A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans

Abstract

Single molecules that combine complementary modes of action with glucagon-like peptide-1 receptor (GLP-1R) agonism are best-in-class therapeutics for obesity treatment. NN1706 (MAR423, RO6883746) is a fatty-acylated tri-agonist designed for balanced activity at GLP-1R and glucose-dependent insulinotropic peptide receptor (GIPR) with lower relative potency at the glucagon receptor (GcgR). Obese mice, rats and non-human primates dosed with NN1706 showed significant body weight reductions and improved glycemic control. In human participants with overweight or obesity, daily subcutaneous NN1706 treatment resulted in substantial body weight loss in a dose-dependent manner without impairing glycemic control (NCT03095807, NCT03661879). However, increased heart rate was observed across NN1706 treatment cohorts, which challenges further clinical development of NN1706.

Keywords: Clinical; Glucagon; Incretins; Obesity.

Figure 1

NN1706 is a potent and balanced tri-agonist of the GLP-1, GIP, and Gcg receptors. A. Structure schematic of NN1706 (MW 4611.08 g/mol). B. Agonist potencies (mean apparent 50% stimulatory concentration [EC₅₀] values) from in vitro CRE-Luc 0% HSA assays in BHK cells expressing human recombinant GLP-1R, GcgR, or GIPR (n≥3). BHK, baby hamster kidney; cAMP, cyclic adenosine monophosphate; CRE-Luc, cAMP response element-luciferase; EC₅₀, half maximal effective concentration; Gcg, glucagon; GIP,glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; hGcgR, human Gcg receptor; hGIPR, human GIP receptor; hGLP-1R, human GLP-1 receptor; HSA, human serum albumin; MW, molecular weight.

Figure 2

NN1706 lowers body weight and improves glycemic control in diet-induced obese mouse models and increases heart rate in telemetered Wistar Han rats. A-B. Relative change in body weight (mean baseline body weight 62.3 g; n = 8) (A) and cumulative food intake (B), in male DIO mice administered NN1706, IUB447 or SAR441255 over 28 days (n = 8). C-D. Acute glucose tolerance assessed at day 0 (C) and chronic glucose tolerance assessed at day 27 (chronic; D) of vehicle, NN1706, IUB447 or SAR441255 treatment in male DIO mice (n = 8). E-F. Body weight loss (E) and energy expenditure (F) in DIO mice treated with NN1706 over 10 days in comparison to vehicle and pair-fed controls (n = 8). G-J. Effect of NN1706 or vehicle on mean heart rate and mean blood pressure after a single dose (G–H), and after 7 days of dosing (I–J) in male telemetered Wistar Han rats (n = 8). One-minute mean data were collected every 4 min. Rats were injected at time = 0 h, and data are reported from 1 h post-dose. The 45 μg/kg dose was stopped after 2 days as heart rate and blood pressure increases were similar to those produced by the 20 μg/kg dose. Rats in the 45 μg/kg group received no treatment on days 3–7. Values represent mean ± SEM. DIO, diet-induced obese.

Figure 3

NN1706 reduces body weight and caloric intake in DIO cynomolgus monkeys and increases heart rate in lean cynomolgus monkeys. A. Relative change in body weight over 8 days s.c. NN1706 (5 μg/kg/day), liraglutide (20 μg/kg/day) or vehicle in DIO cynomolgus monkeys (n = 8; mean baseline body weight 10.4 kg). B-E. Ascending dose study of NN1706 in DIO cynomolgus monkeys treated with s.c. vehicle (n = 9) or escalating doses of NN1706 (n = 9) or liraglutide (n = 8) for 39 days (mean baseline body weight 9.6 kg). Relative change in body weight (B), cumulative caloric intake over days 0–38 (C) and total body fat (D) and lean mass (E) at day 32. F–I. Cardiovascular outcomes in conscious telemetered lean cynomolgus monkeys. Heart rate in a single dose pilot study with vehicle or 5, 30 or 100 μg/kg s.c. NN1706 (n = 3–4; F), and follow-up (n = 6; G) study of vehicle or 3, 10 or 30 μg/kg s.c. NN1706. Heart rate (H) and mean arterial blood pressure (I) at day 1, 7 and 14 after repeated doses of 30 μg/kg NN1706 (s.c.). A-E, G–I: Values represent mean ± SEM. F: Mean values without error are plotted. Data were analyzed using analysis of variance (ANOVA) for repeated measurements (A), ANOVA for repeated measures for the entire study and per study period (B), ANOVA followed by Dunnett's test (C), ANOVA followed by Dunnett's test and paired t-test (D–E), descriptive statistics (F), or ANOVA for repeated measurements (G–I). Statistical significance indicated for tests of treatment group vs vehicle (∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001), Liraglutide vs NN1706 (#p<0.05, ###p<0.001), baseline vs follow-up (§p<0.05, §§p<0.01). ANOVA, analysis of variance; BMC, bone mineral content; DIO, diet-induced obese.

Figure 4

NN1706 in male participants in a phase 1 single ascending dose clinical study. A. Participant disposition. B. NN1706 plasma concentrations after single dose of NN1706. Dotted line indicates the LLOQ. Values below LLOQ were imputed. C. Relative change in body weight after a single dose of NN1706. D-H. Changes in clinical laboratory parameters and heart rate after a single dose of NN1706. Change in fasting plasma glucose (D), non-fasting plasma glucose (E), fasting insulin (F), and fasting C-peptide (G) from baseline as well as baseline-corrected Holter heart rate (H). B: Values represent geometric mean. C–H: Values represent mean ± SEM. bpm, beats per minute; FAS, full analysis set; LLOQ, lower limit of quantification; SAS, safety analysis set.

Figure 5

NN1706 in a phase 1 multiple ascending dose clinical study. A. Participant disposition. Three cases of second degree atrioventricular (AV) block were reported in three participants in the 150-μg cohort (C3); dosing was stopped in the 150-μg cohort (C3), amended to 100 μg in the 300-μg cohort (C4) and repeated with 150 μg in the 600-μg cohort (C5). B. NN1706 plasma concentration at steady state. C-D. Relative change in body weight after repeated NN1706 dosing. Change from baseline over 70 days (C) and relative body weight change from baseline after 10 weeks (D; ∗∗∗p < 0.001, ∗p < 0.05). E-H. Cardiovascular outcomes after repeated NN1706 dosing. Mean pulse rate (E), mean heart rate (F) as well as change in heart rate from baseline (G) by 12-lead ECG over the study as well as placebo adjusted QTcI change from baseline (H). B: Values represent geometric mean. C–G: Values represent mean ± SEM. E–G: Vertical dotted lines in graphs represent first and last dosing of NN1706. H: Solid line with shaded area denotes model-predicted mean placebo-adjusted delta QTcI with 90% CI. Reference line at 10 msec represents unacceptable prolongation of QTcI interval [57]. ECG, electrocardiogram; FAS, full analysis set; QT, specific ECG interval corresponding to ventricular depolarization/repolarization; QTcI, individual corrected QT interval; SAS, safety analysis set.