Non-clinical and first-in-human characterization of ECC5004/AZD5004, a novel once-daily, oral small-molecule GLP-1 receptor agonist

Abstract

Aims: GLP-1 receptor agonists (GLP-1 RAs) are proven therapies for type 2 diabetes mellitus (T2DM) and overweight or obesity. We performed non-clinical and first-in-human (FIH) evaluation of ECC5004/AZD5004, an oral small-molecule GLP-1 RA.

Materials and methods: ECC5004 was profiled in cell lines overexpressing human GLP-1R, in glucose-stimulated insulin secretion (GSIS) assays in a human β-cell line and non-human primates (NHPs). To evaluate safety, ECC5004 was orally administered to NHPs for 9 months and a phase I, double-blind, placebo-controlled FIH study was conducted. This study evaluated single doses of ECC5004 (1-300 mg) in healthy volunteers, and multiple daily doses (5, 10, 30 and 50 mg) in patients with T2DM for 28 days.

Results: ECC5004 bound to the hGLP-1R (IC₅₀ = 2.4 nM) augmented cAMP signalling without β-arrestin-2 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC-βH5 cells (EC₅₀ = 5.9 nM) and in vivo in NHPs (EC₅₀ = 0.022 nM). Dose-dependent body weight changes compared to control were seen in the 9-month NHP toxicity study. In the first-in-human study, ECC5004 was well tolerated with no serious adverse events. Dose-dependent reductions in glucose and body weight were observed with a dose-proportional exposure at doses ≥25 mg.

Conclusion: ECC5004 engaged the GLP-1R across the therapeutic dose range tested and had a safety and tolerability profile consistent with other GLP-1 RAs, along with a pharmacokinetic profile compatible with once-daily oral dosing. These data support continued development of ECC5004 as a potential therapy for T2DM and overweight or obesity.

Clinical trial registration: NCT05654831.

Keywords: AZD5004; ECC5004; GLP‐1; GLP‐1 RA; obesity; overweight; small molecule; type 2 diabetes mellitus.

FIGURE 1

In vitro profiling of ECC5004 on the hGLP‐1R. ECC5004 potently binds the human GLP‐1R (A) triggering downstream signalling through cAMP in HEK‐293 cells (B) and CHO‐K1 cells (C). Binding of ECC5004 to the receptor does not lead to β‐arrestin‐2 recruitment (D) or receptor internalization (E), while GLP‐1(7–36)NH₂ potently activates both signalling events. ECC5004 concentration‐dependently potentiated insulin secretion at 11 mM glucose in EndoC‐βH5 cells (F). Curves are derived from three independent test occasions and error bars represent SEM for responses at each concentration, except for (A) and (B), where one representative curve is shown. Data from each assay are presented as percentage of the positive control used in the assay. Potency data and positive controls used are summarized in Table S1. GSIS, glucose‐stimulated insulin secretion.

FIGURE 2

Pharmacokinetics (PK), pharmacodynamics (PD) and body weight change in non‐human primates (NHPs). ECC5004 showed a dose‐dependent effect on cAMP in a cell line overexpressing the cynomolgus GLP‐1R (A). ECC5004 presented a favourable PK profile with a half‐life of 1.72 ± 0.405 h (mean ± SD) and plasma clearance of 14.7 ± 1.32 mL/min/kg (mean ± SD) in lean NHPs following a single intravenous dose (0.5 mg/kg) (B). ECC5004 potentiated insulin secretion following an intravenous glucose tolerance tests in obese NHPs as exemplified by the effect on insulin following 33 μg/kg intravenous of ECC5004 compared to vehicle administered before the glucose bolus (0.5 g/kg) (C). From the insulin profiles measured following the six different doses of ECC5004 evaluated, an area under the concentration–time curve (AUC) was calculated for each dose and plotted against the corresponding free average exposure of ECC5004 (PK/PD plot) (D). From the PK/PD data, an in vivo potency of 0.022 nM (EC₅₀) was estimated. ECC5004 dose‐dependently decreased body weight gain compared to control in low‐, mid‐ and high‐dose groups over time in both females and males, including 95% confidence interval (CIs) (shaded area) (E). Least squares mean (darker line) and 95% CI were obtained from a mixed models for repeated measures analysis. During the dose titration period from day −14 to day 0, the low‐ and mid‐dose groups received ECC5004 10 and 30 mg/kg/day, respectively. The high‐dose group was administered ECC5004 30 mg/kg/day for 14 days and 50 mg/kg/day from day 1 and beyond.

FIGURE 3

Pharmacokinetic analysis—single ascending dose (SAD) study. Plasma concentration profiles of ECC5004 at doses from 1 to 300 mg in the SAD study in healthy volunteers. Plasma concentration profiles were normalized by individual's body weight at baseline. One participant in the 300 mg group had a missing pharmacokinetics (PK) data point at 48 h after dosing.

FIGURE 4

Glucose levels during oral glucose tolerance test (OGTT)—single ascending dose study. Changes in OGTT glucose area under the plasma concentration–time curve from time 0 to 2 h after dosing (AUC_0–2) levels on day (D) −1 to day 1. The bottom panel shows the corresponding percent changes, darker lines represent the median, while the lighter lines represent individual observations.