Ligand Pharmaceuticals has announced positive top-line results from a Phase 2 clinical study evaluating the efficacy and safety of LGD-6972, as an adjunct to diet and exercise, in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy. LGD-6972 is Ligand’s novel, oral, small molecule, glucagon receptor antagonist (GRA). The study achieved statistical significance (p < 0.0001) in the primary endpoint of change from baseline in hemoglobin A1c (HbA1c) after 12 weeks of treatment at all doses tested, demonstrating a robust, dose-dependent reduction in HbA1c of 0.90%, 0.92% and 1.20% with 5 mg, 10 mg and 15 mg of LGD-6972, respectively, compared to a 0.15% reduction with placebo.
LGD-6972 was safe and well tolerated, with no drug-related serious adverse events and no dose dependent changes in lipids (including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), body weight or blood pressure after 12 weeks of treatment.
“Diabetes is a growing and global medical epidemic and despite many approved therapies, there is need for new mechanisms to treat the disease,” said John Higgins, Chief Executive Officer. “Based on these trial results and previous data, we believe LGD-6972 has best-in-class type properties given its potency and effectiveness in patients with type 2 diabetes and given its potential applicability to type 1 diabetes as well. We look forward to presenting the full data set at an upcoming conference and to exploring potential partnership opportunities for this program.”
In this Phase 2 study, subjects with T2DM on a stable dose of metformin were treated with one of three doses of LGD-6972 (5 mg, 10 mg, or 15 mg) or placebo once daily for 12 weeks. The primary endpoint was change from baseline in hemoglobin A1c (HbA1c) after 12 weeks of treatment compared to placebo. Secondary endpoints included change from baseline compared to placebo in fasting plasma glucose, insulin, glucagon and GLP-1, as well as changes in lipids, blood pressure and body weight. In a subset of subjects, an oral glucose tolerance test was conducted at baseline and at the end of treatment. A total of 166 subjects were randomized to drug treatment among 29 clinical sites. Ligand plans to present detailed study results, including data from the secondary efficacy and safety endpoints, at upcoming medical meetings and in a peer-reviewed publication.
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. GRAs are designed to lower glucose levels by reducing the production of glucose by the liver. Other small molecule GRAs have demonstrated a reduction of glucose and hemoglobin A1c (HbA1c) in mid-stage clinical trials, but also produced dose-dependent or significant side effects, such as increases in LDL cholesterol, body weight and blood pressure, that have impeded further clinical development.
LGD-6972 is Ligand’s potent, small molecule Glucagon Receptor Antagonist. Based in part on unique elements of the chemical structure of LGD-6972 as compared to other small molecules that have been tested clinically, Ligand believes LGD-6972 to potentially be a best-in-class molecule. Details of the chemical structure of LGD-6972 will be submitted for presentation at a future scientific meeting.
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 the single- and multiple-dose Phase 1 studies, LGD-6972 demonstrated favorable safety, tolerability and pharmacokinetics in normal healthy volunteers and in subjects with T2DM, and demonstrated a robust, dose-dependent reduction of fasting plasma glucose. Baseline adjusted glucose values showed dose-dependent effects of LGD-6972 on subjects with T2DM with a maximal decrease of 57 mg/dL after 14 days of treatment. The robust glycemic responses were not associated with dose-related or clinically meaningful changes in hematology, clinical chemistry, including liver enzymes and lipids, urinalysis, electrocardiography or vital signs, and no subject experienced a hypoglycemic event during the 14-day treatment or follow-up periods.
Diabetes is a growing global epidemic that as of 2015 affected over 400 million adults worldwide. According to a new report by the Centers for Disease Control and Prevention (CDC), approximately 30 million people in the United States have diabetes, or roughly 9% of the total population. Another 84 million have prediabetes, a condition that may lead to diabetes if not treated. If current trends continue, by 2050 fully 33% of the U.S. population will be affected. People with type 2 diabetes either are resistant to the effects of insulin or do not produce enough insulin to maintain a normal glucose level. Sustained high glucose levels can cause diabetic complications such as heart disease, stroke, kidney failure, neuropathy, lower-limb amputations and blindness. Although type 2 diabetes is more common in adults, it increasingly affects children as rates of childhood obesity increase. An estimated 95% of Americans with diabetes have type 2 diabetes.
The global market for diabetes drugs is expected to nearly double to $68 billion by 2022 as treatment paradigms shift toward combination therapies and novel non-insulin drugs. Global sales of the top 10 non-insulin diabetes drugs exceeded $15 billion in 2016 and are expected to increase to $20 billion by 2020.