On October 9, 2024 Exscientia plc (Nasdaq: EXAI) reported three abstracts to be presented at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Symposium 2024 from October 23-25, in Barcelona, Spain (Press release, Exscientia, OCT 9, 2024, View Source [SID1234647123]).

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"As our precision-designed LSD1 and MALT1 inhibitors continue to progress towards the clinic, we are excited to share new preclinical data from both programmes," said David Hallett, Ph.D., interim Chief Executive Officer and Chief Scientific Officer of Exscientia. "These posters, as well as an additional focus on our assay development, highlight the potential of our platform to design best-in-class molecules with improved properties. As our state-of-the-art automation facility continues to ramp up in scale, we look forward to further accelerating the design and development of future molecules."

The ENA posters will be available on the Exscientia website from their time of presentation.

Poster Presentations
Title: Combining next-generation BTK and MALT1 inhibitors to enhance efficacy and therapeutic utility in B-cell malignancies
Session Title: Combination therapies
Catalog Number: 218
Poster Board Number: PB206
Date/Time: Thursday, October 24 / 9:00 a.m. – 5:30 p.m. CEST

EXS73565 (‘565) is a potent, selective allosteric MALT1 inhibitor designed to have an improved safety profile, with clinical studies expected to start in early 2025
Combining MALT1 inhibitors, such as ‘565, with BTK inhibitors has the potential to provide enhanced efficacy in B-cell malignancies, by greater inhibition of pathogenic nuclear factor-kappa B (NF-kB) signalling and addressing BTK-resistance mechanisms
Exscientia researchers combined ‘565 with the BTK inhibitor zanubrutinib and observed deeper, more durable efficacy responses in xenograft models of B-cell malignancies, with long-lasting tumour eradication seen for activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL)
Studies also confirmed target pathway biology engagement, with ‘565 alone and in combination with zanubrutinib inhibiting NF-kB target gene expression in in vivo models
Overall, the selective profiles of ‘565 and zanubrutinib may maximise the therapeutic index of MALT1 and BTK inhibition in combination, providing scope for enhanced efficacy for patients with B-cell malignancies
Title: In vivo pharmacokinetics, pharmacodynamics and anti-tumour efficacy of EXS74539: A novel, reversible LSD1 inhibitor for acute myeloid leukaemia
Session Title: Epigenetic modulators (HDAC bromodomain modulators, EZH2)
Catalog Number: 250
Poster Board Number: PB238
Date/Time: Thursday, October 24 / 9:00 a.m. – 5:30 p.m. CEST

‘539 is a novel, potent, selective and reversible LSD1 inhibitor, with a highly differentiated profile and designed to be brain penetrant, expected to enter the clinic in early 2025
The poster highlights that by combining ex vivo perturbation of primary human acute myeloid lymphoma (AML) samples with ‘539 and omics profiling, 12 potential pharmacodynamic (PD) biomarker gene candidates were identified that correlate with LSD1 inhibitor activity
Upregulation of the identified biomarker gene candidates was confirmed in an in vivo AML xenograft model post ‘539 treatment
Treatment of the in vivo model with the reversible inhibitor ‘539 resulted in limited platelet level effects, highlighting how ‘539 was designed to maximise target engagement while limiting thrombocytopenia
Title: Xcellomics: Powering rapid translation of HTS outputs to AI-driven drug discovery programmes
Session Title: Functional genomics
Catalog Number: 414
Poster Board Number: PB402
Date/Time: Friday, October 25 / 9:00 a.m. – 3:00 p.m. CEST

Xcellomics is a collaboration between Exscientia and The Centre for Medicines Discovery at the University of Oxford, used to rapidly translate the results of cell-based, high-throughput screens into transformative oncology therapies
The collaboration has successfully identified and validated novel essential regulators of a key oncogenic pathway
Automated assay development and chemical hit ID performed by Exscientia rapidly pushed these novel therapeutic targets into drug discovery programmes