Novel NPY2R agonist BI 1820237 provides synergistic anti-obesity efficacy when combined with the GCGR/GLP-1R dual agonist survodutide

Abstract

Objective: Nutrient-stimulated gut hormone peptide YY3-36 (PYY3-36) selectively activates the neuropeptide Y2 receptor (NPY2R) and reduces energy intake in humans. We describe the discovery and pharmacology of the long-acting NPY2R agonist BI 1820237 and its potential bodyweight-lowering efficacy alone and in combination with the glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) dual agonist survodutide.

Methods & results: BI 1820237 dose-dependently reduced food intake and gastric emptying in lean mice. Significant bodyweight reductions were not observed with BI 1820237 alone in diet-induced obese mice, however combination with survodutide led to bodyweight reduction of 22% which was significantly (p < 0.01) greater than the 17% bodyweight reduction with survodutide alone. Regression-based interaction analysis demonstrated that BI 1820237 increased the efficacy of survodutide by 265% at an ED50 of 11.7 nmol/kg over a range of dose combinations.

Conclusion: Synergistic NPY2R and GCGR/GLP-1R agonism provides an attractive mode of action for clinically relevant weight loss in patients with obesity.

Keywords: BI 1820237; G protein coupled receptor; NPY; NPY2R; Obesity; PYY3–36; Survodutide.

Figure 1

Structural properties and pharmacokinetic profile of BI 1820237. A) Peptide sequence of human PYY3–36 and BI 1820237. K∗ shows the C18 diacid lipidated lysine. B) Affinity of BI 1820237 to human NPY1R, NPY2R, NPY4R, and NPY5R compared with PYY3–36 and PP were investigated by competitive binding assays using membrane preparations from cells recombinantly expressing each receptor. Calculation of the affinity constant K_i was performed according to the Cheng–Prusoff equation K_i = IC₅₀/(1 + [S])/K_m). C) Potency of BI 1820237, at the human NPY2R based on cAMP and luciferase induction in CRE-Luc cells in the presence of 0.5% and 100% human plasma. CRE-Luc, cAMP response element-luciferase; EC₅₀, half-maximal effective concentration; IC₅₀, half-maximal inhibitory concentration; NPYR, neuropeptide Y receptor; pIC₅₀, negative log IC₅₀; PP, pancreatic polypeptide; PYY3–36, polypeptide Y.

Figure 2

NPY2R receptor engagement by BI 1820237 to reduce food intake and gastric emptying in lean animals after single dosing. A–F) Dose-dependent effect of BI 1820237 on food intake (A), gastric emptying (B–D), and glucose clearance (E,F). The ED₅₀ for BI 1820237 to reduce food intake and gastric emptying was calculated by linear regression analysis using one-way ANOVA followed by a Dunnett’s test for multiple comparisons versus vehicle. ∗p < 0.05, ∗∗p < 0.01. APAP, acetaminophen; AUC, area under the curve; ED₅₀, half-maximal effective dose; SEM, standard error of mean.

Figure 3

Daily dosing of BI 1820237 shows a transient reduction in food intake and bodyweight and provides a more-than-additive bodyweight-lowering efficacy in combination with survodutide in diet-induced obese mice. A–B) The effect of repeated dosing of BI 1820237 on food intake (A) and bodyweight (B) across the study period. C–D) The effect of repeated dosing of BI 1820237, survodutide, and the combination thereof on food intake (C) and bodyweight (D) across the study period. The food intake of the treated groups was normalized (in %) to the average food intake of the group receiving vehicle. E–G) The effect of repeated dosing of BI 1820237, survodutide, and the combination thereof on epididymal adipose tissue (E), plasma triglycerides (F), and liver triglycerides (G) at study end. ^aFor BI 1820237 3 nmol/kg and 10 nmol/kg + survodutide 7.5 nmol/kg dosing was discontinued as bodyweight reduction exceeded the allowance defined in the animal welfare license. ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001. BW, bodyweight; DIO, diet-induced obese; FI, food intake; SEM, standard error of mean.

Figure 4

BI 1820237 added to a stable dose of survodutide provides a more-than-additive bodyweight-lowering efficacy compared with survodutide alone in diet-induced obese mice. A–C) The effect of survodutide, BI 1820237 in combination with survodutide, and BI 1820237 added after 8 days of daily survodutide dosing on food intake (A), change in bodyweight % (B), and absolute change in bodyweight (C). The food intake of the treated groups was normalized (in %) to the average food intake of the group receiving vehicle. D–E) The effect of survodutide, BI 1820237 in combination with survodutide, and BI 1820237 added after 8 days of daily survodutide dosing on body fat (D) and lean mass (E). ^aDashed line denotes the addition of BI 1820237 on Day 9, after 8 days of daily survodutide. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001. DIO, diet-induced obese; SEM, standard error of mean.

Figure 5

The combination of BI 1820237 and survodutide provides synergistic bodyweight-lowering efficacy in diet-induced obese mice. A) The effect of BI 1820237, survodutide, and the combination thereof on bodyweight. B) Change in bodyweight versus baseline at Day 28 following dosing with BI 1820237 and BI 1820237 in combination with survodutide. C) Study design and model-derived bodyweight loss heatmap for BI 1820237 in combination with survodutide. Left Panel: model-derived bodyweight loss based on “additivity model”. Right panel: model-derived bodyweight loss based on final “interaction model”. White points indicate the dosing regimens included in the study design. D) Dose–response profiles of survodutide when combined with different doses of BI 1820237. Lines: “interaction model”-derived dose–response profiles. Points: observed body weight at d28 (mean of n = 5 or n = 10). ^aDosing group stopped at Day 15 as bodyweight reductions exceeded the allowance defined in the animal welfare license. ∗∗∗∗p < 0.0001. D28, Day 28; SEM, standard error of mean.

Figure 6

BI 1820237, and the Cyanine5 fluorophore analog BI 3005788, bind to centers of the arcuate nucleus of the hypothalamus and area postrema. A-B) Group-averaged whole brain images (coronal view) showing BI 3005788 targeting the ARH (A) and the AP (B). Fluorescence signal intensity from every light sheet imaged brain was mapped to Gubra average 3D brain volume to reconstruct group average fluorescence distribution patterns. Section is taken from the 3D reconstructed brain at the level of the ARH (A) and the AP (B). Scale bar, 1 mm. C) Heat map representing the mean log2 fold-change in region-wise mean fluorescence signal intensity for 7 pre-selected CVOs for chow-fed male C57BL/6JRj mice that received either a single subcutaneous dose of BI 3005788 (100 nmol/kg) or three consecutive subcutaneous doses of BI 1820237 (100 nmol/kg), followed by a single subcutaneous dose of BI 3005788 (100 nmol/kg). D-E). Region-wise mean fluorescence signal intensity for the ARH (D) and AP (E) for BI 1820237, BI 3005788, and BI 1820237 plus BI 3005788 competition analysis dose groups. Values expressed as mean of n = 8 + SEM. Dunnett’s test one-factor linear model. Region delineation was obtained by alignment to a digital LSFM-based mouse brain atlas. ∗p < 0.05 compared with BI 3005788, ∗∗p < 0.01 compared with BI 3005788, ∗∗∗p < 0.001 compared with BI 1820237. ARH, arcuate nucleus of the hypothalamus; AP, area postrema; CVO, circumventricular organs; LSFM, light sheet fluorescence microscopy; SC, subcutaneous; SEM, standard error of mean.

Figure 7

BI 1820237 and survodutide in combination synergistically increase c-Fos activity in the central nervous system. A) Brain regions and the mean log2 fold-change in the number of c-Fos positive cells in these regions in DIO mice that received either BI 1820237 (8 nmol/kg), survodutide (7.5 nmol/kg), or combination BI 1820237 and survodutide, compared with vehicle. B) Up (red) and down (blue) regulation of c-Fos expression in DIO mice that received either BI 1820237 (8 nmol/kg), survodutide (7.5 nmol/kg), or combination BI 1820237 and survodutide, compared with vehicle. C-F) Number of c-Fos positive cells in the CEA (C), NTS (D), DMX (E), and PB (F) of DIO mice that received either vehicle, BI 1820237 (8 nmol/kg), survodutide (7.5 nmol/kg), or combination BI 1820237 and survodutide. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. CEA, central amygdala nucleus; DIO, diet-induced obese; DMX, dorsal motor nucleus of the vagus nerve; NTS, nucleus of the solitary tract; PB, parabrachial nucleus; SEM, standard error of mean. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)