PGE2

HTL0039732 (also known as NXE0039732) is Nxera’s novel oral EP4 antagonist with the potential to treat a wide range of cancers in combination with other immunotherapies Cancer Research UK’s Centre for Drug Development is sponsoring and managing the ongoing Phase 1/2a clinical trial of HTL0039732 13 September 2024 – Nxera Pharma (TSE: 4565, “Nxera”) and Cancer Research UK announce an upcoming presentation on the ongoing Phase 1/2a clinical trial (NCT05944237) of Nxera’s immunotherapy drug HTL0039732 (also known as NXE0039732) at the European Society for Medical Oncology Congress (ESMO) 2024, taking place on 13–17 September in Barcelona, Spain. The trial’s co-chief investigator, Dr. Debashis Sarker from Guy's and St Thomas’ NHS Foundation Trust, will present a “Trial in Progress1” poster at ESMO 2024 on Saturday 14 September (presentation 679TiP, available on the ESMO website here). The first-in-human trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of HTL0039732 as a monotherapy and in combination with the checkpoint inhibitor atezolizumab, in patients with advanced solid tumors. HTL0039732 is an oral small molecule drug candidate that was rationally designed using Nxera’s NxWave™ platform and evaluated through rigorous translational and preclinical studies. HTL0039732 works by blocking signaling through a specific type of prostaglandin receptor, the prostaglandin E2 (PGE2)-type prostanoid receptor 4 (EP4). PGE2 acts in the tumor microenvironment to trigger cancer cells to evade the immune system. Targeting EP4 to block the effects of PGE2 increases the ability of the immune system to detect and control cancer cells and makes HTL0039732 a potential candidate to treat patients with cancers that generally do not respond well to current immunotherapies. Cancer Research UK’s Centre for Drug Development is sponsoring and managing the trial, which is led by chief investigator Dr Bristi Basu, University of Cambridge, and Dr Sarker. The first patient was dosed in August 2023 and the trial is currently open for recruitment at Addenbrooke’s Hospital in Cambridge, Guy’s Hospital in London, and the Christie Hospital in Manchester. Dr. Debashis Sarker says: “We are excited to present this ‘Trials in Progress’ poster at ESMO, outlining the scientific rationale and design of the clinical trial of HTL0039732, given alone and in combination with immunotherapy for patients with advanced solid cancers. HTL0039732 targets an important protein within the tumor immune microenvironment called EP4, triggering cancer cells to evade the immune system. Targeting EP4 potentially increases the ability of the immune system to detect and control cancer cells. Enrolment to the trial began in the UK in August 2023 and is ongoing across multiple cancer types. “We are hopeful that this trial will identify a novel way to target the immune system and improve treatment options for patients with a range of different solid cancers.” Nxera Pharma (formerly Sosei Heptares) is a technology powered biopharma company, in pursuit of new specialty medicines to improve the lives of patients with unmet needs in Japan and globally. In addition to several products being commercialized in Japan, we are advancing an extensive pipeline of over 30 active programs from discovery through to late clinical stage internally and in partnership with leading pharma and biotech companies. This pipeline is focused on addressing major unmet needs in some of the fastest-growing areas of medicine across neurology, GI and immunology, metabolic disorders and rare diseases, and leverages the power of our unique and industry leading GPCR-targeted structure-based drug discovery “NxWaveTM” platform to provide a sustainable source of best- or first-in-class candidates. Nxera employs over 350 talented people at key locations in Tokyo and Osaka (Japan), London and Cambridge (UK), Basel (Switzerland) and Seoul (South Korea) and is listed on the Tokyo Stock Exchange (ticker: 4565). Cancer Research UK has an impressive record of developing novel treatments for cancer. The Cancer Research UK Centre for Drug Development has been pioneering the development of new cancer treatments for 30 years, taking over 160 potential new anti-cancer agents into clinical trials in patients. Six of these new agents have made it to market, including temozolomide for brain cancer, abiraterone for prostate cancer and rucaparib for ovarian cancer. Two other drugs are in late development Phase 3 trials. Thirteen agents remain in active development with the potential to reach the market. It currently has a portfolio of 16 projects in preclinical development, Phase 1 or early Phase 2 clinical trials. www.cruk.org.uk/cdd 1 A “Trial in Progress” presentation describes the rationale behind and design of a clinical trial. No data will be presented. The content above comes from the network. if any infringement, please contact us to modify.

A new study has discovered how a lipid molecule found at high levels within tumors undermines the anti-cancer immune response and compromises a recently approved immunotherapy known as adoptive cell therapy (ACT) using tumor infiltrating lymphocytes, or TIL-ACT. A Ludwig Cancer Research study has discovered how a lipid molecule found at high levels within tumors undermines the anti-cancer immune response and compromises a recently approved immunotherapy known as adoptive cell therapy (ACT) using tumor infiltrating lymphocytes, or TIL-ACT. In this individualized cell therapy, TILs -- CD8+ T cells that kill cancer cells -- are expanded in culture from a patient's tumor samples and reinfused into the patient as a treatment. Researchers led by Ludwig Lausanne's Matteo Morotti, Alizee Grimm, Denarda Dangaj Laniti and Director George Coukos report in the current issue of Nature their discovery -- based on analyses of data and samples collected in TIL-ACT clinical trials -- of the mechanism by which the lipid, prostaglandin E2 (PGE2), poisons TIL metabolism to serve as a checkpoint against their anti-tumor activity. They also show that disrupting that mechanism during the cell culture processes employed in TIL-ACT dramatically improves the therapeutic potential of transferred TILs in mouse models of cancer. A companion study led by researchers at the Technical University of Munich, done using mouse models of cancer, confirms the Ludwig Lausanne team's findings and appears in the same issue of Nature. Several researchers share authorship of both papers. "These findings have important implications for cancer immunotherapy in general, as they identify a novel and eminently targetable checkpoint against the function of infiltrating cytotoxic T cells in the tumor microenvironment," said Coukos. "More immediately, we can now complete the circle here at Lausanne: we have harnessed the data and materials obtained from TIL-ACT trials in humans to advance our understanding of tumor immunology and can now apply what we have learned to improve outcomes for patients undergoing such therapies. This is a key element of our strategy -- and of Ludwig's overall mission." The Ludwig Lausanne researchers began by examining gene expression data collected from T cells isolated from patients for TIL-ACT. Their analysis revealed that the TILs that already bore markers of response to interleukin-2 (IL-2) -- a factor essential to functional vitality and proliferation of T cells -- were the ones that expanded best in culture. The researchers also tracked the growth in culture of 215 individual tumor-reactive TILs that respond to IL-2, which is a key component of TIL cultures, and showed that this is indeed the case. Further examination of gene expression data collected from clinical trial samples revealed that TILs that responded poorly to IL-2 expressed relatively large numbers of receptors for PGE2 on their surfaces. In line with that finding, anti-cancer TILs from tumor fragments that had high levels of PGE2 were found to expand poorly in culture. To explore how PGE2 compromises TIL-ACT, the researchers began by identifying a signature of gene expression associated with PGE2's effects on T cells. "We found that patients' tumor-reactive TILs that bore this PGE2 signature expanded very poorly in culture, and that these TILs were often in states that would otherwise be essential to therapeutic responses," said Morotti. "Further, corresponding clinical trial data revealed that the melanoma patients whose TILs bore that signature had responded poorly to TIL-ACT therapy." The researchers next probed how PGE2 exerts its effects on TILs. They found that the lipid, acting through its receptors (EP2 and EP4), disrupts the ability of T cells to sense and respond to IL-2 by monkeywrenching the assembly of the IL-2 receptor's component proteins. The resulting loss of IL-2 stimulation initiates a cascade of biochemical events in the cells that culminates in profound metabolic dysfunction, inducing a functional lethargy in the TILs known as "anergy" and ultimately triggering ferroptosis, a type of programmed cell death. The researchers also examined whether blocking PGE2 could overcome these effects. "By adding a drug that inhibits PGE2 production to the TIL culture medium we restored the ability of TILs to respond to IL-2 and improved the expansion of tumor-reactive TILs more than two-fold," said Grimm. "Small molecules that block PGE2 interaction with its receptors had a similar effect. These studies not only confirmed our hypothesis but also identify a means to swiftly translate our findings for clinical application." The researchers show that, grown in the presence of PGE2 inhibitor, tumor-reactive TILs become responsive to IL-2 once again and show signs of renewed metabolic fitness and functional vitality. These TILs prevented cancer cells taken from the tumors they previously inhabited from forming new tumors in mice, while the same TILs grown sans PGE2-inhibitor did not. The revitalized TILs were also better agents of TIL-ACT therapy in a mouse model. The companion study in Nature, led by the Jan Böttcher lab in Munich, confirms the findings of this study in mouse models of cancer. It also shows that the inhibition of IL-2 signaling in TILs occurs within the microenvironment of tumors. Engagement of the PD-1 checkpoint on T cells, which is currently targeted by several immunotherapies, is by contrast thought to occur mainly in the lymph nodes around tumors. "When we learned we were working on essentially the same problem, we decided to combine our efforts and publish our shared discoveries as back-to-back publications in the same journal," said Dangaj Laniti. "That spirit of cooperation, rather than the usual, fierce competition, has borne fruit in the discovery of a previously unknown immune checkpoint in tumors that is mechanistically distinct from the PD-1 checkpoint that cancers exploit to foil anti-tumor T cells. It has been very gratifying to be a part of this partnership, whose discoveries will surely be of great benefit to cancer patients." In addition to their posts at Ludwig Lausanne, George Coukos directs the Department of Oncology at the Lausanne University Hospital (UNIL CHUV) and codirects the Swiss Cancer Center Léman and Denarda Dangaj Laniti is the Head of the Tumor Microenvironment and Biomarker Discovery Lab at Ludwig Lausanne. This study was supported by Ludwig Cancer Research, Swiss Cancer League Foundation, the German Research Foundation and grants from the Biltema Foundation, Paul Matson Foundation and Cancera Foundation.

Press Release Poster October 23, 2023 Monza (Italy) – Rottapharm Biotech announces favourable clinical results of CR6086, its potent and selective small molecule antagonist of the prostaglandin EP4 receptor, combined with the anti PD-1 antibody balstilimab (Agenus Inc, Nasdaq: AGEN) in advanced colorectal cancer (CRC). Study results have been presented at the European Society for Medical Oncology (ESMO) annual congress in Madrid, Spain, held from October 20-24, 2023. Patients with CRC have limited treatment options, given the aggressive behaviour of their tumours. In fact, more than 80% of CRC is classified as mismatch-repair-proficient (pMMR) and microsatellite stable (MSS), which correlates with low tumour mutation burden and poor immune cell infiltration in the tumour microenvironment (TME), and they are therefore classified as immunologically “cold” tumors. These patients generally do not benefit from Immune Checkpoint Inhibitors (ICIs) and combination strategies are needed to address immunosuppression in the TME and improve sensitivity to ICIs. The involvement of prostaglandin E2 (PGE2) in cancerogenesis has been known for decades. “PGE2, through its EP4 receptor, is a major contributor to immunosuppression in the TME and blockade of this pathway may sensitize cold tumors to ICIs.” said Dr. Lucio Rovati, CEO and CSO at Rottapharm Biotech. “CR6086 is designed to increase the activity and infiltration of several different immune cell types while reversing the immunosuppressive role of PGE2 in the TME. CR6086 is a potential best-in-class EP4 receptor antagonist and has demonstrated a strong safety profile in >250 subjects treated to date.” added Dr. Lucio Rovati. The Phase 1/2 clinical study, conducted at the National Cancer Institute (Istituto Nazionale dei Tumori) in Milan (Italy), evaluated the safety and efficacy of CR6086 combined with balstilimab in 28 patients with advanced pMMR/MSS metastatic CRC. The trial met the designated primary endpoint, with a disease control rate (DCR) of 50% associated with good safety. A DCR of 25% was observed in the difficult to treat subgroup of patients with liver metastases. The overall objective response rate (ORR) was 11%, with 3 patients having partial response (PR): one durable PR is ongoing (>1 year) in a patient with liver metastases. Disease control for all the 11 patients with stable disease lasted ≥ 12 weeks, and for 5 patients lasted ≥ 24 weeks. At a median follow-up of 8 months, the median progression-free survival (PFS) and overall survival (OS) were 2.6 months (CI 95% 1.7-3.6) and 13.7 months (CI 95% 8.8-not reached), respectively. A study expansion in other gastrointestinal tumors is ongoing. “Given the promising results, we are committed to progress CR6086 development in a randomized Phase 2 study in pMMR/MSS metastatic CRC and we look forward to advancing discussions with potential partners” concluded Dr. Lucio Rovati. Rottapharm Biotech Rottapharm Biotech is a research company dedicated to the discovery and development of innovative drugs. It is located in Monza (Italy). The company expertise in research and development includes medicinal/computational chemistry for small molecules, development of biologics and advanced therapies, new targets validation, pharmacological and pharmacokinetic characterization of new drug candidates, original formulations, and design of innovative clinical trials. The company strategy is to develop its own pipeline independently and then seek partnerships with pharmaceutical companies, as well as investing in alliances on innovative projects of other biotech companies or university spin-offs. Rottapharm Biotech Contact Federica Girolami, Business Development Director Tel. +39 346 4131428 federica.girolami@rottapharmbiotech.com About Agenus Agenus is a leading immuno-oncology company targeting cancer and infectious diseases with a comprehensive pipeline of immunological agents. The company’s mission is to expand patient populations benefiting from cancer immunotherapy through combination approaches, using a broad repertoire of antibody therapeutics, adoptive cell therapies (through MiNK Therapeutics) and adjuvants (through SaponiQx). Agenus is headquartered in Lexington, MA. For more information, visit www.agenusbio.com or @agenus_bio. Information that may be important to investors will be routinely posted on our website and social media channels. About balstilimab Balstilimab (Agenus, Inc.) is an investigational monoclonal antibody inhibitor of programmed cell death 1 (PD-1) protein. It has been evaluated in >900 patients to date and has demonstrated strong clinical activity and an excellent safety profile in several tumour types. Agenus Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding clinical development and regulatory plans and timelines, anticipated corporate milestones, new clinical data and program updates to be presented. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. Agenus Inc. Media 781-674-4784 communications@agenusbio.com