Date: 2016-08-15
Type of information: Publication of results in a medical journal
phase: 1b
Announcement: publication of results in Diabetes, Obesity and Metabolism
Company: Ligand Pharmaceuticals (USA - CA)
Product: LGD-6972
Action
mechanism: glucagon receptor agonist. Glucagon receptor antagonists are designed to lower glucose levels by reducing the production of glucose by the liver. LGD-6972 has been studied in previously-published preclinical and clinical studies. Presentations from preclinical studies have shown that LGD-6972 is highly potent and selective and inhibits glucagon-induced hyperglycemia in both rats and monkeys, and that it also significantly lowers glucose in a mouse model of type 2 diabetes. Additionally, LGD-6972 significantly lowered fasting and non-fasting glucose levels in a mouse model of type 1 diabetes and also reduced HbA1c, ketone bodies and free fatty acids. LGD-6972 also has been shown to have additive effects when used in combination with insulin therapy and may also be useful in an insulin-sparing regimen. In a previous Phase 1a single-ascending dose clinical study, LGD-6972 was well-tolerated, with no clinically significant or dose-dependent changes in hematology, clinical chemistry or urinalysis panels, ECG or vital signs, and no serious adverse events. After a single dose, LGD-6972 reduced fasting plasma glucose in normal healthy volunteers and in subjects with type 2 diabetes; fasting plasma glucose was reduced by 57 mg/dL (placebo-adjusted) in subjects with type 2 diabetes. Preclinical studies have shown that LGD-6972 is highly potent and selective and inhibits glucagon-induced hyperglycemia in both rats and monkeys, and that it also significantly lowers glucose in a mouse model of type 2 diabetes. Additionally, LGD-6972 significantly lowered fasting and non-fasting glucose levels in a mouse model of type 1 diabetes and also reduced HbA1c, ketone bodies and free fatty acids. LGD-6972 also has been shown to have additive effects when used in combination with insulin therapy and may also be useful in an insulin-sparing regimen. Glucagon is a hormone produced by the pancreas that stimulates the liver to produce glucose (sugar). Overproduction of glucose by the liver is an important cause of high glucose levels in patients with type 2 diabetes and is believed to be due in part to inappropriately elevated levels of glucagon. Glucagon receptor antagonists are designed to lower glucose levels by reducing the production of glucose by the liver. Glucagon receptor antagonists are novel molecules that have demonstrated a reduction of glucose and hemoglobin A1c (HbA1c) in mid-stage clinical trials.
Disease: type 2 diabetes
Therapeutic area: Metabolic diseases
Country: USA
Trial
details: 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. (NCT02250222)
Latest
news: * On August 15, 2016, Ligand Pharmaceuticals announced that results from two Phase 1 clinical trials with LGD-6972, the company’s investigational glucagon receptor antagonist, were published online in the August issue of the journal Diabetes, Obesity and Metabolism. The article is titled "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". The single- and multiple-dose Phase 1a and Phase 1b studies demonstrated favorable safety, tolerability and pharmacokinetics in normal healthy volunteers and in subjects with type 2 diabetes mellitus. The trial results also demonstrate a robust, dose-dependent reduction of fasting plasma glucose. In the randomized, double-blind, placebo-controlled Phase 1 trials, LGD-6972 was administered in single or multiple oral doses to both healthy subjects and subjects with type 2 diabetes to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics. Highlights of the Phase 1 studies include: LGD-6972, tested at single doses from 2 mg to 480 mg, and multiple daily doses of 5 mg, 10 mg and 15 mg over 14 days, was generally safe and well-tolerated with no clinically significant or dose-dependent changes in hematology, clinical chemistry or urinalysis panels, electrocardiography or vital signs, and no subject experienced a hypoglycemic event. There were no serious adverse events and no study discontinuations. Most treatment-emergent adverse events were of mild or moderate severity (grade 1 or 2). Ligand is preparing to initiate a Phase 2 trial with LGD-6972 in September 2016 with the goal to establish additional safety and efficacy for the program in 12 consecutive weeks of dosing in subjects with type 2 diabetes. The randomized, double-blind, multicenter trial will enroll 148 subjects whose blood glucose levels are inadequately controlled with metformin, and should be completed in 2017. * On June 7, 2015, Ligand Pharmaceuticals announced results from a Phase 1b clinical trial with LGD-6972 that demonstrate favorable safety, tolerability and pharmacokinetics in normal healthy volunteers and in subjects with type 2 diabetes mellitus. The trial results also demonstrate a robust, dose-dependent reduction of fasting plasma glucose. In this randomized, double-blind, placebo-controlled trial, LGD-6972 was administered in sequential increasing oral doses daily over two weeks to both healthy subjects and subjects with type 2 diabetes. A total of 48 subjects were enrolled in the trial. Highlights of the study include: LGD-6972 tested at 5mg, 10mg and 15mg was safe and well-tolerated with no clinically significant or dose-dependent changes in hematology, clinical chemistry or urinalysis panels, ECG or vital signs. There were no serious adverse events and no study discontinuations. All treatment-emergent adverse events were of mild or moderate severity (grade 1 or 2). Plasma levels increased linearly with LGD-6972 dosage, and the pharmacokinetic profiles were comparable between normal and type 2 diabetes subjects, supporting once-daily dosing.
Plasma levels increased linearly with LGD-6972 dosage, and the pharmacokinetic profiles were comparable between normal healthy volunteers and type 2 diabetes subjects, supporting once-daily dosing.
LGD-6972 lowered fasting plasma glucose in normal healthy volunteers and in subjects with type 2 diabetes after single and multiple doses. Baseline adjusted glucose values showed dose-dependent effects of LGD-6972 on subjects with type 2 diabetes with a maximal decrease of 57 mg/dL on day 14.
LGD-6972 decreased glucose in both fasting and post-prandial states, and was accompanied by an increase in insulin and a decrease in glucagon in response to an oral glucose load.
The robust glycemic responses in subjects with type 2 diabetes treated with LGD-6972 were not associated with dose-related or clinically meaningful changes in liver enzymes during the 14-day treatment or follow-up periods.
The safety and pharmacological profile of LGD-6972 after 14 days of dosing supports continued clinical development as an adjunct to diet and exercise for the treatment of type 2 diabetes.
LGD-6972 lowered fasting plasma glucose in normal subjects and in subjects with type 2 diabetes. Glucose was reduced throughout the 14-day dosing period. Baseline adjusted glucose values showed dose-dependent effects of LGD-6972 in type 2 diabetic subjects with a maximal decrease of 60 mg/dL.
7 point glucose measurements were performed at baseline and Day 14 and illustrated that LGD-6972 decreased glucose throughout a 24-hour period in both fasting and post-prandial states.
LGD-6972 is a highly potent and selective glucagon receptor antagonist and is a promising agent for the treatment of type 2 diabetes.
Ligand is preparing to initiate a Phase 2 trial with LGD-6972 in 2016 with the goal to establish additional safety and efficacy for the program in 12 consecutive weeks of dosing in subjects with type 2 diabetes. Approximately 100 subjects will be enrolled in this randomized, double-blind, multicenter trial. The trial is estimated to cost approximately $10 million and should be completed in 2017. Any incremental increase to Ligand’s annual R&D spending as a result of this program is expected to be covered within Ligand’s financial operations, and there is no change to the company’s long-term earnings guidance.
