21 days significantly lost their weight after 18 days in a range of 5–7%. These results imply the development of PEG-BHD1028 as a potential adiponectin replacement therapeutic agent.

Pharmaceutics

Enhanced Immunomodulation, Anti-Apoptosis, and Improved Tear Dynamics of (PEG)-BHD1028, a Novel Adiponectin Receptor Agonist Peptide, for Treating Dry Eye Disease

Article

Author: Lee, Kwanghyun ; Lee, In-Kyung ; Seon, Su-Kyung ; Yoon, Kyung-Chul ; Kim, Brian B. ; Kang, Seong-Soo

Dry eye disease (DED) is characterized by impaired tear dynamics, leading to complex pathophysiological conditions. (PEG)-BHD1028, a peptide agonist to AdipoRs, was evaluated as a potential therapeutic agent for DED based on the reported physiological function of adiponectin, including anti-inflammation and epithelial protection. Therapeutic effects of (PEG)-BHD1028 were evaluated in experimentally induced EDE with 0.001%, 0.01%, and 0.1% (PEG)-BHD1028 in mice and 0.1%, 0.2%, and 0.4% in rabbits for 10 days. In the rabbit study, 0.05% cyclosporine was also tested as a comparator. The results from the mouse study revealed significant improvement in tear volumes, tear breakup time (TBUT), inflammation, and corneal severity score (CSS) within 10 days at all (PEG)-BHD1028 concentrations. In the rabbit study, the tear volume and TBUT significantly increased in (PEG)-BHD1028 groups compared with vehicle and 0.05% cyclosporine groups. The CSS, apoptosis rate, and corneal thickness of all (PEG)-BHD1028 and 0.05% cyclosporine groups were significantly improved relative to the vehicle group. The immune cell counts of 0.2% and 0.4% (PEG)-BHD1028 treated groups were significantly lower than those of the vehicle group. These results represent the potential of (PEG)-BHD1028 as an effective therapeutic agent for DED.

PLOS ONE

Discovery of a novel potent peptide agonist to adiponectin receptor 1

Article

Author: Kim, Brian B ; Ma, Min Jung ; Lee, Younho ; Kim, Sunghwan ; Son, Young-Jin ; Um, Jee-Hyun ; Kim, Jun Woo ; Kim, Nam Doo ; Kim, Dong Il ; Min, Sang Hyun

Activation of adiponectin receptors (AdipoRs) by its natural ligand, adiponectin has been known to be involved in modulating critical metabolic processes such as glucose metabolism and fatty acid oxidation as demonstrated by a number of in vitro and in vivo studies over last two decades. These findings suggest that AdipoRs' agonists could be developed into a potential therapeutic agent for metabolic diseases, such as diabetes mellitus, especially for type II diabetes, a long-term metabolic disorder characterized by high blood sugar, insulin resistance, and relative lack of insulin. Because of limitations in production of biologically active adiponectin, adiponectin-mimetic AdipoRs' agonists have been suggested as alternative ways to expand the opportunity to develop anti-diabetic agents. Based on crystal structure of AdipoR1, we designed AdipoR1's peptide agonists using protein-peptide docking simulation and screened their receptor binding abilities and biological functions via surface plasmon resonance (SPR) and biological analysis. Three candidate peptides, BHD1028, BHD43, and BHD44 were selected and confirmed to activate AdipoR1-mediated signal pathways. In order to enhance the stability and solubility of peptide agonists, candidate peptides were PEGylated. PEGylated BHD1028 exhibited its biological activity at nano-molar concentration and could be a potential therapeutic agent for the treatment of diabetes. Also, SPR and virtual screening techniques utilized in this study may potentially be applied to other peptide-drug screening processes against membrane receptor proteins.

100 Deals associated with BHD-1028

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Insulin Resistance	Phase 1	US	EncuraGen Co., Ltd.	18 Apr 2022
Obesity	Phase 1	US	EncuraGen Co., Ltd.	18 Apr 2022
Diabetes Mellitus, Type 2	Preclinical	KR	EncuraGen Co., Ltd.	09 May 2023
Metabolic dysfunction-associated steatotic liver disease	Preclinical	KR	EncuraGen Co., Ltd.	09 May 2023
Xerophthalmia	Preclinical	KR	EncuraGen Co., Ltd.	09 May 2023

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