Dedifferentiated Liposarcoma

This announcement contains inside information for the purposes of Article 7 of the UK version of Regulation (EU) No 596/2014 which is part of UK law by virtue of the European Union (Withdrawal) Act 2018, as amended ("MAR"). Upon the publication of this announcement via a Regulatory Information Service, this inside information is now considered to be in the public domain. 14 September 2024 Avacta Group plc (“Avacta” or “the Group” or “the Company”) Avacta Reports Updated Phase 1 Clinical Data of AVA6000 at the European Society for Medical Oncology (ESMO) Congress Demonstrating Multiple Ongoing, Durable Responses in Solid Tumors AVA6000 is safe and well-tolerated in both study arms: every three weeks (Q3W) and every two weeks (Q2W) dosing, with an early lack of serious cardiac safety signal and preliminary evidence of efficacy Multiple ongoing and durable RECIST responses observed in patients with FAPhigh and doxorubicin sensitive diseases including in patients with stroma-only expression of FAP pre|CISION-enabled doxorubicin (AVA6000) results in multiple fundamental changes in the pharmacokinetics of released doxorubicin in plasma and tumor versus conventional doxorubicin Avacta Group plc (AIM: AVCT), a life sciences company developing innovative, targeted cancer treatments and powerful diagnostics, is today presenting updated data from the ongoing Phase 1a trial of AVA6000 in patients with FAP-positive solid tumors at the 2024 European Society for Medical Oncology (ESMO) Congress, in Barcelona, Spain. The results demonstrate that AVA6000 is well-tolerated across the every 2 weeks and every 3 weeks dosing schedules with early evidence of efficacy supported by ongoing and durable RECIST responses in patients with FAPhigh disease. AVA6000 is the first peptide drug conjugate (PDC) in the Avacta pipeline and consists of doxorubicin conjugated with a peptide moiety that is specifically cleaved by Fibroblast Activation Protein (FAP) in the tumor microenvironment (TME). Professor Chris Twelves, Lead Investigator and Professor of Medicine, University of Leeds, commented: "The AVA6000 data presented at ESMO continue to demonstrate encouraging efficacy with several ongoing, durable responses. The observed efficacy aligns with a highly favorable safety profile including a lack of the significant cardiac toxicity that is often seen with doxorubicin treatment. “The mechanism of action of the pre|CISION™ peptide drug conjugates with the observed warhead release in tumors with lower FAP activity together speak to the potential of this platform to treat a broad range of solid tumor patient populations with clinical needs that are not being met. I am looking forward to working with the Company, colleagues and patients on the continued development of AVA6000." Christina Coughlin MD, PhD, Chief Executive Officer of Avacta, added: “With nearly six months of added follow-up, these compelling data strengthen the clinical validation for AVA6000 and the pre|CISIONTM drug delivery platform to challenge current drug delivery methods and expand the reach of highly potent therapeutics using peptide drug conjugates. “We believe our platform has the potential to revolutionize cancer treatment by enabling patients to achieve improved outcomes with fewer side effects by leveraging the tumor specific enzyme FAP to protect normal tissues from toxic drugs. The observation of warhead release in the tumor even in the setting of lower FAP activity is highly encouraging for our pipeline. We are excited to move our Company into the next stage of development, implementing these findings of this drug release mechanism across our innovative pipeline.” Trial Results Summary As at the latest data cut-off date, ten dose cohorts (n=57) have completed the Phase 1a trial under the Arm 1 dosing schedule of every three weeks (“Q3W”) and the Arm 2 dosing schedule of every two weeks (“Q2W”). In total, 57 patients were enrolled and are evaluable for safety (primary outcome measure) and 49 patients formed the efficacy evaluable dataset (secondary outcome measure). Efficacy data Cancer indications were categorized based on published data regarding both immunohistochemistry and FAPI-PET studies as FAPhigh (soft tissue sarcoma and salivary gland cancer) or FAPmid (pancreatic cancer, colorectal cancer, lung cancer and other malignancies). Patients with indications considered FAPlow were excluded from the trial. Patients had a median of two prior systemic cancer therapies (range 0-7) with 65% including cytotoxic exposure. Reduction in the sum of longest diameters (SLD) is used to measure response per RECIST 1.1 with partial responses of >30% reduction and minor responses of between >10% and <30% reduction. Among patients with FAPhigh cancers (n=23), three partial responses and four minor responses were observed, including: A durable, confirmed partial response at 12 weeks in a 79-year-old male patient with progressive salivary gland cancer (SGC). After an initial minor response (22% reduction in SLD), the observed durable PR is ongoing despite patient discontinuation due to lifetime maximum dosing (duration of response >18 weeks, with 46.2% reduction in SLD). Tumor histology demonstrates no expression of FAP in tumor cells with only stromal cell expression noted.A minor response (14.6% reduction in SLD at first 8-week scan) in a 65-year-old female patient with SGC who remains on the trial. This patient was dosed in the 250 mg/m2 Q2W cohort of the trial and had progression on a prior line of therapy. This patient continues on study. Similarly, the histology shows FAP-negative tumor cells and FAP expression only in the stromal compartment.A partial response (40.5% reduction in SLD) in a 55-year-old male patient with dedifferentiated liposarcoma who had progressed on two prior lines of therapy in the metastatic setting. After an initial minor response this patient experienced a partial response with SLD change of -40.6%. The patient experienced new lesions at their latest follow-up scan. Eight patients remain on study in the Phase 1a cohorts with a diagnosis of FAPhigh cancers Among patients with FAPmid cancers (n=26), two minor responses were observed. Safety and Pharmacokinetics Data Treatment with AVA6000 continues to be well-tolerated with the addition of the Q2W dosing regimen (Arm 2) with a favorable safety profile and reduction in severe and mild-to-moderate treatment-emergent toxicities as compared with conventional dose doxorubicin. A maximum tolerated dose has not been identified in either arm of the trial. Severe (CTCAE grade 3 or 4) neutropenia was observed in 14% of AVA6000 patients vs 49% treated with conventional dose doxorubicin (comparison made to a Ph III trial where doxorubicin monotherapy is the comparator arm in a similar patient population).1 There were no cases of febrile neutropenia in the AVA6000 trial compared to 16.5% of patients receiving conventional doxorubicin alone in a similar patient population1 The observed cardiac safety profile of AVA6000 compares favorably to conventional dose doxorubicin, with low incidence of left ventricular ejection fraction (LVEF) changes (LVEF dysfunction 12.3% v. 48.4% with conventional doxorubicin1,2) and no grade 3 or 4 severe cardiac events reportedReductions were observed in toxicities that impact quality of life including nausea, mouth sores, decreased appetite, constipation and vomiting and similar reductions were observed with both the Q3W and Q2W dosing schedules.as compared to conventional doxorubicin dosing1No new dose limiting toxicities were observed and neither arm has determined an MTD Treatment with AVA6000 results in multiple fundamental changes in the PK of released doxorubicin (compared to conventional doxorubicin administration3) including: Extension of the plasma half-life by ~40% Reduction of approximately 40-50% in both Cmax and the peripheral volume of distribution, suggesting AVA6000-released doxorubicin demonstrates a more limited distribution into normal tissues versus conventional doxorubicin4,5 Tumor biopsies taken 24 hours after the first dose of AVA6000 reveal additional insights regarding the role of FAP, in that the level of FAP positivity in the tumor appears not to correlate with the level of released doxorubicin in the TME (n=9). This lack of correlation indicates that lower levels of FAP activity are sufficient for warhead release. These data provide evidence for targeting of the FAPmid tumor types with novel warheads. pre|CISIONTM technology Many solid tumors have higher levels of FAP compared with healthy tissues. Avacta’s pre|CISIONTM technology is designed to leverage the tumor-specificity of FAP expression by rendering a therapeutic warhead inert with the bound peptide moiety attached to the warhead, until it encounters FAP and is cleaved, releasing active warhead into the TME. FAP targeted release of the warhead specifically in the TME aims to reduce damage to healthy tissues and systemic side effects, improving the tolerability for patients and allowing optimization of the dosing schedule to improve efficacy. References1Tap WD, et al. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial. JAMA. 2020;323(13):1266-1276. doi: 10.1001/jama.2020.17072Jones, RL et al. Prospective evaluation of doxorubicin cardiotoxicity in patients with advanced soft tissue sarcoma in the ANNOUNCE Phase III randomized trial. Clin Ca Res 2021;27:3751-66. doi: 0.1158/1078-0432.CCR-20-4592 3Villalobos VM, et al. Pharmacokinetics of doxorubicin following concomitant intravenous administration of olaratumab (IMC-3G3) to patients with advanced soft tissue sarcoma. Cancer Med. 2020;9(3):882-893. doi: 10.1002/cam4.27284Kontny N et al, Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years, Cancer Chemother Pharmacol 2013;71(3):749-63. doi: 10.1007/s00280-013-2069-15Pérez‐Blanco JS et al, Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non‐Hodgkin's lymphoma, Br J Clin Pharmacol. 2016; 82(6): 1517–1527 -Ends- For further information from Avacta Group plc, please contact: Avacta Group plcChristina Coughlin, CEOMichael Vinegrad, Group CommunicationsDirector Tel: +44 (0) 1904 21 7070www.avacta.com Peel Hunt (Nomad and Broker)James Steel / Chris Golden / Patrick Birkholm www.peelhunt.com ICR ConsiliumMary-Jane Elliott / Jessica Hodgson / Sukaina Virji avacta@consilium-comms.com About Avacta Group plc - www.avacta.com Avacta Group is a UK-based life sciences company focused on improving healthcare outcomes through targeted cancer treatments and diagnostics. Avacta Therapeutics: a clinical stage oncology biotech division harnessing proprietary therapeutic platforms to develop novel, highly targeted cancer drugs. Avacta Diagnostics focuses on supporting healthcare professionals and broadening access to diagnostics. Avacta has two proprietary platforms, pre|CISION™ and Affimer®. The pre|CISION™ platform is a highly specific substrate for fibroblast activation protein (FAP) which is upregulated in most solid tumors compared with healthy tissues. The pre|CISION™ platform harnesses this tumor specific protease to activate pre|CISION™ peptide drug conjugates and pre|CISION™ antibody/Affimer® drug conjugates in the tumor microenvironment, reducing systemic exposure and toxicity, allowing dosing to be optimised to deliver the best outcomes for patients. The lead pre|CISION™ program AVA6000, a peptide drug conjugate form of doxorubicin, is in Phase 1 studies. It has shown an improvement in safety and tolerability in clinical trials to date compared with standard doxorubicin and preliminary signs of clinical activity in multiple patients. To register for news alerts by email go to www.avacta.com/investor-news-email-alerts

LEXINGTON, Mass.--( BUSINESS WIRE )--Agenus Inc. (“Agenus”) (Nasdaq: AGEN), a leader in developing novel immunological agents to treat various cancers, presented data today at the European Society for Medical Oncology (ESMO) Congress held in Barcelona, Spain. The data from a Phase 1 study of botensilimab (BOT), an investigational Fc-enhanced CTLA-4 inhibitor, in combination with balstilimab (BAL), an investigational PD-1 antibody, showed clinical activity in patients with refractory sarcomas, a population with limited treatment options. "The continued activity with additional patients and longer follow-up of BOT/BAL in this study reinforces it's potential as an important treatment option for patients with sarcomas," said Dr. Breelyn A Wilky, University of Colorado Cancer Center. "The deep and durable responses we are observing, particularly in late line patients with poorly immunogenic or ‘cold’ sarcomas like visceral angiosarcoma, leiomyosarcoma, and dedifferentiated liposarcoma, are significant. These findings highlight the potential of BOT/BAL to deliver extended survival and a meaningful clinical benefit for patients who previously had very limited options." Study Highlights 64 patients with relapsed/refractory sarcomas (median of 3 prior lines of therapy) were treated with 1 or 2 mg/kg BOT + 3 mg/kg BAL. 52 patients were efficacy evaluable with at least one post-baseline 6-week imaging scan. ORR and DOR reporting will be based on the unconfirmed response in this cohort. Majority of sarcoma subtypes included angiosarcoma (39%) and leiomyosarcoma (34%). Clinical Findings 23% overall response rate (ORR) was observed in the full sarcoma cohort, with a median duration of response (DOR) of 21.7 months. 12-month overall survival (OS) was 69% and the median OS was not reached. 39% ORR achieved in the angiosarcoma subtype (33% in cutaneous and 44% in visceral), with a median DOR of 21.7 months. 12-month OS was 64% and the median OS was not reached. A representative patient with visceral angiosarcoma achieved a durable response, ongoing beyond 3 years, that has been maintained off-therapy. The adverse event profile of BOT+ BAL was manageable and reversible with no new safety signals identified. "The updated sarcoma data presented at ESMO underscore the transformative potential of botensilimab and balstilimab for patients with refractory sarcomas who have exhausted other treatment options," said Dr. Steven O’Day, Chief Medical Officer at Agenus. "Seeing these metastatic sarcoma patients experience tumor reduction, with significant and durable responses is incredibly encouraging. BOT/BAL not only offers hope to patients with sarcoma but also holds promise for redefining the standard of care across other historically IO-resistant cancers." The presentation is available on the Agenus website at https://agenusbio.com/publications . About Botensilimab Botensilimab is an investigational human Fc enhanced CTLA-4 blocking antibody designed to boost both innate and adaptive anti-tumor immune responses. Its novel design leverages mechanisms of action to extend immunotherapy benefits to “cold” tumors which generally respond poorly to standard of care or are refractory to conventional PD-1/CTLA-4 therapies and investigational therapies. Botensilimab augments immune responses across a wide range of tumor types by priming and activating T cells, downregulating intratumoral regulatory T cells, activating myeloid cells and inducing long-term memory responses. Approximately 1,100 patients have been treated with botensilimab in phase 1 and phase 2 clinical trials. Botensilimab alone, or in combination with Agenus’ investigational PD-1 antibody, balstilimab, has shown clinical responses across nine metastatic, late-line cancers. For more information about botensilimab trials, visit www.clinicaltrials.gov with the identifiers NCT03860272, NCT05608044, NCT05630183, and NCT05529316. About Agenus Agenus is a leading immuno-oncology company targeting cancer with a comprehensive pipeline of immunological agents. The company was founded in 1994 with a 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 has robust end-to-end development capabilities, across commercial and clinical cGMP manufacturing facilities, research and discovery, and a global clinical operations footprint. 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. 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 its botensilimab and balstilimab programs, expected regulatory timelines and filings, and any other statements containing the words "may," "believes," "expects," "anticipates," "hopes," "intends," "plans," "forecasts," "estimates," "will," “establish,” “potential,” “superiority,” “best in class,” and similar expressions are intended to identify forward-looking statements. 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 Annual Report on Form 10-K for 2023, and subsequent Quarterly Reports on Form 10-Q 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.

On July 29, Boehringer Ingelheim announced a major acquisition, with plans to buy Nerio Therapeutics for $1.3 billion. Nerio Therapeutics, a pharmaceutical company focused on phosphatase research, has successfully developed highly selective phosphatase PTPN2/N1 inhibitors for an innovative regimen of tumor immunotherapy. With a leading position in the global oncology market, Boehringer Ingelheim has continuously strengthened its strategic presence in oncology in recent years. According to preliminary statistics, the company has established cooperative relationships with a number of well-known pharmaceutical companies in recent years to accelerate the construction of tumor research and development pipelines: In December 2020, Boehringer Ingelheim acquired NBE Therapeutics for 1.18 billion euros to acquire novel antibody-coupled drugs to address the challenge of refractory solid tumors. In the same month, Boehringer Ingelheim acquired Labor Dr. Merk & Kollegen to increase its research and development and clinical manufacturing capabilities to support its next generation cancer immune drug development program. In January 2021, the company entered into a strategic partnership with Enara Bio to develop innovative cancer immunotherapies using its Dark Antigen™ platform. In September 2021, Boehringer Ingelheim acquired Abexxa Biologics to gain expertise in targeting cancer-specific proteins within cells, expanding the range of potential cancer antigen targets. In June 2022, the company entered into A global licensing agreement with the Agency for Science, Technology and Research of Singapore (A*STAR) to acquire the development and commercialization rights for A*STAR's series of innovative tumor-specific antibodies. In January 2023, Boehringer Ingelheim and 3T Biosciences entered into a strategic collaboration and licensing agreement to jointly explore and develop the next generation of cancer therapies. In March 2023, the company partnered with Covant Therapeutics to develop a covalent drug candidate for the ADAR1 cancer target. In November 2023, Boehringer Ingelheim acquired T3 Pharmaceuticals for CHF 450 million (approximately $508 million), which specializes in innovative therapeutic platforms that enhance immunotherapy with live bacteria. In the same month, Boehringer Ingelheim established a strategic collaboration and licensing agreement with Phenomic AI to jointly discover key targets in rich stromal cancers. In February 2024, Boehringer Ingelheim and CBmed entered into a long-term strategic partnership to accelerate the development of first-of-its-kind oncology drugs using translational medicine to improve the lives of patients. In May 2024, Boehringer Ingelheim and OSE expanded their collaboration to jointly develop first-of-its-kind therapies for tumor and cardio-renal metabolic diseases, including the anti-SIRRP α tumor Immunity program and the cis targeted anti-PD1 / cytokine platform. While Boehringer Ingelheim does not yet have a significant oncology product in the market, its oncology pipeline includes several promising candidates, such as Zongertinib(Phase 1), Brigimadlin (Phase two-thirds) and BI-764532 (Phase 2). Zongertinib is an innovative covalently bound, orally effective and selective HER2 small molecule inhibitor. It covalently binds to the tyrosine kinase domain (TKD) of both wild-type and mutant HER2 receptors, including exon 20 mutations, while preserving the wild-type signal of EGFR, thereby demonstrating good tolerability and safety while ensuring efficacy. Data from the Phase 1a/1b clinical study of Zongertinib monotherapy for HER2-variant advanced solid tumors (NCT04886804), presented at the ASCO meeting in 2024, showed that Zongertinib demonstrated superior efficacy and was well tolerated in patients with HER2-mutation-positive advanced NSCLC. Brigimadlin is a mouse dual microhomologous gene 2 (MDM2) -p53 antagonist targeting MDM2-amplified tumors such as biliary adenocarcinoma, non-small cell lung cancer, and pancreatic cancer. Currently, Brigimadlin's first-line treatment of dedifferentiated liposarcoma (DDLPS) has entered phase 2/3 of clinical trials. New results from the Phase 1a/1b study (NCT03449381) presented at the ASCO Meeting in 2024 show that Brigimadlin induces proteomic changes in DDLPS that may serve as potential biomarkers for predicting treatment response and adverse events. BI 764532 is a first-in-class T cell-mediated bisspecific antibody developed at Boehringer Ingelheim that induces a patient's own T cells to attack cancer cells expressing DLL3. BI 764532 has received fast track approval from the FDA for the treatment of advanced SCLC and advanced or metastatic extrapulmonary neuroendocrine carcinoma. In both DLL3-positive cell and xenograft models, BI 764532 showed potential preclinical antitumor activity. PTPN2 and PTPN1 (also known as PTP-1B) are phosphatases that negatively regulate multiple cytokine signaling pathways and T cell receptor (TCR) signaling pathways. They inhibit inflammation by dephosphorylation of JAK and STAT family members, and reduce T-cell sensitivity to antigens by phosphorylation of LCK and FYN. PTPN2 deletion was found to increase the number of activated cytotoxic CD8+T cells in the tumor, improve antigen presentation and sensitivity to IFNγ, and thus enhance tumor sensitivity to CD8+T cells. Given the critical role of PTPN2/N1 in tumor and immune cells and its highly conserved active sites, researchers are developing PTPN2/N1 inhibitors. Currently, there are several PTPN2/N1 inhibitors, such as ABBV-CLS-579 and ABBV-CLS-484 (AC484). AC484 is an oral PTPN2/N1 active site inhibitor that enhances the response to interferon and promotes the activation and function of immune cell subsets. In a PD-1-resistant mouse model, AC484 monotherapy showed significant antitumor effects. Currently, a Phase 1 clinical trial of AC484 is underway to evaluate its efficacy alone or in combination with PD-1 inhibitors or VEGFR tyrosine kinase inhibitors (TKI) in the treatment of advanced or metastatic solid tumors. In addition, using Chemistry42, its generating-AI platform, Insili has also developed a novel PTPN2/N1 inhibitor that has drug-like properties, good oral bioavailability in vivo, and strong in vivo anti-tumor activity, demonstrating nanoscale inhibitory efficacy.