Ligand Licenses Glucagon Receptor Antagonist Program to Roivant Sciences
LGD-6972 is a novel, potent, oral, small-molecule GRA. In September 2017 Ligand announced positive topline results from a Phase 2 clinical study evaluating the efficacy and safety of LGD-6972 as an adjunct to diet and exercise in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy. Full data from the Phase 2 trial has been submitted for presentation at the 78th annual Scientific Sessions of the American Diabetes Association being held in Orlando from June 22-26, 2018.
"This global license with Roivant for our diabetes program is another important deal in a long history of success converting our inventions, data and intellectual property into licenses to advance promising medicines and deliver value to our shareholders," said John Higgins, Chief Executive Officer, Ligand Pharmaceuticals. "Roivant is well capitalized and they are assembling an experienced team at Metavant to efficiently drive the program forward. This is a major partnership that has the potential to generate substantial medical value for both type 1 and type 2 diabetes patients. If LGD-6972 is successfully developed, this license with Roivant has the potential to be Ligand's largest financial asset with the possibility of annual royalties into the late 2030s given current and pending IP."
Roivant is a privately-held company that has established multiple subsidiary biopharmaceutical companies focused on distinct disease areas, each with dedicated leadership and development-stage programs. With its affiliates, Roivant has raised more than $2.7 billion in capital to date to fund clinical programs and pursue adjacent business opportunities in healthcare. Roivant recently formed Metavant Sciences to develop LGD-6972 (now RVT-1502) as well as imeglimin (RVT-1501), another novel clinical-stage oral antidiabetic therapy. Metavant is focused on addressing the significant unmet medical needs of patients with cardiometabolic disorders. Roivant is also evaluating additional assets for Metavant’s pipeline.
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 T2DM and is 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 a small-molecule GRA. Based in part on unique elements of the chemical structure of LGD-6972 compared with other small molecules that have been tested clinically, Ligand believes LGD-6972, if approved, could potentially be a valuable addition to the armamentarium of treatments for diabetes.
LGD-6972 has been studied in preclinical and Phase 1 and Phase 2 clinical studies in subjects with T2DM. 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 T2DM. 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 was shown in this model to have additive effects when used in combination with insulin therapy, suggesting it may also be useful in an insulin-sparing regimen.
In 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 glucose1. 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.
Safety and efficacy of LGD-6972 was evaluated in a Phase 2 clinical study as an adjunct to diet and exercise, in subjects with T2DM inadequately controlled on metformin monotherapy. The Phase 2 clinical study achieved statistical significance (p<0.0001) in the primary endpoint of change from baseline in 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.