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Clinical data builds upon body of evidence suggesting EXS-21546 is a highly potent and selective A2AR antagonist with low CNS exposure
Exscientia anticipates initiating Phase 1b/2 in patients with high adenosine signature cancers in second half of 2022
Ongoing translational work to establish predictive biomarker to enable targeting of patients most likely to benefit from EXS-21546
OXFORD, England--(BUSINESS WIRE)-- Exscientia plc (NASDAQ:EXAI) today 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 ((Frankfurt Stock Exchange: EVT, MDAX/TecDAX, OTC:EVOTF, NASDAQ:EVO). 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.
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“Topline data from our phase 1a study of EXS-21546 demonstrate the ability of our AI-based platform to create novel molecules based upon defined design objectives and with a high level of translatability to human biology. EXS-21546 is a pilot programme from the early days of our platform, and we are proud that it achieved our targeted objectives of potency, selectivity and pharmacokinetics,” said David Hallett, Ph.D., Chief Operating Officer and head of drug discovery for Exscientia. “Moving forward, a primary challenge in clinical development of an A2AR antagonist is identifying patients who will benefit the most from this type of immunomodulatory therapy. We believe that utilising our unique precision medicine platform to analyse patient tumour microenvironments ex vivo, including immune function, will help us identify the right patients for our drug.”
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.
The Company expects to share additional data from this Phase 1a study at future medical meetings.
About EXS-21546
EXS-21546, an AI-designed A2A receptor antagonist, was co-invented and developed by Exscientia and Evotec. Exscientia designed the compound leveraging its AI-driven platform and Evotec provided biology and chemistry capabilities.
Some tumours produce high levels of adenosine, which binds and activates A2A receptors on immune cells, resulting in the suppression of the anti-tumour activity of the immune system. EXS-21546 is being investigated for its ability to prevent high concentrations of adenosine from activating the A2A receptor, and thereby its potential to promote the anti-tumour activity of the immune cells.
About the EXS-21546 Phase 1a Trial
The Phase 1 study was a three-part study in male healthy volunteers to assess the safety, tolerability, pharmacokinetics and pharmacodynamics (PK/PD) of EXS-21546. Part 1 was a randomised, double-blind, placebo-controlled, SAD study with a food effect assessment where 41 healthy volunteers were randomised 3:1 (in a ratio of 6 active to 2 placebo per cohort). Part 2 was a randomised, double-blind, placebo controlled, MAD study over 14 days. Part 2 was completed after the enrolment of 1 cohort (8 subjects) who received 150mg EXS-21546 BID. Part 3 was a 3-way crossover, open label, randomised study, where 11 subjects were enrolled to evaluate a capsule formulation (fed and fasted) as compared to an oral suspension (fasted) formulation.