Abstract CT114: Data from first-in-human study of EXS21546, an A2A receptor antagonist, now progressing into phase 1 in RCC/NSCLC
Authors: Diaz Nieves , Garratt Holly , Zemla-Brown Aleksandra , Dominguez Maria , Helmer Eric , Alt Isabella , Sehlke Robert , Hieger Norbert , Winkler-Penz Thomas , Boudesco Christophe , Vladimer Gregory , Wilde Tom , Evans Philip , Italiano Antoine , Krams Michael 
Published: April 2023

Abstract
Background: EXS21546 (discovered in collaboration with Evotec) is a clinical stage A2AR selective antagonist with high potential in cancer immunotherapy as a combination agent. A completed healthy volunteer (HV) first-in-human (FIH) study is now being followed by the IGNITE Phase 1/2 trial in patients, which includes the retrospective study of an adenosine-specific patient enrichment biomarker strategy.
Methods: A 3-part Phase 1 FIH study in 60 HV was completed (NCT04727138). Parts 1 and 2 were double-blind, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) studies investigating EXS21546 safety, tolerability, PK and PD. Part 3 was a 3-period, open label, randomized, sequential study evaluating bioavailability of oral EXS21546 as a granule in capsule vs reference powder suspension. The ongoing Phase 1/2 IGNITE trial will study EXS21546 in patients with immunotherapy relapsed or refractory RCC or NSCLC directly in combination with a PD-1 inhibitor. This combination aims to leverage the properties of A2AR antagonism in the tumor microenvironment, to drive the immune system through PD-1 inhibition. IGNITE will also provide clinical data to support the validation of our adenosine signature to identify patients with adenosine rich tumor microenvironments who may benefit from treatment (Alt et al, 2022). Data will be continually reassessed to determine the recommended Phase 2 dose. A dose escalation phase will be followed by an expansion phase.
Results: PK/PD modeling of Phase 1 study results, along with the EXS21546 safety profile, allowed identification of a potential therapeutic starting dose. PK results aligned with design specifications, based upon predictive preclinical modeling, and support twice-daily (BID) dosing for continuous A2AR antagonism. EXS21546 induced dose-dependent inhibition of CREB phosphorylation in CD8-positive cells, with the PD profile mirroring plasma exposure. Inhibition of A2AR signaling was sustained over the BID dosing period, demonstrating a level of lasting target engagement. PoP PK/PD simulations informed the starting dose and dosing regimen for the Phase 1/2 trial.
EXS21546 was well-tolerated with no CNS adverse events reported in the SAD at all doses and in the MAD at 150 mg BID. The majority of adverse events were considered mild and unrelated to EXS21546, with the exception of one Grade 3 Serious Adverse Event of elevated ALT/AST.
Conclusions: Safety and tolerability of our A2AR antagonist EXS21546 were confirmed in a HV study, allowing selection of a starting dose for the ongoing IGNITE Phase 1/2 study. IGNITE trial design was based on extensive simulations to enable the most efficient continuous reassessment method settings, and will allow further verification of the patient enrichment biomarker strategy.
Citation Format: Nieves Diaz, Holly Garratt, Aleksandra Zemla-Brown, Maria Dominguez, Eric Helmer, Isabella Alt, Robert Sehlke, Norbert Hieger, Thomas Winkler-Penz, Christophe Boudesco, Gregory Vladimer, Tom Wilde, Philip Evans, Antoine Italiano, Michael Krams. Data from first-in-human study of EXS21546, an A2A receptor antagonist, now progressing into phase 1 in RCC/NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT114.