LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept

Abstract

ObjectiveA novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM).MethodsLY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice.A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25–8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5–10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5–15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.ResultsLY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist.A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25–15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: −49.12 mg/dL [−78.14, −20.12] and −43.15 mg/dL [−73.06, −13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: −1.75 kg [−3.38, −0.12], −5.09 kg [−6.72, −3.46] and −4.61 kg [−6.21, −3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: −2.62 kg [−3.79, −1.45] and −2.07 kg [−3.25, −0.88], respectively.The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.ConclusionsBased on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.

Incretins in obesity and diabetes

“…The widespread distribution of the GLP-1R throughout different tissues suggests that GLP-1 has other physiological effects in addition to glucose regulation. [125][126][127] This dual incretin receptor concept was recently reviewed. [102][103][104] GLP-1 stimulates insulin secretion in a glucose concentration-dependent manner at glucose level above 4.3 mmol/L (77 mg/dL).…”

“…124 Recently, there has been significant interest in developing unimolecular dual agonists of GIPR and GLP-1R (dual incretin receptor) with activity at each constitutive receptor. [125][126][127] This dual incretin receptor concept was recently reviewed. 121…”

“…Recently, there has been a surge in interest in developing unimolecular dual agonists of GIPR and GLP-1R with activity at both incretin receptors for even greater glucoselowering effects than seen with GLP-1R agonists alone. [125][126][127] A randomized, placebo-controlled and active comparator-controlled Phase II trial was reported for one of these dual incretin receptor agonists, LY3298176, in patients with type 2 diabetes. After 26 weeks, LY3298176 showed superior A1c control with greater weight loss and acceptable tolerability profile, compared with dulaglutide.…”

Evaluation of a rare glucose‐dependent insulinotropic polypeptide receptor variant in a patient with diabetes

“…In contrast, targeting both incretin receptors, GIPR and GLP‐1R, in a dual‐agonistic approach has shown body weight‐lowering effects and improved glycaemic control in mice . Another dual‐agonistic agent targeting both incretin receptors was discovered recently and investigated in a phase 2b trial in humans . Treatment with the new dual‐agonist showed improved glucose control and weight loss in patients with type 2 diabetes compared to treatment with dulaglutide, a GLP‐1 receptor agonist.…”

“…33 Another dual-agonistic agent targeting both incretin receptors was discovered recently and investigated in a phase 2b trial in humans. 34,35 Treatment with the new dualagonist showed improved glucose control and weight loss in patients with type 2 diabetes compared to treatment with dulaglutide, a GLP-1 receptor agonist. These studies support the translation from preclinical to clinical studies by including GIP/GIPR as a beneficial target in drug therapy.…”