Background & Aims
A comprehensive in vitro and in vivo assay system was used to identify and select AAT-076, a centrally acting COX-2 inhibitor, as a development candidate. AAT-076 demonstrated efficacy in well-established preclinical models of acute, chronic, and neuropathic pain. Approximately 800 subjects participated in five Phase 1 and two Phase 2 studies evaluating single and multiple doses. In a Phase 2 post-operative dental pain study with 350 subjects, AAT-076 showed faster onset, greater analgesic potency, and longer duration of action when compared to ibuprofen. We hypothesized that this potent analgesic activity is due to effective COX-2 inhibition within the CNS compartment.
Methods
Human recombinant COX-1 and COX-2 assays and a whole blood assay followed by a comprehensive in vivo assay, i.e., a rat air pouch model of inflammation, carrageenan-induced edema and hyperalgesia were used to evaluate compounds. In the rat adjuvant-induced arthritis, hyperalgesia was assessed by measurement of the mechanical pressure. For measurements of tissue PGE2 levels, samples were collected at 4 hours after dosing. Tissue PGE2 levels were determined by a standard ELISA and expressed as ng/g tissue for CNS and paw tissue and as ng/ml for CSF samples. AAT-076 was tested in three standard neuropathic pain models in rats, i.e., spinal nerve ligation (SNL), chronic constriction injury (CCI), and spared nerve injury (SNI). A battery of safety pharmacology tests was conducted in rats, dogs and monkeys to assess overall safety. Around 800 patients have been exposed to AAT-076 to demonstrate its pharmacokinetic properties, efficacy, and safety in post-operative dental pain.
Results
AAT-076 showed a 198X selectivity for COX-2 v. COX-1, with this selectivity maintained in human whole blood. AAT-076 inhibited COX-2-derived PGE2 in the air pouch with an EC50 of 0.43 mg/kg, while a dose of 26.5 mg/kg was required to inhibit COX-1 in the stomach. AAT-076 demonstrated analgesic activity with an ED50 of 4.0 mg/kg v. 35 mg/kg for celecoxib in the carrageenan-induced hyperalgesia model. In the rat adjuvant arthritic model, an ED50 of 0.08 mg/kg completely inhibited PGE2 in the midbrain and spinal cord. AAT-076 reversed tactile allodynia in rat neuropathic pain models, SNL, CCI and SNI. In clinical studies, AAT-076 was well tolerated up to a single dose of 360 mg and 180 mg qd for 10 days, with a T1/2 ~30 hours consistent with QD dosing. In a Phase 2 dental pain study, pain relief was recorded at 18 minutes after taking AAT-076 v. 30 minutes for ibuprofen. Furthermore, >60% patients rated AAT-076 as “very satisfied” with pain relief v. 28% with ibuprofen.
Conclusions
AAT-076 is a centrally active COX-2 inhibitor under development and has demonstrated potent efficacy in acute, chronic, and neuropathic pain models. AAT-076 is clinically validated, i.e., superior efficacy v. ibuprofen in terms of onset, potency, and duration of action, with a substantial safety database in clinical studies with ~800 subjects. AAT-076, with unique pharmacological properties, has the potential to offer patients an effective analgesic medication for acute and chronic pain conditions, and in so doing could help end the prescription opioid crisis.
References
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