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Glucagon Receptor Antagonist Completes Clinical Trials

Early studies of novel agent LGD-6972 show potential as an adjunct therapy to diet and exercise for patients with type 2 diabetes.

Glucagon receptor antagonists (GRA) are a novel class of drugs that are showing promise as adjunct therapy for the treatment of type 2 diabetes (T2D). GRAs work by inhibiting glucagon action and reducing hepatic glucose production. LGD-6972 is a once-daily, orally bioavailable GRA from Ligand Pharmaceuticals that has completed Phase 1 (P1) trials and shows strong potential for progression into Phase 2 studies.

Two P1 studies were conducted to evaluate single and multiple ascending doses of LGD-6972 in both healthy patients and patients with T2D. The primary objective of the P1 studies was to establish safety and tolerability of LGD-6972, and the secondary objective was to evaluate pharmacokinetics and pharmacodynamic characteristics. The single ascending dose (SAD) (n=48) and multiple ascending dose (MAD) (n=48) studies were randomized, double blind, placebo controlled trials. Two weeks prior to the start of the trial, T2DM participants in the SAD trial had to discontinue their diabetes medications and could not resume until follow up had concluded. In the MAD trial, T2DM study participants were required to be on a standard metformin dose for three months or more and also had to discontinue use of other diabetes medications for > 3 weeks. Study participants received either LGD-6972 or placebo once daily in a fasted state, and also received standardized meals for the duration of the study. SAD study participants were required to remain at the site for 48 hours post dose, while MAD study participants remained at the site for the full 14 days of treatment. Safety and tolerability of LGD-6972 was evaluated through physical examination, vital sign measurement, lab tests, ECG administration, and observation for each subject in both SAD and MAD studies for 14 days following the last dose of study drug.

When 40 mg LGD-6972 was administered to healthy and T2DM participants in the SAD study, fasting plasma glucose (FPG) was maximally decreased at 24 hours post-dose by approximately 50 mg/dL and continued to be reduced relative to baseline throughout the 144 hours of measurement. In the MAD study, the mean weighted average 7-point glucose was lower on day 14, and the mean glucose values were decreased at all 7 time points, (fasting, premeal, and postprandial) in the subjects who received study drug, compared with baseline. FPG was decreased from baseline in a dose-dependent manner with a range of -41.04 mg/dL to -48.96 mg/dL in the 5 mg daily and 15 mg daily groups, respectively. Subjects that were administered placebo had no changes in 7-point glucose at day 14 compared to baseline.  Based on the mean change from baseline, the projected HbA1c reduction could be as much as 1.5% with long-term dosing.

With regards to safety, doses administered ranged from 2 mg to 480 mg, however there were no serious adverse events detected in either of the trials, and most adverse effects were mild to moderate and related to headaches or gastrointestinal disorders.  No participants discontinued the study due to adverse events, and there were no reports of hypoglycemia for any of the subjects. Studies of previous GRAs showed unfavorable effects on plasma lipids, body weight, and blood pressure.  There were no clinically meaningful effects on these parameters observed with LGD-6972.  While patients with T2D in the MAD study who received LGD-6972 were found to have minor elevations in ALT at day 14 compared to baseline, the group mean remained within the normal range and the effect resolved by the end of the follow-up period.

While further study is needed, LGD-6972 shows potential to reduce fasting and postprandial blood glucose in patients with T2D, and unlike previous GRAs does not seem to cause dose-related or clinically meaningful alterations in hepatic enzymes, plasma lipids, body weight, or blood pressure.

Practice Pearls:

  • LGD-6972 is a glucagon receptor antagonist that can lower fasting and postprandial blood glucose in patients with T2D.
  • Phase 1 trials showed no reports of hypoglycemia in both healthy and T2D subjects.
  • More trials are needed to better understand the risks and benefits of LGD-6972.

Reference:

Vajda, Eric G. “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.” Diabetes, Obesity and Metabolism 2016: 1-26. Wiley Online Library. Web. 19 Aug. 2016.

Researched and prepared by Jillian Popek, Pharm.D. Candidates, Class of 2017. Reviewed by Michelle Caetano, Pharm.D., BCPS, BCACP, CDOE, CVDOE