On March 15, 2023 Exscientia plc (Nasdaq: EXAI) reported that four abstracts have been accepted for poster presentation at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, being held April 14-19, 2023, at the Orange County Convention Center in Orlando, FL (Press release, Exscientia, MAR 15, 2023, View Source [SID1234628851]). These abstracts highlight the components of Exscientia’s approach to precision discovery, design and personalised medicine as well as planned innovation in the clinic.
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"The clinical and preclinical data showcased at AACR (Free AACR Whitepaper) further validate Exscientia’s functional precision medicine platform and translational research capabilities," said Andrew Hopkins, D.Phil, founder and Chief Executive Officer of Exscientia. "These new data demonstrate the potential of integrating outstanding science with cutting-edge AI, to efficiently identify novel targets with the potential for increased probability of clinical success. We also believe that our platform can be used to predict outcomes that help identify cancer patients with high unmet need who may benefit most from treatment. We look forward to advancing these programmes and expanding our pipeline with the goal of developing precision-designed, truly personalised medicines for patients around the world."
Abstracts Accepted for Poster Presentation:
Title: Identification of transcript adenosine fingerprint to enrich for A2AR and PD-1 inhibition responders
Session Title: Biomarkers of Therapeutic Benefit 2
Abstract Number: #2151
Date/Time: Monday, April 17 / 9:00 AM – 12:30 PM EDT
Next generation precision cancer medicine mandates a deep understanding of the disease milieu and drug function to create complex patient selection biomarkers, more than single mutations. To enrich for patients who will most likely respond to EXS21546 (‘546), Exscientia’s clinical stage A2AR-selective antagonist targeting the adenosine pathway, Exscientia researchers leveraged a combination of single cell functional and transcriptomics from complex primary patient samples to identify an adenosine-induced immunosuppression biomarker signature (adenosine burden score or ABS). The ABS correlates with checkpoint inhibitor (CI) response prediction to potentially predict patients likely to benefit from combined A2AR antagonism and CI. Here, researchers show that the adenosine burden, as monitored by ABS, is reduced following antagonism of A2AR with ‘546, which in turn restores CI response potential. The ABS is being confirmed retrospectively in the ongoing IGNITE Phase 1/2 clinical study of ‘546 in combination with a PD-1 inhibitor in relapsed/refractory renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC).
Title: Characterizing antitumor responses to EXS74539, a novel, reversible LSD1 inhibitor with potential in small-cell lung cancer
Session Title: Epigenetics
Abstract Number: #6290
Date/Time: Wednesday, April 19 / 9:00 AM – 12:30 PM EDT
LSD1 is an epigenetic target with critical roles in oncology, notably demethylating histones and other proteins, thereby suppressing the expression of genes required for cellular differentiation. Historically, LSD1 inhibitors in development have been unable to achieve the combination of appropriate pharmacokinetics, good brain penetrance and a reversible mechanism of action. By leveraging generative design algorithms and active learning, Exscientia designed a highly differentiated LSD1 inhibitor, EXS74539 (‘539). ‘539 is a potent, selective and reversible brain-penetrant molecule, combining the potential to treat tumours and metastases in the brain with potential clinical safety benefits through reversible inhibition of LSD1. ‘539 is currently in IND-enabling studies as a potential treatment across oncology and haematology. Preclinical data has shown that ‘539 has potent anti-proliferative activity in in vitro models of small cell lung cancer (SCLC), with anti-tumour activity observed in selected SCLC xenograft tumour-bearing mice.
Title: Discovering novel targetable pathways by combining functional and multi-omic data from primary ovarian cancer samples
Session Title: Novel Targets and Pathways
Abstract Number: #4956
Date/Time: Tuesday, April 18 / 1:30 PM – 5:00 PM EDT
Mapping and interpreting single cell functional and multi-omics data at baseline and after perturbation of complex primary model systems reveals a previously unexplored convergent putative target landscape that Exscientia is further validating as potential next-generation anticancer nodes. The high unmet medical need in indications such as high grade serous ovarian cancer (HGSOC) drives a requirement for innovation to uncover novel targets. Standard target discovery processes that often heavily rely upfront on outgrown cell line models with well-averaged readouts have hindered approval rates for drugs entering trials. This study highlights ongoing work using Exscientia’s precision medicine platform in combination with proprietary methodology for multi-omics and multi-modal dataset mapping which could have the potential to improve patient outcomes by uncovering clinical relevance at the target discovery stage. Here, researchers report a novel way of uncovering several high confidence convergent putative targets, seemingly overlooked in cell line studies. By mechanistically characterising one such functional sensitivity node, ALK/FAK1/IGF1R, the study reveals tumour necrosis factor (TNF) via the nuclear factor kappa B (NFкB) pathway as a promising focus area for HGSOC via the evaluation of malignant pleural effusion and ascites from patients with late stage ovarian cancer.
Title: Data from first-in-human study of EXS21546, an A2A receptor antagonist, now progressing into Phase 1 in RCC/NSCLC
Session Title: Phase I Clinical Trials in Progress
Abstract Number: #CT114
Date/Time: Monday, April 17 / 1:30 PM – 5:00 PM EDT
Pharmacokinetics, pharmacodynamics, safety and tolerability of EXS21546 were confirmed in a healthy volunteer study, allowing selection of a starting dose for the ongoing IGNITE Phase 1/2 study in combination with a PD-1 inhibitor in relapsed/refractory RCC and NSCLC. The 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 (adenosine burden score or ABS).