AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys

Abstract

Objectives: Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment.

Methods: We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period.

Results: AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (P = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (P = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (P = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (P = 0.008), glucose by 30% (P = 0.02), triglycerides by 39% (P = 0.05), total cholesterol by 29% (P = 0.03), and LDL cholesterol by 48% (P = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects.

Conclusions: This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.

Keywords: Cynomolgus monkeys; GIP receptor antagonist; GLP-1; Metabolic improvements; Obesity; Weight loss.

Graphical abstract

Figure 1

AT-7687 is a potent and selective GIPR antagonist. A) Binding of AT-7687 and GIP(1–42) to hGIPR. B) Percent GIP(1–42)-mediated cAMP accumulation from hGIPRs without and with increasing concentrations of AT-7687. C) Schild regression analysis of AT-7687 on GIP(1–42)-induced cAMP accumulation from hGIPRs. D) Percent GIP(1–42)-induced β-arrestin 2 recruitment. E) Percent GIP(1–42)-mediated cAMP accumulation from macaque GIPRs without and with increasing concentrations of AT-7687. F) Schild regression analysis of AT-7687 on GIP(1–42)-induced cAMP accumulation from macaque GIPRs. Data are presented as mean ± SEM, n = ≥3 independent experiments carried out in duplicates. GIP, glucose-dependent insulinotropic polypeptide; hGIPR, human GIP receptor; DR, dose–response; mqGIPR, macaque GIP receptor; cAMP, cyclic adenosine monophosphate.

Figure 2

Plasma half-life of AT-7687, semaglutide and tirzepatide in Göttingen minipigs. Concentration time curve for AT-7687, semaglutide and tirzepatide in Göttingen minipigs. n = 2 for all groups. Data are presented as mean.

Figure 3

AT-7687 combined with liraglutide, provides the most significant reduction in weight and TEI in obese NHPs. A) Changes in BW (%) from predose during the entire study period, including a 42-day treatment period followed by a 15-day washout period in obese NHPs. B) Placebo-adjusted change (%) in BW from predose to the last day of dosing (day 42). C) Cumulative energy intake during the 42-days treatment period D) Total energy intake during the entire treatment period from day 1–42. n = 10 NHPs for placebo, AT-7687 monotreatment and AT-7687 + liraglutide groups, n = 9 NHPs for liraglutide group. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, and ∗∗∗∗P < 0.0001 versus placebo. Data are presented as mean ± SEM.

Figure 4

AT-7687 combined with liraglutide, improves glycemic control and lipid metabolism in obese NHPs. A) (%) change in insulin from predose at day 42. B) (%) change in glucose from predose at day 42. C) HOMA-IR calculated for day 42. D) (%) change in triglycerides from predose at day 42. E) (%) change in total choleterol from predose at day 42. F) (%) change in LDL-cholesterol from predose at day 42. G) (%) change in HDL-cholesterol from predose at day 42. H) Change from predose at day 42 for CTX (ng/mL). I) Change from predose at day 42 for PTH (pg/mL). N = 10 NHPs for placebo, AT-7687 monotreatment and AT-7687 + liraglutide groups, n = 9 NHPs for liraglutide group. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 versus placebo. Data are presented as mean ± SEM. HOMA-IR, homeostatic model assessment for insulin resistance; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CTX, C-terminal telopeptide of type I collagen; PTH, parathyroid hormone.