2289P - Determining anti-cancer efficacy of a reversible LSD1 inhibitor, EXS74539, in primary AML tissues with limited thrombocytopenic effects

Background

Acute myeloid leukaemias (AML) are characterised by distinct chromatin dynamics and aberrant histone methylation regulations. The reversible nature of such epigenetic modifications has become attractive for the design of new AML therapies. Histone methylation is controlled by histone methyltransferases and demethylases, and among them, LSD1 has recently gained interest and tractability with the emergence of new LSD1 inhibitor clinical candidates. Here, we describe efforts to transcriptionally and functionally define the activity of EXS74539 (‘539) - a novel potent, selective and reversible LSD1 inhibitor - as a monotherapy or in combination with AML standard of care (SoC) at the single cell level, leveraging our expertise in the use of primary AML and healthy bone marrow samples as model systems (Kornauth et al, 2022).

Methods

Using primary human material as a disease relevant model system, combined with our proprietary deep learning enabled high content imaging and image analysis platform, we explored the capacity of ‘539 to induce AML blast differentiation and/or improve first line SoC therapy potential both in primary AML samples and in non-transformed healthy bone marrow or peripheral blood mononuclear cells. Collecting baseline and treatment condition genomics and transcriptomics, we modelled the AML specific sensitivity to ‘539.

Results

Through combining single cell omics and functional response data, we demonstrate, preclinically, the capacity of ‘539 monotherapy to induce AML cell differentiation marker expression ex vivo, and the usability of ‘539 together with SoC agents. Using healthy non-transformed bone marrow and colony formation assays, we demonstrate that an adapted drug regimen limits ‘539 thrombocytopenic potential.

Conclusions

Our preclinical data demonstrated ex vivo efficacy of ‘539 against AML blast cells and supported the combinatorial potential of ‘539 with first line clinical AML treatment strategies. Leveraging the reversibility of ‘539 allowed the design of adapted drug regimens, to preserve the safety profile of this inhibitor on non-transformed healthy cells.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Exscientia.

Funding

Exscientia.

Disclosure

C. Boudesco, R. Okumura, M. lautizi, N. Hieger, V. Thatikonda, M. Ssenekowitsch, T. Lin, G. Fiume, R. Sehlke, T. Winkler-Penz, A. Payne, R. Paveley: Financial Interests, Personal, Full or part-time Employment: Exscientia. G.I. Vladimer: Financial Interests, Personal, Full or part-time Employment: Exscientia; Financial Interests, Personal, Stocks or ownership: Exscientia; Financial Interests, Personal, Stocks/Shares: Exscientia.