On March 21, 2024 Exscientia plc (Nasdaq: EXAI) reported recent advancements in the Company’s pipeline, collaborations and operations, as well as financial results for the fourth quarter and full year 2023, are summarised below (Press release, Exscientia, MAR 21, 2024, View Source [SID1234641325]). Exscientia will host a conference call Thursday, March 21 at 12:30 p.m. GMT / 8:30 a.m. EDT.

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"In 2023, we significantly expanded our technological capabilities with the opening of our automation facility, concentrated our internal research on high value oncology targets and steadily progressed multiple new and existing programmes with our large pharma partners," said Dr. David Hallett, interim Chief Executive Officer and Chief Scientific Officer of Exscientia. "In 2024 we will continue to advance our pipeline programmes through clinical development. This includes GTAEXS617 (‘617), our CDK7 inhibitor currently in a Phase 1/2 clinical trial; LSD1, for which we anticipate initiating a Phase 1 patient study this year; and MALT1, which continues to progress through IND-enabling studies. In addition, we look forward to advancing our partnered programmes through potential milestones, while simultaneously inking new partnerships and expanding our technological capabilities to further cement our leadership in AI-powered drug design and development."

Key Business Highlights

Pipeline

•Patient enrolment is continuing to progress for the dose escalation phase of ELUCIDATE, the adaptive Phase 1/2 trial studying ‘617, a potential best-in-class CDK7 inhibitor, for the treatment of advanced solid tumours. The Company expects to announce a transition from the dose escalation to dose expansion phase in the second half of 2024
•EXS74539 (‘539), a highly differentiated LSD1 inhibitor, is continuing through IND/CTA enabling studies, and the Company anticipates initiating a Phase 1 clinical trial in cancer patients in 2024. ‘539 was precision designed by Exscientia to optimise the therapeutic window by combining reversible binding, brain penetration and a short half-life
•EXS4318 (‘4318), a PKC-theta inhibitor designed by Exscientia and in-licensed by Bristol Myers Squibb for immunology and inflammation indications, is continuing to advance in a Phase 1 study. Exscientia retains rights to receive milestone payments and potential royalties for ‘4318
•EXS73565 (‘565), the Company’s differentiated MALT1 inhibitor, precision designed with selectivity over UGT1A1, is also advancing through IND/CTA-enabling studies. The Company expects to provide further updates in 1H 2024

Collaborations & Partnerships

•In December 2023, the Company announced the addition of an existing Exscientia programme to its Sanofi collaboration
◦Preliminary data shows these compounds have good potency and selectivity towards the target and differentiated molecular properties
◦The addition of this discovery stage programme, identified and initially advanced by Exscientia, includes financial milestones over and above programmes initiated as part of the collaboration agreement
◦Exscientia received a $4 million in upfront payment in the first quarter of 2024 for this programme. The Company is eligible to receive up to an additional $41 million in preclinical milestone payments, as well as over $300 million in further milestone payments if the programme achieves all milestones under the agreement
◦Exscientia is also eligible to receive tiered royalties on sales of products that may be developed from this programme
•In October 2023, Exscientia also announced the achievement of the first discovery stage milestone from a different programme within the Sanofi collaboration
•Exscientia’s collaboration with Merck KGaA, Darmstadt, Germany, initially announced in September 2023, is ongoing, leveraging Exscientia’s precision design capabilities to design and discover novel small molecule drug candidates across oncology and immunology
•In December 2023, Exscientia announced that it had received a $2.3 million grant from Open Philanthropy to drive research on the host-interferon response as a pathway to treating and preventing pandemic influenza
◦Focus aligns with Exscientia’s ongoing commitment to pandemic preparedness, initiated with support from the Bill & Melinda Gates Foundation in 2021

•DSP-2342, a dual 5-HT2A/5-HT7 antagonist designed by Exscientia for Sumitomo Pharma for the treatment of psychiatric diseases, entered Phase I studies in April 2023
•DSP-2342 is the third compound designed by Exscientia that Sumitomo Pharma has advanced into the clinic

Platform

•Exscientia opened its novel automated discovery laboratory in mid-2023. This facility has the capability to integrate AI design methods with chemical synthesis and biological testing. This integration has the potential to bring significant further efficiencies to the drug design process and enhance the rate of learning of Exscientia’s generative design platform
•Exscientia continues to drive the development of its functional precision medicine platform with new studies and collaborations
◦In January 2024, Exscientia launched EXCYTE-2, a multi-centre observational study to evaluate the precision medicine platform in patients with acute myeloid leukaemia. This study has the potential to support the ongoing development of ‘539, Exscientia’s LSD1 inhibitor
◦In July 2023, Exscientia launched EXCYTE-1, a first-of-its-kind prospective observational study in ovarian cancer. This ongoing trial is the first trial evaluating the potential of Exscientia’s functional precision medicine platform in a solid tumour indication
◦The collaboration with Charité – Universitätsmedizin Berlin, announced in March 2023, evaluating Exscientia’s precision medicine platform as a tool to predict response in haematological cancers is also ongoing. This collaboration highlights the scalability of the primary patient tissue platform as Charité will be able to utilise cloud-based AI to analyse samples imaged onsite
•In the fourth quarter of 2023, Exscientia deployed large language models (LLMs) internally for the use of target hypothesis generation. These LLMs, based on both public and proprietary datasets, have been integrated with the Company’s existing target identification infrastructure with the aim to further enhance the productivity of Exscientia’s discovery platform

Investor Call and Webcast Information

Exscientia will host a conference call on Thursday, March 21 at 12:30 p.m. GMT / 8:30 a.m. EDT.
A webcast of the live call can be accessed by visiting the "Investors and Media" section of the Company’s website at investors.exscientia.ai. Alternatively, the live conference call can be accessed by dialling +1 (888) 596 4144 (U.S.), +44 800 358 0970 (U.K.), +1 (646) 968 2525 (International) and entering the conference ID: 8333895. A replay will be available for 90 days under "Events and Presentations" in the "Investors and Media" section of the Exscientia website.

Fourth Quarter and Full Year 2023 Financial Results

For the convenience of the reader, the Company has translated pound sterling amounts to U.S. dollars at the rate of £1.000 to $1.2743, which was the noon buying rate of the Federal Reserve Bank of New York on December 29, 2023.

Revenue: Revenue for the three and twelve months ended December 31, 2023 was $3.1 million and $25.6 million respectively, compared to $8.7 million and $34.7 million for the three and twelve months ended December 31, 2022. The decrease in revenue quarter on quarter and year on year is primarily the result of multiple new programmes starting with partners in the second half of 2023 with revenue recognition constrained by the early nature of these programmes, as well as pipeline prioritisation activities.

Research and development expenses: R&D expenses for the three and twelve months ended December 31, 2023 were $37.5 million and $163.7 million respectively, as compared to $45.4 million and $164.2 million for the same period ended December 31, 2022. The current quarter over quarter decrease in research and development expenses was primarily due to pipeline prioritisation activities and cost efficiency savings, including achieving faster cycle times and lower outsourcing costs.

General and administrative expenses: G&A expenses for the three and twelve months ended December 31, 2023, were $14.8 million, or 24.7% of total operating expenses, and $57.8 million, or 22.5% of total operating expenses respectively. For the three and twelve months ended December 31, 2022, G&A expenses increased by $4.3 million and $8.8 million compared to the three and twelve months ended December 31, 2022, primarily associated with increased personnel expenses.

Cash inflows: For the full year 2023, Exscientia received $27.4 million in cash inflows from its collaborations as compared to $117.8 million during the full year 2022, when the upfront payment for the Sanofi collaboration was received.

Net operating cash flow and cash balance: For the full year ending December 31, 2023, net operating cash outflows were $149.9 million, in comparison to $77.1 million for the full year 2022. Cash, cash equivalents and short term bank deposits as of December 31, 2023 were $462.6 million, as compared to $644.6 million as of December 31, 2022 using the December 29, 2023 constant currency rate.

Based on our current operating plans, the Company believes that its existing cash, cash equivalents and short-term bank deposits and anticipated milestones will be sufficient to fund its operations and capital expenditure requirements well into 2026.

On March 21, 2024 Breakpoint Therapeutics GmbH ("Breakpoint"), a company dedicated to the discovery and development of drugs targeting the DNA Damage Response (DDR), reported that it has nominated its first preclinical development candidate, BTX-011, an inhibitor of polymerase theta (Pol θ / POLQ) with best-in-class potential, for the treatment of solid tumours. IND-enabling activities have already commenced (Press release, Breakpoint Therapeutics, MAR 21, 2024, View Source [SID1234641324]).

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BTX-011 is an oral, highly potent and selective inhibitor of DNA polymerase theta that shows strong and durable in vivo efficacy in relevant cancer models when combined with standard of care PARP inhibitors. Tumour-specific potentiation of drug efficacy is achieved without adding toxicity or detrimental side effects on normal cells. Combining existing therapies with BTX-011 could deliver superior and synergistic tumour cell killing and inhibit the development of therapy resistance. BTX­­­-011 therefore could transform outcomes for cancer patients, through improving the efficacy and duration of therapy response, and providing a potentially curative treatment.

This potential best-in-class preclinical candidate was discovered leveraging Evotec’s fully integrated small molecule drug discovery and development platform. Breakpoint holds all development and commercial rights to the compound.

Dr Daniel Speidel, Managing Director of Breakpoint Therapeutics, commented: "We are proud to announce this important milestone for the company as we deliver the first preclinical development candidate molecule from Breakpoint’s DDR pipeline. From the beginning, Breakpoint’s commitment has been to select only molecules with best-in-class profile and a clear potential to be transformative for cancer therapy. Our polymerase theta inhibitor has these properties, and we look forward to progressing it into the clinic to deliver benefit to patients."

Dr Jonathan Hollick, Managing Director and Head of Research, added: "The nomination of BTX-011 as our first DDR candidate drug is the result of a comprehensive drug discovery effort executed in close collaboration with Evotec. By leveraging our expertise in drugging challenging targets and a suite of technologies within Evotec’s integrated drug discovery framework, we have optimised multiple chemical series, each with different modes of action against pol theta, to select compounds that we believe have unparalleled development potential. Based on the strong, durable antitumour efficacy that BTX-011 has displayed in preclinical cancer models, we are excited to take this step towards the clinic where we can tackle the challenge of therapy resistance in oncology."

Dr Cord Dohrmann, Chief Scientific Officer of Evotec and Advisory Board Member of Breakpoint Therapeutics, commented: "We are very excited to celebrate this milestone, together, with Breakpoint Therapeutics. Since the formation of Breakpoint Therapeutics, there has been strong collaboration to advance early projects through discovery and pre-clinical development. This milestone, marking the progression from target ID to a preclinical development candidate molecule, validates Evotec’s spin-out and virtual operations model. It highlights that the creation aligns well with our strategy of generating upside with an optimal risk-reward profile, advancing highly capital-efficient virtual biotech initiatives with the mission to develop first- and best-in-class drugs, for patients."

On March 20, 2024 Tyligand Bioscience, a clinical-stage biotechnology company dedicated to developing innovative therapeutics against drug resistant tumors, reported its participation at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 5-10, San Diego, where it will present results of preclinical studies of TSN1611 (Poster# 3315), a potent and selective small molecule inhibitor targeting tumors harboring KRAS G12D mutation, a pivotal driver of cancer progression in numerous malignancies (Press release, Tyligand Bioscience, MAR 20, 2024, View Source [SID1234644983]).

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On Feb 14th, an oral formulation of TSN1611 has received clearance from the U.S. Food and Drug Administration (FDA) for clinical trials, an essential step forward in the development of this promising therapy.

"Preclinical studies indicate that TSN1611 has the potential to make a meaningful difference in the lives of patients with KRAS G12D driven cancers, and we are excited to share our findings with the scientific and medical community," said Tony Zhang, Ph.D., CEO of Tyligand Bioscience. "We remain committed to advancing its development with quality and speed for the global cancer patients in need".

KRAS mutations are among the most prevalent oncogenic alterations in cancer patients, with the G12D mutation being one of the most challenging to target effectively. Despite significant advances in cancer research and therapy, KRAS-driven cancers present a substantial unmet medical need, underscoring the urgency for innovative treatment options.

The preclinical data to be presented by Tyligand Bioscience at AACR (Free AACR Whitepaper) 2024 demonstrates the promising efficacy and safety profile of TSN1611 in inhibiting KRAS G12D. FDA’s IND approvals marks the achievement of an important milestone in advancing TSN1611 towards clinical evaluations for its safety and efficacy.

On March 20, 2024 Clasp Therapeutics, a biotechnology company bringing unparalleled precision to immuno-oncology using next-generation T cell engagers (TCEs), reported to have launched with $150 million in financing (Press release, Clasp Therapeutics, MAR 20, 2024, View Source [SID1234641311]).

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The round was led by Catalio Capital Management, Third Rock Ventures and Novo Holdings, with participation from Vivo Capital, Cure Ventures, Blackbird BioVentures, Pictet Alternative Advisors, American Cancer Society’s Bright Edge and Alexandria Venture Investments. Clasp is developing modular TCEs tailored to each patient’s immune system that are directed to common oncogenic driver mutations, resulting in off-the-shelf, antibody-like medicines that can specifically target a wide variety of hard-to-treat tumor types.

"At Clasp we strive to help people with cancer lead longer and healthier lives by engaging each patient’s own immune cells to eradicate their cancer with absolute specificity," said Chief Executive Officer Robert Ross, M.D. "Clasp brings together leading researchers, clinicians and drug developers to develop groundbreaking cancer immunotherapies that are precise and potent, but without the toxicities commonly associated with on-target, off-tumor binding."

Clasp is leveraging advances made by its scientific founders at Johns Hopkins University, including leading cancer geneticist and HHMI investigator Bert Vogelstein, M.D., and immuno-oncology pioneer Drew Pardoll, M.D., Ph.D., who have envisioned a new approach to single out cancer cells for destruction by the immune system. The researchers’ structure-driven understanding of human leukocyte antigen (HLA)-antibody interactions enables the engineering of advanced TCEs that can precisely target common oncogenic mutations with exquisite specificity.

"We have the ability to redirect T cells to kill cancer cells while sparing healthy cells throughout the body," said Andrea Van Elsas, Ph.D., Partner at Third Rock Ventures and Chief Scientific Officer at Clasp. "Clasp’s proprietary technology enables immune targeting of intracellular oncogenic driver mutations to achieve durable tumor killing, even with low levels of surface presentation. Furthermore, the modularity of Clasp’s TCE platform gives it potential to address unmet need across a broad range of hard-to-treat tumor types."

Clasp’s TCEs are bispecific antibody-like molecules designed to simultaneously bind both a T cell and a tumor-specific mutant peptide, presented in the context of the patient’s HLA immune signature. A key aspect of this approach is Clasp’s ability to select patients for treatment by focusing on common tumor-specific driver mutations, including many that are unresponsive to standard immunotherapies. By binding both the T cell and the tumor cell with absolute specificity, this approach ensures immune activation against the tumor itself while sparing normal tissue, which lacks the tumor-specific mutated peptide.

"Clasp’s novel technology has tremendous potential to help the many cancer patients who are unable to benefit from existing treatments," said Jacob Vogelstein, Ph.D., and George Petrocheilos, Managing Partners of Catalio Capital Management. "We are excited to partner with Third Rock Ventures, Novo Holdings and the other members of the syndicate to support the company and advance immuno-oncology into a new era."

As part of the financing, Ray Camahort, Partner in the Venture Investments group at Novo Holdings U.S., and Jack Nielsen, Managing Partner of Vivo Capital, joined the Board of Directors.

On March 20, 2024 Agendia, Inc. reported new data from the I-SPY 2 trial showcasing its ImPrint signature for patients with triple negative (TN) breast cancer, shared by I-SPY 2 researchers in an oral presentation at the 14th European Breast Cancer Conference in Milan, Italy (Press release, Agendia, MAR 20, 2024, View Source [SID1234641310]). Agendia has been in partnership with Quantum Leap Healthcare Collaborative, the sponsors of the neoadjuvant biomarker-rich I-SPY 2 trial, since 2010. I-SPY 2 established a new benchmark for the efficacy of Phase 2 clinical trials and is widely regarded as the pioneer of the platform trial.

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The presentation, titled Immune subtyping in the Response Predictive Subtypes (RPS) identifies a subset of triple negative (TN) early-stage breast cancer patients with a very low likelihood of response to neoadjuvant immunotherapy (IO): results from 5 IO arms of the I-SPY 2 TRIAL (van ’t Veer, L, J., et al.), investigates the utility of a refined version of ImPrint, called ImPrintTN, designed to provide more accurate predictions to response to common immunotherapy (IO) regimens for TN patients. The study, examining the responses of patients who received a variety of IO regimens in the I-SPY 2 trial, showed that ImPrintTN predicts both response and non-response, suggesting that the test may help inform prioritization of IO versus other treatments for TN patients to best balance likely benefit versus the risk of the serious adverse effects that often accompany IO.

"Many immunotherapy treatments can have difficult, severe adverse side effects on patients that can outweigh the benefit of the treatment. It is imperative to understand what a patient’s response will be to these therapies prior to using them," said Laura van ‘t Veer, Professor of Laboratory Medicine, Co-leader of the Breast Oncology Program and Director of Applied Genomics at the Helen Diller Family Comprehensive Cancer Center, University of California, and Co-Founder of Agendia, Inc. "The data we are presenting at the European Breast Cancer Conference demonstrates ImPrintTN’s predictive ability to help patients with triple negative breast cancer avoid immunotherapy if they are not likely to benefit – these insights are critical and can be used to inform alternative treatment strategies and customize our approach to meet the needs of each patient’s cancer diagnosis."

ImPrint was developed to be used in the clinic to predict the likelihood of patients responding to immunotherapies by looking at the biology of the patient’s tumor. Agendia currently holds an FDA Investigational Device Exempt status for the ImPrint signature, allowing for its use in the I-SPY 2 trial and for other ongoing research with collaborators.

About the I-SPY TRIALs

The I-SPY TRIAL (Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular analysis 2) (I-SPY 2 TRIAL) was designed to rapidly screen promising experimental treatments and identify those most effective in specific patient subgroups based on molecular characteristics (biomarker signatures). The trial is a unique collaborative effort by a consortium that includes the Food and Drug Administration (FDA), industry, patient advocates, philanthropic sponsors, and clinicians from over 40 major U.S. cancer research centers. Under the terms of the collaboration agreement, Quantum Leap Healthcare Collaborative is the trial sponsor and manages all study operations. For more information, visit www.ispytrials.org.