PII-030 - PHASE 1 EVALUATION OF THE SAFETY, TOLERABILITY AND PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF THE ADENOSINE A1R/A3R AGONIST AST-004 AFTER INTRAVENOUS INFUSION IN HEALTHY VOLUNTEERS

P. Dogterom¹, K. Abd-Elaziz¹, W. Aalders¹, T. Liston², L. Manna², M. Matson², W. Korinek²; ¹QPS Netherlands, ²Astrocyte Pharmaceuticals.

Background: AST-004 is a new adenosine A1 and A3 receptor (A1R, A3R) agonist and promising neuronal cerebroprotectant, that preclinically promotes neuronal recovery and survival after brain injury. The small molecule maintains astrocyte mitochondrial energy production and it is a blood brain barrier (BBB) penetrant. In a Phase 1 first in human study, AST-004 up to 100 mg infused over 10 minutes, showed a favorable safety and tolerability profile in healthy volunteers. The pharmacokinetic (PK) results of that study supported further evaluation of the safety and PK, with increased infusion durations and targeted plasma and cerebrospinal fluid (CSF) exposure of AST-004 that associated with observed pre-clinical cerebroprotective efficacy.

Methods: Four cohorts of 5 healthy male and female volunteers (2 on placebo and 3 on active per cohort), one confirmatory, additional cohort (1 on placebo and 3 on active) and a final CSF collection cohort (4 on active) received an intravenous loading dose of AST-004, infused over 10 minutes, followed by a continuous infusion over 6 hours. Upon completion of each of the double blinding first four cohorts, safety and PK were evaluated and a next dosing paradigm was selected until pre-defined plasma exposures (mean Cmax of ≥ 2500 ng/mL) were reached. The final CSF cohort received this dose and underwent serial CSF samplings (10 collections of at least 0.4 mL CSF each over 16 hours) to determine CSF exposure.

Results: Two initial cohorts received a loading dose of 100 mg AST-004, infused over 10 minutes followed by a continuous infusion of 30 mg/hour (cohort 1a) and 80 mg/hour (cohort 2a) over 6 hours. Subsequent cohorts received a loading dose of 130 mg AST-004 infused over 10 minutes followed by a continuous infusion of 130 mg/hour (cohort 3a) and 180 mg/hour over 6 hours (cohorts 4a, 4b and 5a). All treatments were safe and well tolerated without specific treatment related abnormalities. The PK of AST-004 was dose proportional and the final dose demonstrated fast steady state conditions and mean plasma and CSF concentrations over 6 hrs of approx. 2131 and 112 ng/ml, respectively.

Conclusion: Ascending, intravenous infusion regimens with AST-004 were safe and well tolerated at plasma and CSF exposures associated with cerebroprotective efficacy.