STAT1

New Mechanistic Insights Underscore Multiple Potential Roles for Elraglusib as an Immune Modulator in the treatment of NeuroblastomaStudy Illustrates Potential to Activate the Immune System Even in Cancers That Have Not Previously Responded to Checkpoint Inhibitors CHICAGO and FORT WORTH, Texas, Sept. 23, 2024 (GLOBE NEWSWIRE) -- Actuate Therapeutics, Inc. (NASDAQ: ACTU) (“Actuate” or the “Company”), a clinical-stage biopharmaceutical company, focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers through the inhibition of glycogen synthase kinase-3 beta (GSK-3β), announced the Scientific Reports publication of novel mechanistic data for its development candidate, elraglusib. The article, entitled, “Targeted inhibition of glycogen synthase kinase‑3 using 9‑ING‑41 (elraglusib) enhances CD8 T‑cell‑reactivity against neuroblastoma cells” is available online. “The mechanistic data published in Scientific Reports provides crucial evidence of elraglusib’s ability to enhance activation of the immune system by tumor cells,” said Daniel Schmitt, President & Chief Executive Officer of Actuate. “By improving antigen presentation and enhancing the activation of CD8+ cytotoxic T cells, we are paving the way for more effective immunotherapeutic strategies including combinations of elraglusib with checkpoint inhibitors.” Using neuroblastoma, which is typically refractory to checkpoint inhibitors, as a model system, these findings illustrate the potential to activate the immune system even in cancers that have not previously responded to checkpoint inhibitors and underscore elraglusib’s potential as a highly innovative treatment for challenging cancers. The summary of key mechanistic findings: Elraglusib significantly enhances MHC-I molecule surface expression of neuroblastoma cells, improving their recognition by cytotoxic T lymphocytes (CTLs)Treatment with elraglusib leads to the disruption of NK-κB signaling, a key contributor to tumor cell survival, promoting cancer cell apoptosis and reducing treatment resistanceElraglusib boosts IFNγ signaling through the JAK/STAT pathway, particularly STAT1, which further supports improved antigen presentation and immune responseWhen combined with an anti-PD-1 treatment, elraglusib boosted CD8+ T cell proliferation and activation by neuroblastoma cells, showing potential for further development of these tumor immune response enhancing therapeutics. “Despite the clinical benefit observed with checkpoint inhibitors in many advanced cancer types, the majority of patients treated with checkpoint inhibitors fail to respond,” said Dr. Andrew Mazar, Actuate’s Scientific Co-founder and Chief Operating Officer. “The ability to enhance immunogenicity in a tumor such as neuroblastoma that is not unrecognized by the immune system, holds therapeutic promise for neuroblastoma patients and could potentially be translated for the treatment of other immunologically cold tumors as well.” Elraglusib is currently being evaluated in Phase 2 Trial in metastatic pancreatic cancer (NCT03678883) and Phase 1/2 Trial (NCT04239092) in Ewing Sarcoma (EWS) and EWS-related sarcomas. About Actuate Therapeutics, Inc. Actuate is a clinical-stage biopharmaceutical company focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers. Actuate’s lead investigational drug product, elraglusib (a novel GSK-3β inhibitor), targets molecular pathways in cancer that are involved in promoting tumor growth and resistance to conventional cancer drugs such as chemotherapy including EMT, NF-kB-mediated resistance and several DDR pathways. Elraglusib also acts as a mediator of anti-tumor immunity through the inhibition of NF-kB in immune cells and regulates multiple immune checkpoints and immune cell function. For additional information, please visit the Company’s website at http://www.actuatetherapeutics.com. Forward-Looking Statements This press release contains forward-looking statements about us, including our clinical trials and development plans, and our industry. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “ongoing,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would,” or the negative of these terms or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. All statements, other than statements related to present facts or current conditions or of historical facts, contained in this press release are forward-looking statements. Accordingly, these statements involve estimates, assumptions, substantial risks and uncertainties which could cause actual results to differ materially from those expressed in them, including but not limited to that clinical and preclinical drug development involves a lengthy and expensive process with uncertain timelines and outcomes, results of prior preclinical studies and early clinical trials are not necessarily predictive of future results, and elraglusib may not achieve favorable results in clinical trials or preclinical studies or receive regulatory approval on a timely basis, if at all; that we may not successfully enroll additional patients or establish or advance plans for further development; that elraglusib could be associated with side effects, adverse events or other properties or safety risks, which could delay or preclude regulatory approval, cause us to suspend or discontinue clinical trials or result in other negative consequences; our reliance on third parties to conduct our non-clinical studies and our clinical trials; our reliance on third-party licensors and ability to preserve and protect our intellectual property rights; that we face significant competition from other biotechnology and pharmaceutical companies; and our ability to fund development activities. In addition, any forward-looking statements are qualified in their entirety by reference to the factors discussed under the heading “Risk Factors” in our final prospectus filed with the SEC on August 13, 2024 pursuant to Rule 424(b)(4) under the Securities Act with respect to our Registration Statement on Form S-1 (File No. 333-279734) and other filings with the SEC. Because the risk factors referred to above could cause actual results or outcomes to differ materially from those expressed in any forward-looking statements made by us or on our behalf, you should not place undue reliance on any forward-looking statements. Further, any forward-looking statement speaks only as of the date on which it is made. New factors emerge from time to time, and it is not possible for us to predict which factors will arise. In addition, we cannot assess the impact of each factor on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. Unless legally required, we do not undertake any obligation to release publicly any revisions to such forward-looking statements to reflect events or circumstances after the date of this press release or to reflect the occurrence of unanticipated events. Investor Contact Mike Moyer Managing Director LifeSci Advisors, LLC mmoyer@lifesciadvisors.com

--In a preclinical model of psoriasis, the efficacy of oral small molecule REX-7117 was comparable to an anti-IL-17A biologic SAN DIEGO, May 17, 2024 (GLOBE NEWSWIRE) -- Recludix Pharma, Inc., a leader in discovery of inhibitors of challenging targets for inflammatory disease and cancer, presented new data today in an oral plenary presentation at the Society for Investigative Dermatology (SID) Annual Meeting titled “Oral selective STAT3 inhibitors demonstrate differentiated efficacy and safety potential in preclinical models of Th17 mediated skin inflammation” (abstract #738). Recludix’s senior vice president of biology, Paul Smith, Ph.D., reviewed preclinical data on the company’s potent, selective, and orally bioavailable small molecule STAT3 inhibitors, including REX-7117. Data demonstrated that REX-7117 achieves deep, durable, and selective STAT3 inhibition and exhibits similar efficacy to biologics targeting IL-17 in in vivo models of plaque psoriasis. Data was also presented that, unlike JAK1/2 and TYK2 inhibitors, REX-7117 does not impair broader immune responses, such as interferon-dependent anti-viral immunity or growth factor signaling critical for hematologic homeostasis. “These exciting data on our oral STAT3 inhibitors demonstrate that deep STAT3 inhibition has the potential to drive potent efficacy -- such as that seen with clinically validated biologics but with improved convenience as an orally-administered medication, while high selectivity for the downstream STAT3 target may avoid some of the safety concerns observed with JAK and TYK2 inhibitors,” said Ajay Nirula, M.D., Ph.D., executive vice president and head of research and development. “Inhibiting STAT3 could be a favorable and effective approach to treating Th17- and Th1-mediated diseases, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and inflammatory bowel disease.” Both REX-7117 and REX-5376 are highly potent and selective orally-available STAT3 inhibitors, as demonstrated across biochemical and cellular assays, which have the potential to: Impair inflammatory Th17 cell function, while sparing activation of other cytokine pathways which play critical roles in the defense against viruses, bacteria, extra cellular pathogens, and parasites Spare STAT1 mediated-signaling, in contrast to the impact on STAT1 signaling seen with baricitinib (JAK1/2) and deucravacitinib (TYK2) Not impair either type I or type II interferon (IFN)-mediated antiviral activity, as shown in in vitro models Not impair STAT5-mediated signaling by hematopoietic growth factors, unlike some JAK inhibitors which have the risk of inducing anemia, thrombocytopenia, and neutropenia In a murine IL-23 induced psoriasis model, REX-7117 achieved efficacy responses similar to an anti-IL-17A antibody surrogate treatment and was more efficacious than an estimated clinically relevant dose of deucravacitinib. About STAT3 The interleukin cytokines IL-23 and IL-6 signal through STAT3 and promote the generation and function of pathogenic T helper type-17 (Th17) cells, a type of immune cell that is pro-inflammatory. Th17 cells are considered pivotal players in certain inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease and others. Inhibiting STAT3 can also offer potential efficacy beyond Th17 / IL-17 driven diseases in clinical indications where blocking the IL-6 pathway is clinically validated. Furthermore, clinical trials inhibiting oncostatin M (OSM) and IL-22, both STAT3 dependent cytokines, have been reported as efficacious in inflammatory disease. A selective, oral STAT3 inhibitor has potential to provide an attractive alternative to JAK/TYK2 inhibitors and biologics for multiple inflammatory diseases. STAT3 inhibitors may also have significant opportunity in cancer settings, as STAT3 is activated in greater than 70% of human cancers. About Recludix Recludix is a leader in developing platform approaches to discover potent and selective inhibitors of challenging protein targets. The company’s management team includes industry veterans with a track record of success, including former leaders of Seagen, Blueprint Medicines, and Lilly. Recludix has developed a unique drug discovery platform that integrates custom generated DNA-encoded libraries, massively parallel determination of structure activity relationships, and a proprietary screening tool to ensure selectivity. The company is employing this approach first in the development of SH2 domain inhibitors. Recludix’s most advanced programs are focused on STAT (signal transducer and activator of transcription) proteins where abnormal activation is found in inflammatory diseases, such as rheumatoid arthritis, asthma, atopic dermatitis, and inflammatory bowel disease, as well as numerous cancer types, such as multiple leukemias and lymphomas. The company has a strategic partnership with Sanofi for the development and commercialization of a STAT6 inhibitor. Recludix is also advancing STAT3 inhibitors for Th17-mediated I&I diseases and oncology indications, as well as additional programs. For more information, please visit the company’s website at . Recludix Contacts: Alexandra Santos asantos@wheelhouselsa.com Aljanae Reynolds areynolds@wheelhouselsa.com

AGOURA HILLS, Calif., March 25, 2024 (GLOBE NEWSWIRE) -- Oncotelic Therapeutics, Inc (OTCQB:OTLC) announced today the peer reviewed publication of Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas: Past, Present, and Future Strategies in the Treatment and Management of Gliomas. Dr. Vuong Trieu, CEO and Chairman of Oncotelic, stated, ”Our R&D team has discovered crosstalk between the TGF-β and IFN signaling pathways, linking gliomas and Systemic Lupus Erythematosus (SLE). This publication has identified IRF5 as a common target for both diseases, opening up a new avenue for combating cancer,” Our findings place IRF5 at the intersection of inflammation and cancer. Understanding the role of IRF5 in both SLE and cancer opens an avenue for targeting IRF5 or its downstream pathways. This could offer new strategies for treating SLE and various cancers by modulating the immune response. The article can be accessed for free online: https://www.mdpi.com/2072-6694/16/6/1202 Abstract: Gliomas develop in the central nervous system from the glial cells that support it. Low-grade gliomas (LGGs) are characterized by a reduced number of immune cells infiltrating the tumor, requiring immune-boosting therapies to release the immunosuppressive environment of the tumor. We conducted a bioinformatics-led study to evaluate the prognostic impact of cell surface receptor markers for tumor-associated macrophages (TAMs) that produce transforming growth factor beta (TGFB) ligands and interferon-gamma receptor activation to maintain the tumor microenvironment in an immunosuppressed state. Detailed investigation of messenger RNA levels and their impact on OS in LGG patients demonstrated that low mRNA levels of a specific TGFB ligand, TGFB2, and the receptor along with the signaling molecules from interferon-gamma receptor activation (IFNGR2, IRF1, IRF5, and STAT1) result in improved survival of LGG patients. LGG patients expressing high levels of TGFB2 and IFNGR2 are over-represented in IDH wild-type tumor samples, suggesting that TGFB2 and IFNGR2 mRNA can be therapeutically targeted in these high-risk patients. Furthermore, demethylation of TFGB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 genes also results in worse survival outcomes, pointing to a molecular mechanism that increases the negative prognostic effects of increased mRNA levels of these target genes. We observed that significant upregulation of mRNA expression levels for three TAM markers, MSR1/CD204, CD86, and CD68, suggested that TGFB2 is pivotal in establishing a pro-tumorigenic TME in gliomas mediated through TAMs. Interestingly, a tumor-associated antigen CD276/B7-H3 mRNA expression increased in tumor tissue, giving further insights into the roles of macrophages and tumor cells in the immunosuppressive TME. Therefore, to improve OS in LGG patients, combination therapies must target TGFB2 and IFN-γ activation (via IRF5 inhibition) or immune therapies targeted against CD276/B7-H3 About Oncotelic Oncotelic (f/k/a Mateon Therapeutics, Inc.), was formed in the State of New York in 1988 as OXiGENE, Inc., was reincorporated in the State of Delaware in 1992, and changed its name to Mateon Therapeutics, Inc. in 2016, and Oncotelic Therapeutics, Inc. in November 2020. Oncotelic is seeking to leverage its deep expertise in oncology drug development to improve treatment outcomes and survival of cancer patients with a special emphasis on rare pediatric cancers. Oncotelic has rare pediatric designation for Diffuse Intrinsic Pontine Glioma (“DIPG” through OT-101) through its 45% joint venture, GMP Biotechnology Limited, melanoma (through CA4P), and Acute Myeloid Leukemia (through OXi 4503). Oncotelic acquired PointR Data Inc. in November 2019 to build an AI driven biotechnology company. Further, Oncotelic acquired AL-101, during the 4th quarter of 2021, for the intranasal delivery of apomorphine. We intend to develop AL-101 for the treatment of Parkinson Disease, erectile dysfunction, female sexual disorder and hypoactive sexual desire disorder. All these ailments have a very large population suffering from them and there is a need for treatments for each. For more information on AL-101, refer to our Annual Report on Form 10-K/A filed with the SEC on April 19, 2023. Oncotelic's Cautionary Note on Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in this communication regarding strategy, future operations, future financial position, prospects, plans and objectives of management are forward-looking statements. Words such as "may", "expect", "anticipate" "hope", "vision", "optimism", "design", "exciting", "promising", "will", "conviction", "estimate," "intend," "believe", "quest for a cure of cancer", "innovation-driven", "paradigm-shift", "high scientific merit", "impact potential" and similar expressions are intended to identify forward-looking statements. Forward looking statements contained in this press release include, but are not limited to, statements about future plans related to the operations of the JV, taking the JV into an initial public offering or the success thereof, the progress, timing of clinical development, scope and success of future clinical trials, the reporting of clinical data for the Company’s product candidates and the potential use of the Company's product candidates to treat various cancer indications as well as obtaining required regulatory approval to conduct clinical trials and upon granting of approval by the regulatory agencies, the successful marketing of the products; building and the success of our nanoparticle platform and the related success of launching the platform, the development of the Company’s AI suite including but not limited to AI Chatbots, the public access to the Company’s AI suite, the success of the development of the AI suite or any other AI technologies and whether if any or portion thereof the Company’s AI suite or technologies will be commercialized and launched for sale. Each of these forward-looking statements involves risks and uncertainties, and actual results may differ materially from these forward-looking statements or may not occur at all. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data observed during preclinical or clinical studies, clinical trial site activation or enrollment rates that are lower than expected, changes in expected or existing competition, changes in the regulatory environment, failure of collaborators to support or advance collaborations or product candidates and unexpected litigation or other disputes, taking the Company or its affiliates through initial public offerings. These risks are not exhaustive, the company faces known and unknown risks, including the risk factors described in the Company's Annual Report on Form 10-K/A filed with the SEC on April 19, 2023 and in the company's other periodic filings. Forward-looking statements are based on expectations and assumptions as of the date of this press release. Except as required by law, the company does not assume any obligation to update forward-looking statements contained herein to reflect any change in expectations, whether because of new information, future events, or otherwise. Contact Information: For Oncotelic Therapeutics, Inc.:Investor Relationsir@oncotelic.com