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

Objective: A 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).

Methods: LY3298176 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.

Results: LY3298176 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.

Conclusions: Based 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.

Keywords: Glucagon-like peptide-1; Glucose-dependent insulinotropic polypeptide; LY3298176; Obesity; Type 2 diabetes mellitus.

Figure 1

Discovery and Characterization of LY3298176, a GIP-based Dual Incretin Receptor Agonist. (A) Structure schematic of the dual GIP and GLP-1 receptor agonist, LY3298176. (B) Representative concentration response curves for stimulation of cAMP accumulation by GIP, GLP-1 or LY3298176 in HEK293 cells expressing human GIPR or GLP-1R. (C) cAMP accumulation in human pancreatic ECN90 beta-cells in response to treatment with GLP-1, GIP, the combination of GLP-1 plus GIP, or LY3298176. P < 0.05 using one-way ANOVA versus GLP-1 (#) or GIP (++). (D) cAMP accumulation in human adipocytes. All data are expressed as mean ± SEM.

Figure 2

LY3298176 Enhances Islet Insulin Secretion and Improves Glucose Tolerance in Mice. Glucose-stimulated insulin secretion by GIP, GLP-1, or LY3298176 in isolated islets from wild-type (A), GIPR null (B), and GLP-1R null mice (C). Antagonists to GLP-1R (exendin-4_(9-39)) and GIPR (modified GIP_(3-30)NH2) were used to assess receptor specificity. P < 0.05 using one-way ANOVA versus vehicle treatment in high glucose (*). Glucose excursions from intraperitoneal glucose tolerance tests in wild-type (D), GIPR null (E), and GLP-1R null (F) mice administered LY3298176 or the selective agonists semaglutide or [d-Ala²]GIP. Glucose was administered 18 h after a single injection of LY3298176 or semaglutide and 1 h following [d-Ala2]GIP; glucose AUC(0–120 min, mg. min/dL) is depicted in the upper right panels of (D, E, and F). Data are presented as Mean ± SEM of 6 mice per group. P < 0.05 using one-way ANOVA versus vehicle (*).

Figure 3

LY3298176 Lowers Body Weight in Obese Mice. The starting body weight of DIO mice was around 45 g. Body weight loss in DIO mice chronically administered semaglutide (A), LA-GIPRA (B), or LY3298176 (C). Metabolic effects of LY3298176 (♦) or semaglutide (▲) compared to vehicle treatment (■) on body weight (D), cumulative food intake (E), and energy expenditure (F) in DIO mice. For body weight and food consumption differences, P < 0.05 using one-way ANOVA repeated measures versus the vehicle (*) or semaglutide (+) treated groups. For energy expenditure, data presented are least square means for each treatment over time, which were adjusted for body weight as indicated in the statistical model as described in the methods. P < 0.05 using ANCOVA versus the vehicle (*) or semaglutide (+) treated groups. All data are expressed as mean ± SEM.

Figure 4

Body Weight Change and Glucose Response to a OGTT in Healthy Subjects (MAD Part) *Statistically significant at a 5% confidence level compared to placebo. (A) Change from baseline in body weight over time. Data presented as LSM (SE) (B) Treatment differences in body weight on Day 29. Data presented as LSM difference (95% CI) for LY3298176 versus placebo (C) Glucose AUC(0–2 h) on Day 23. Data presented as mean ± SD. Subjects in the 5/5/8/10 mg group received 5 mg LY3298176 on Day 1 and Day 8, 8 mg LY3298176 on Day 15, and 10 mg LY3298176 on Day 22. DU = dulaglutide; LY = LY3298176.

Figure 5

Body Weight Change, Glucose and Insulin Response to a OGTT and Fasting Glucose Response in Patients with T2DM (Phase 1 b POC Part) *Statistically significant at 5% significance level compared to placebo (A) Change from baseline in body weight over time. Data presented as LSM (SE) (B) Treatment differences in body weight on Day 29. Data presented as LSM difference (95% CI) for LY3298176 versus placebo (C) Glucose AUC(0–2 h) on Day 23. Data presented as mean ± SD (D) Insulin AUC(0–2 h) on Day 23. Data presented as arithmetic mean ± SD (E) 7-Point SMBG on Days −2 (baseline), 8 (2nd dose), 15 (3rd dose) and 22 (4 t h dose). Data presented as mean ± SD (F) Treatment differences in fasting glucose on Day 29. Data presented as LSM difference (95% CI) for LY3298176 versus placebo. Subjects in the 5/5/10/10 mg group received 5 mg LY3298176 on Day 1 and Day 8, and 10 mg LY3298176 on Day 15 and Day 22. Subjects in the 5/5/10/15 mg group received 5 mg LY3298176 on Day 1 and Day 8, 10 mg LY3298176 on Day 15, and 15 mg LY3298176 on Day 22. LY = LY3298176.