Exscientia plc announced data from its phase 1 healthy volunteer study of EXS-21546, its highly selective A2A receptor antagonist ??co-invented and developed through a collaboration between Exscientia and Evotec SE. Topline data from this healthy volunteer study confirmed Exscientia's target product profile design, including potency, high receptor selectivity and expected low brain exposure with no CNS adverse events reported, supporting advancement of EXS-21546 to a phase 1b/2 study in patients with solid tumours exhibiting high adenosine signatures. The EXS-21546 phase 1a study was a three-part dose-finding trial evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending doses (SAD) and multiple ascending doses (MAD) of EXS-21546.

The study randomised 60 healthy male subjects across all three parts. One of the study's primary goals was to inform the optimal starting dose for EXS-21546 for the phase 1b/2 study in cancer patients. The study showed that observed human PK for EXS-21546 was in line with what had been designed for and predicted in preclinical modeling, supporting a twice-daily (BID) dose for continuous A2A receptor inhibition over a dosing interval.

EXS-21546 showed dose-dependent inhibition of CREB phosphorylation in CD8-positive cells, with the PD profile mirroring plasma exposure. Inhibition of A2A receptor signaling was sustained over the BID dosing period, demonstrating a level of lasting target engagement. EXS-21546 was well-tolerated with no CNS adverse events reported in the SAD portion at all doses (30mg, 90mg, 250mg, 400mg) and in the MAD portion at 150mg BID.

In the MAD phase, a lab abnormality of elevated ALT and AST was observed in one subject that was classified as a grade 3 serious adverse event. This event was observed in one subject three days after completion of 14 days of treatment and resolved without medical intervention. The subject was asymptomatic during the treatment period and reported no adverse events while on drug.

Based on these results, Exscientia expects to initiate a phase 1b/2 study of EXS-21546 in patients with high adenosine signature solid tumours in the second half of 2022. The Phase 1b/2 study is being designed to evaluate higher doses of EXS-21546.