Lesogaberan (AZD3355)
Preclinical pharmacology
AZD3355 is a selective γ-aminobutyric acid type B (GABAB) receptor agonist.
| Potency (EC50) | 8nM (Increased intracellular Ca2+ in CHO cells transfected with human GABAB1a/2) |
| Binding (IC50) | 2nM (displaced GABA binding from rat brain membranes) |
| Selectivity | 600x greater selectivity for GABAB |
In the dog, when administered directly into the stomach, AZD3355 reduced transient lower oesophageal sphincter relaxations (TLESRs), producing approximately 50% inhibition at 3mg/kg (AZD3355 concentration ~600 x EC50 in plasma).
Safety and tolerability
AZD3355 has been administered to healthy volunteers in single-doses of up to 1800mg and in multiple ascending doses of up to 800mg BID for 5-days. In five clinical Phase 2 studies, a total of 930 patients have been treated with AZD3355 at oral doses of up to 240mg BID for 4-weeks. Increases, usually mild, in liver enzymes were seen in small numbers (<2%) of subjects on AZD3355 in two of these patient studies; these resolved after treatment was stopped.
Preclinical studies of up to 12-month duration and lifetime bioassays in rat and mouse have been performed. The toxicity profile showed no hepatic effect. AZD3355 has been shown to induce decreased body weight and decreased food consumption. A dose-dependent diuretic effect was also noted in rats.
Clinical pharmacology
In healthy volunteers, AZD3355 dosed at 0.8mg/kg showed a 36% reduction in TLESRs at plasma compound concentrations of ~120 x EC50. In GERD patients, AZD3355 at 65mg BID, compared to placebo as add-on treatment to a proton pump inhibitor (PPI), reduced the number of TLESRs by 25%, increased LES pressure by 28%, and reduced the number of reflux episodes by 47% between zero to three hours post-prandially. In a dose-finding study on GERD symptoms, four-doses of AZD3355 (60, 120, 180 and 240mg BID) for 4 weeks as add-on to PPI, showed statistically significant efficacy at the highest dose (26% response rate for the treatment group compared to 18% for placebo).
Suitable for and exclusions
Preclinical reprotoxicology data are available and have not identified any specific risks. Women of child-bearing potential using highly effective contraception can be included. Given the potential effects on liver enzymes, dosing regimen (level and duration) as well as inclusion/exclusion criteria should be selected carefully to support a favourable risk-benefit.
Mechanism of Action
Gamma-aminobutyric acid receptor B (GABAB) agonist
Original Therapeutic Area
Other
CNS Penetrant
Low
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Lehmann A., et al. (2009).
(R)-(3-amino-2-fluoropropyl) phosphinic acid (AZD3355), a novel GABAB receptor agonist, inhibits transient lower esophageal sphincter relaxation through a peripheral mode of action. J Pharmacol Exp Ther. Nov;331(2):504-12. doi: 10.1124/jpet.109.153593. PMID: 19648470.
2. Tian J., et al. (2017).
Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication. J Diabetes Res.;2017:6403539. doi: 10.1155/2017/6403539. Epub 2017 Sep 5. PMID: 29018828; PMCID: PMC5605788.