On March 14, 2023 Exscientia plc (Nasdaq: EXAI) reported two new wholly-owned precision oncology development candidates, EXS74539 (‘539), an LSD1 inhibitor, and EXS73565 (‘565), a MALT1 protease inhibitor (Press release, Exscientia, MAR 14, 2023, View Source [SID1234635630]). These compounds have been precision designed to improve the potential for patient benefit and solve complex design issues that may limit the probability of success of other compounds in development. IND-enabling studies are underway and the Company expects to provide an update on clinical development plans leveraging Exscientia’s personalised medicine platform in the second half of 2023.
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Both molecules were funded through a 2019 collaboration with Celgene, which was acquired by Bristol Myers Squibb, and each molecule met the criteria for which BMS could exercise its option. Bristol Myers Squibb’s options to the candidates have now lapsed and Exscientia maintains all worldwide rights to both compounds. In 2021, an agreement was signed to expand the collaboration to include additional programmes in oncology and immunology. These programmes are currently in active development.
"Building off of our success with the CDK7, A2A and PKC-theta programmes, these candidates clearly show how our AI-driven precision design platform can solve challenging target profiles in a more efficient way than traditional drug discovery," said Professor Andrew Hopkins, D.Phil., founder and Chief Executive Officer of Exscientia. "Both ‘539 and ‘565 met the primary nonclinical design goals for potency, selectivity, dosing and safety. In addition, these molecules also have the potential for meaningful patient selection strategies to optimise clinical design. We are excited about the promise these compounds hold in a broad range of haematologic and solid tumours."
First potent, selective, reversible and brain-penetrant LSD1 inhibitor: EXS74539 (‘539) is a differentiated lysine demethylase 1 (LSD1) inhibitor with potential in both haematology and oncology. LSD1 demethylates histones which play a critical role in regulating the expression of genes which suppress differentiation and drive the proliferation and survival of a number of tumour types. To date, other LSD1 inhibitors in development have failed to achieve the combination of appropriate pharmacokinetics, good brain penetrance and a reversible mechanism of action. Exscientia’s candidate, ‘539, achieves a design objective of suitable CNS penetration to target brain metastases, which are prevalent in certain cancer subtypes. Additionally, in vivo studies of ‘539 have shown favourable activity in small cell lung cancer (SCLC) xenograft models, with dose dependent inhibition of tumour growth. Studies have also shown a favourable absorption, distribution, metabolism, and excretion (ADME) profile, with a shorter predicted human half-life than some LSD1 inhibitors currently in clinical trials. No safety concerns have been observed in preclinical studies conducted to date. Exscientia will present data on the discovery and development of ‘539 at an upcoming scientific conference in the first half of 2023.
Potent and selective MALT1 protease inhibitor with potential safety differentiation: EXS73565 (‘565) is a mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease inhibitor with potential applications in haematology. MALT1 is a protease crucial for activation of the NF-κB pathway which supports the uncontrolled proliferation of malignant T- and B-cells in haematological cancers. Exscientia’s precision design approach was able to optimise the safety profile for agents targeting MALT1 whilst also generating potency and selectivity. Scaffolds of other MALT1 inhibitors in the clinic significantly inhibit UGT1A1, an enzyme involved in the metabolism of bilirubin, often leading to dose-limiting toxicities in the clinic. In vivo studies of ‘565 have shown anti-tumour activity in mouse models and favourable pharmacokinetics both as monotherapy and in combination with ibrutinib. Toxicology studies have shown that ‘565 has an acceptable therapeutic index, with the ability to maintain high levels of potency, selectivity and safety benchmarks while avoiding meaningful inhibition of UGT1A1, which can lead to hyperbilirubinemia.
"With three existing clinical programmes already in the pipeline, we feel very confident we will meet our goal of four clinical stage compounds in 2024," said Prof. Hopkins. "Our vision is to change the way drug design, discovery and development is done, as we have shown in our first eight drug candidates. Over the course of 2023, we expect to provide more details on these programmes as well as on our broader internal and partnered pipeline."