Delving into the Latest Updates on LGD-6972 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

GCGR

Action

antagonists

Mechanism

GCGR antagonists(Glucagon receptor antagonists)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus, Type 2

Inactive Indication

Diabetes Mellitus, Type 1

Originator Organization

Ligand Pharmaceuticals, Inc.

Active Organization

Roivant Sciences Ltd.

Inactive Organization

Ligand Pharmaceuticals, Inc.

License Organization

Ligand Pharmaceuticals, Inc.Roivant Sciences Ltd.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC43H46N2O5S

InChIKeyHKJMCBYPVCGZFB-LDLOPFEMSA-N

CAS Registry1207989-09-0

Ligand Pharmaceuticals Incorporated is developing LGD-6972, a novel, orally-bioavailable addition to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The mechanism of action of LGD-6972 is to reduce the excess liver glucose production characteristic of type 2 diabetes mellitus that is a major contributor to hyperglycemia. This clinical trial will evaluate the safety and tolerability of escalating doses LGD-6972 administered daily over 2 weeks in both healthy subjects and subjects with type 2 diabetes mellitus.

Start Date01 Oct 2014

Sponsor / Collaborator

Ligand Pharmaceuticals, Inc.

100 Clinical Results associated with LGD-6972

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100 Translational Medicine associated with LGD-6972

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100 Patents (Medical) associated with LGD-6972

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3

Literatures (Medical) associated with LGD-6972

01 Jan 2020·Diabetes CareQ1 · MEDICINE

Efficacy and Safety of the Glucagon Receptor Antagonist RVT-1502 in Type 2 Diabetes Uncontrolled on Metformin Monotherapy: A 12-Week Dose-Ranging Study

Q1 · MEDICINE

Article

Author: Frias, Juan P. ; Vajda, Eric G. ; Pettus, Jeremy H. ; Williamson, Gretchen ; Pipkin, James D. ; Zangmeister, Miriam A. ; D’Alessio, David ; Marschke, Keith B. ; Zhi, Lin ; Rosenstock, Julio

OBJECTIVEEvaluate the safety and efficacy of RVT-1502, a novel oral glucagon receptor antagonist, in subjects with type 2 diabetes inadequately controlled on metformin.RESEARCH DESIGN AND METHODSIn a phase 2, double-blind, randomized, placebo-controlled study, subjects with type 2 diabetes (n = 166) on a stable dose of metformin were randomized (1:1:1:1) to placebo or RVT-1502 5, 10, or 15 mg once daily for 12 weeks. The primary end point was change from baseline in HbA1c for each dose of RVT-1502 compared with placebo. Secondary end points included change from baseline in fasting plasma glucose (FPG) and safety assessments.RESULTSOver 12 weeks, RVT-1502 significantly reduced HbA1c relative to placebo by 0.74%, 0.76%, and 1.05% in the 5-, 10-, and 15-mg groups (P < 0.001), respectively, and FPG decreased by 2.1, 2.2, and 2.6 mmol/L (P < 0.001). The proportions of subjects achieving an HbA1c <7.0% were 19.5%, 39.5%, 39.5%, and 45.0% with placebo and RVT-1502 5, 10, and 15 mg (P ≤ 0.02 vs. placebo). The frequency of hypoglycemia was low, and no episodes were severe. Mild increases in mean aminotransferase levels remaining below the upper limit of normal were observed with RVT-1502 but were reversible and did not appear to be dose related, with no other liver parameter changes. Weight and lipid changes were similar between RVT-1502 and placebo. RVT-1502–associated mild increases in blood pressure were not dose related or consistent across time.CONCLUSIONSGlucagon receptor antagonism with RVT-1502 significantly lowers HbA1c and FPG, with a safety profile that supports further clinical development with longer-duration studies (NCT02851849).

01 Jan 2017·Diabetes, Obesity and MetabolismQ2 · MEDICINE

Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD‐6972 in healthy subjects and subjects with type 2 diabetes mellitus

Q2 · MEDICINE

Article

Author: Vajda, Eric G. ; Plotkin, Diane J. ; Zhi, Lin ; Li, Yong-Xi ; Marschke, Keith B. ; Pipkin, JD ; Dilzer, Stacy ; Armas, Danielle ; Klein, David ; Logan, Douglas ; Wei, Xiaoxiong ; Zhou, Rong ; Lasseter, Kenneth

AimTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD‐6972, in healthy subjects and subjects with type 2 diabetes (T2DM).MethodsIn the single ascending dose study, LGD‐6972 (2‐480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD‐6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD‐6972 daily for 14 days.Results LGD‐6972 had linear plasma pharmacokinetics consistent with once‐daily dosing that was comparable in healthy and T2DM subjects. Dose‐dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD‐6972 also reduced plasma glucose in the postprandial state. Dose‐dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD‐6972 was well tolerated at the doses tested without dose‐related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia.ConclusionInhibition of glucagon action by LGD‐6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD‐6972 after 14 days of dosing supports continued clinical development.

International Journal of Molecular Sciences

The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures

Article

Author: Du, Limin ; Shi, Fan ; Wang, Mengru ; Huang, Zichong ; Fu, Xulei ; Yang, Linlin

Glucagon receptor (GCGR) is a class B1 G-protein-coupled receptor that plays a crucial role in maintaining human blood glucose homeostasis and is a significant target for the treatment of type 2 diabetes mellitus (T2DM). Currently, six small molecules (Bay 27-9955, MK-0893, MK-3577, LY2409021, PF-06291874, and LGD-6972) have been tested or are undergoing clinical trials, but only the binding site of MK-0893 has been resolved. To predict binding sites for other small molecules, we utilized both the crystal structure of the GCGR and MK-0893 complex and dynamic conformations. We docked five small molecules and selected the best conformation based on binding mode, docking score, and binding free energy. We performed MD simulations to verify the binding mode of the selected small molecules. Moreover, when selecting conformations, results of competitive binding were referred to. MD simulation indicated that Bay 27-9955 exhibits moderate binding stability in Pocket 3. MK-3577, LY2409021, and PF-06291874 exhibited highly stable binding to Pocket 2, consistent with experimental results. However, LY2409021 may also bind to Pocket 5. Additionally, LGD-6972 exhibited relatively stable binding in Pocket 5. We also conducted structural modifications of LGD-6972 based on the results of MD simulations and predicted its analogues’ bioavailability, providing a reference for the study of GCGR small molecules.

100 Deals associated with LGD-6972

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