STAT5A

MDNA209 is a first-in-class “beta-enhanced” IL-2 Super-antagonist being developed for the potential treatment of autoimmune diseases, a disorder attributed to an imbalance of the immune system and affecting 5 to 10% of the global population MDNA209 restores immune balance by selectively blocking IL-2Rβγc, a receptor highly expressed by effector CD8 T cells which are known to promote tissue damage in autoimmune diseases In an aggressive animal model of graft versus host disease (GvHD) MDNA209 was able to extend overall survival by 400 percent, reduce weight loss and improve clinical scores, highlighting its therapeutic potential for treating GvHD and autoimmune diseases MDNA113 is an IL-13Rα2 tumor-targeted BiSKIT (Bifunctional SuperKine for ImmunoTherapy) which delivers an anti-PD1-IL-2 Superkine (anti-PD1-IL-2SK) directly to the tumor microenvironment (TME) where it is conditionally activated by tumor-associated proteases MDNA113’s efficacy was significantly enhanced in mice harboring tumors engineered to overexpress IL-13Rα2, highlighting its potential to treat immunologically “cold tumors” such as pancreatic, prostate, ovarian, and breast cancers that globally affect over two million patients every year TORONTO and HOUSTON, Sept. 09, 2024 (GLOBE NEWSWIRE) -- Medicenna Therapeutics Corp. (“Medicenna” or the “Company”) (TSX: MDNA, OTCQB: MDNAF), a clinical-stage immunotherapy company focused on the development of Superkines, announced today that, as planned and previously announced, new data from two of its preclinical programs were presented orally at the Promise of Interleukin-2 Conference held in Paris, France from September 4-7, 2024. “Inspired by the promising Phase 1/2 clinical results from the ABILITY-1 clinical trial of MDNA11, we are leveraging the same IL-2 Superkine platform to advance our pipeline of transformative medicines to treat not only cancer but also autoimmune diseases,” said Fahar Merchant, Ph.D., President and CEO of Medicenna. “We are encouraged by these preclinical data, which validates the versatility of our IL-2 Superkines beyond cancer as we further evaluate MDNA209 in GvHD and other disease models. Additionally, our IL-13 Superkines enable us to precisely deliver and localize BiSKITs to the tumor site which could potentially benefit patients with cancers that have not responded to currently approved checkpoint inhibitors, thereby addressing a huge unmet need.” MDNA209 and MDNA113 are preclinical assets based on the MDNA109 platform also used to develop MDNA11, a long-acting IL-2 Super-agonist, currently being evaluated in the Phase 1/2 ABILITY-1 clinical trial for the treatment of solid tumors. The first presentation outlined the potential of MDNA209 to treat autoimmune diseases, including high grade GvHD which has a 1-year survival rate of only 40%. Transplant patients with GvHD experience significant morbidity and mortality with limited therapeutic options to prolong survival. The initial preclinical data presented on the MDNA209 platform highlight the potential of the Company’s long-acting, high-affinity IL-2β biased IL-2/IL-15 Super-antagonists to downregulate the immune system, with therapeutic potential for GvHD and autoimmune diseases.The second presentation focused on MDNA113, which is being developed as a novel, targeted and bifunctional version (anti-PD1-IL-2 Superkine fusion) of a class of blockbuster anti-PD1 therapies, with current annual sales of over $30 billion but lose patent protection from 2028 onwards. Although Anti-PD-1 checkpoint blockade has improved survival outcomes in many types of solid tumors, approximately 70% of cancer patients do not benefit. To further improve patient outcomes, Medicenna has designed an anti-PD1-IL-2SK BiSKIT that uses an IL-13 Superkine to simultaneously target and localize the BiSKIT to the TME while masking the IL-2 domain during peripheral circulation and reducing its toxicity. At the TME, tumor specific proteases cleave the IL-13 component, releasing the BiSKIT to engage with T-cells thereby stimulating T-cell activity via the IL-2 domain and preventing T-cell exhaustion via the anti-PD1 domain. Key highlights from the presentations are: MDNA209, a High Affinity IL-2β Biased IL-2/IL-15 Super-antagonist, for the Treatment of Autoimmune Diseases MDNA209 is an IL-2 Super-antagonist with enhanced affinity for IL-2Rβ but does not engage with the γc subunit, therefore acting as a receptor clamp to exclude native IL-2 as well as native IL-15.MDNA209 is fused to an Fc scaffold (MDNA209-Fc) to extend its in vivo half-life, reducing the need for frequent dosing.MDNA209-Fc inhibits both, IL-2 and IL-15 induced p-STAT5 signaling, reduces IFNγ release and slows immune cell proliferation without reducing Treg population.In an aggressive animal model of acute GvHD, MDNA209 was able to extend overall survival by 400 percent, reduce weight loss and improve clinical scores. MDNA113, an IL-13Rα2 Tumor Targeting and Conditionally Activatable anti-PD1-IL-2SK BiSKIT Shows Enhanced Safety and Potent Therapeutic Efficacy MDNA113 (masked version) showed reduced capacity to induce IL-2R mediated pSTAT5 signaling compared to anti-PD1-IL-2SK (non-mask version) in cell-based assay and human CD8+ T cells without impacting PD1/PDL1 blockade.Proteolytic cleavage of MDNA113 releases anti-PD1-IL-2SK and fully restores its capacity to activate IL-2R signaling.Mice treated with MDNA113 showed reduced peripheral lymphocyte expansion compared to anti-PD1-IL-2SK due to masking by the IL-13 Superkine.MDNA113 showed greater tolerability than anti-PD1-IL-2SK following repeat dose administration in mice.MDNA113, but not a non-cleavable version, demonstrated similar efficacy as anti-PD1-IL-2SK in MC38 colon tumor model despite these tumors lacking IL-13Rα2 expression.Efficacy of MDNA113 is substantially enhanced when tested in mice harboring MC38 tumors that have been engineered to overexpress IL-13Rα2, resulting in complete tumor regression in most animals.Variants of MDNA113 have also been designed with tunable masking of the IL-2 Superkine underscoring the versatility of the platform. Copies of the two presentations are available on the “Scientific Presentations” page of Medicenna’s website. About MDNA209 The Company’s MDNA209 platform consists of IL-2 muteins with targeted mutations enabling high-affinity IL-2 receptor antagonism. MDNA209 blocks the formation of the IL-2Rβγc complex, preventing downstream signaling and blocking effector T-cell functions. MDNA209 outcompetes IL-2 for IL-2Rβ and impedes γc engagement, blocking downstream signaling and restraining reactive effector immune cells, thereby offering therapeutic potential for treating inflammatory and autoimmune diseases. About MDNA113 MDNA113 is a novel, first-in-class tumor-targeted and tumor-activated bi-functional anti-PD1-IL2 Superkine with exceptionally high affinity for IL-13Rα2 without binding to the functional IL-13R⍺1. IL-13Rα2 is overexpressed in a wide range of solid tumors, including cold tumors with minimal to no expression in normal tissues. IL-13Rα2 expressing tumors also have abundant matrix metalloprotease in the tumor microenvironment that may efficiently activate MDNA113. IL-13Rα2 expression is associated with poor clinical outcome in multiple tumor types including prostate cancer, pancreatic cancer, ovarian cancer, liver cancer, breast cancer and brain cancer, with an annual world-wide incidence of over 2 million. About Medicenna Therapeutics Medicenna is a clinical-stage immunotherapy company focused on developing novel, highly selective versions of IL-2, IL-4 and IL-13 Superkines and first-in-class Empowered Superkines. Medicenna’s long-acting IL-2 Superkine, MDNA11, is a next-generation IL-2 with superior affinity toward CD122 (IL-2 receptor beta) and no CD25 (IL-2 receptor alpha) binding, thereby preferentially stimulating cancer-killing effector T cells and NK cells. Medicenna’s IL-4 Empowered Superkine, bizaxofusp (formerly MDNA55), has been studied in 5 clinical trials enrolling over 130 patients, including a Phase 2b trial for recurrent GBM, the most common and uniformly fatal form of brain cancer. Bizaxofusp has obtained FastTrack and Orphan Drug status from the FDA and FDA/EMA, respectively. Medicenna’s early-stage high-affinity IL-2β biased IL-2/IL-15 Super-antagonists, from its MDNA209 platform, are being evaluated as potential therapies for autoimmune and graft-versus host diseases. Medicenna’s early-stage BiSKITs™ (Bifunctional SuperKine ImmunoTherapies) and the T-MASK™ (Targeted Metalloprotease Activated SuperKine) programs are designed to enhance the ability of Superkines to treat immunologically “cold” tumors. For more information, please visit www.medicenna.com, and follow us on Twitter and LinkedIn. Forward-Looking Statements This news release contains forward-looking statements within the meaning of applicable securities laws. Forward-looking statements include, but are not limited to, express or implied statements regarding the future operations of the Company, estimates, plans, strategic ambitions, partnership activities and opportunities, objectives, expectations, opinions, forecasts, projections, guidance, outlook or other statements that are not historical facts, such as statements on the therapeutic potential and safety profile of MDNA209 and MDNA113. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage pre-clinical or clinical studies may not be indicative of full results or results from later stage or larger scale clinical studies and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented. Forward-looking statements are often identified by terms such as “will”, “may”, “should”, “anticipate”, “expect”, “believe”, “seek”, “potentially” and similar expressions. and are subject to risks and uncertainties. There can be no assurance that such statements will prove to be accurate and actual results and future events could differ materially from those anticipated in such statements. Important factors that could cause actual results to differ materially from the Company’s expectations include the risks detailed in the latest annual information form of the Company and in other filings made by the Company with the applicable securities regulators from time to time in Canada. The reader is cautioned that assumptions used in the preparation of any forward-looking information may prove to be incorrect. Events or circumstances may cause actual results to differ materially from those predicted, as a result of numerous known and unknown risks, uncertainties, and other factors, many of which are beyond the control of the Company. The reader is cautioned not to place undue reliance on any forward-looking information. Such information, although considered reasonable by management, may prove to be incorrect and actual results may differ materially from those anticipated. Forward-looking statements contained in this news release are expressly qualified by this cautionary statement. The forward-looking statements contained in this news release are made as of the date hereof and except as required by law, we do not intend and do not assume any obligation to update or revise publicly any of the included forward-looking statements. This news release contains hyperlinks to information that is not deemed to be incorporated by reference in this new release. Investor/Media Contact: Christina CameronInvestor Relations, Medicenna Therapeutics(647) 953-0673ir@medicenna.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

Updated preclinical data will be presented from Ryvu's synthetic lethality pipeline, including PRMT5 inhibitors in MTAP-Deficient cancers, WRN inhibitors for the treatment of microsatellite unstable (MSI-H) tumors, and Ryvu's cutting-edge synthetic lethality platform based on primary cancer cells. Poster presentation to highlight the synergistic effects of RVU120 in combination with ruxolitinib in myeloproliferative neoplasms. Ryvu's partner Menarini to present data on MEN1703 (SEL24), demonstrating promising anti-tumor activity in preclinical models of myelofibrosis both as a single agent and combined with ruxolitinib. KRAKOW, Poland, March 6, 2024 /PRNewswire/ -- Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, announced today that preclinical data from its synthetic lethality pipeline and RVU120 project, as well as on MEN1703 (SEL24), will be presented at the upcoming 2024 AACR Annual Meeting, scheduled for April 5-10 in San Diego, California. "We are excited to present our latest preclinical data at the AACR Annual Meeting, showcasing our significant progress in advancing novel small molecule therapies for oncology. This year, we will present data from our most advanced preclinical project on MTA-cooperative PRMT5 inhibitors, the lead program within Ryvu's synthetic lethality pipeline. Our PRMT5 inhibitors have demonstrated remarkable efficacy and selectivity in preclinical models of tumors with MTAP gene deletion, providing a strong foundation for further development," said Krzysztof Brzózka, Ph.D., Chief Scientific Officer of Ryvu Therapeutics. "Our discovery platform continues to produce novel precision medicine targets and drugs, and we are proud to highlight platform data based on primary cancer cells, specifically in colorectal cancer models with broader applicability across cancers. " Details on the poster presentations are as follows: Abstract Title: "Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers." Session Name: HDAC and Methyltransferase Inhibitors Session date and time: Tuesday, April 9, 9:00 AM - 12:30 PM EST Poster Number: 4598 Co-deletion of MTAP is observed in approximately 80-90% of tumors with homozygous deletion of CDKN2A, representing 10-15% of all human tumors. These tumor types, including non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma, have a poor prognosis, highlighting the significant unmet medical need in this area. Deletion of MTAP leads to a significant accumulation of methylthioadenosine (MTA) in cells. MTA, at high concentrations, selectively inhibits the PRMT5 methyltransferase enzyme. As a result, the overall level of symmetric arginine dimethylation throughout the proteome is reduced, which makes cells with MTAP deletion more susceptible to therapeutic targeting of PRMT5. Ryvu has developed potentially best-in-class MTA-cooperative PRMT5 inhibitors showing favorable drug-like properties and effective PRMT5 inhibition dependent on MTA binding. Structure-based lead optimization has enabled rapid expansion and delivery of two independent chemical series with novel intellectual property, characterized by high target engagement in cells, and selective potency in MTAP-deleted cell lines, along with favorable DMPK profiles allowing an oral administration. The antitumor activities were compared in vitro and in vivo in MTAP null tumors. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Performed studies confirm that MTA-cooperative PRMT5 inhibitors exert a strong synthetic lethal phenotype in MTAP-deleted cancers, offering an exciting therapeutic opportunity for a large patient population. Abstract Title: "A comprehensive platform for identification of KRAS-specific synthetic lethal targets using patient-derived cells." Session Name: New Targets, Technologies, and Drug Delivery Systems Session date and time: Tuesday, April 9, 9:00 AM - 12:30 PM EST Poster Number: 4684 Ryvu's cutting-edge drug discovery platform uniquely combines high throughput capabilities with the precision and translational impact traditionally associated with later, lower throughput stages. Our approach taps into the power of primary cells to transform cancer treatment, focusing especially on colorectal cancer (CRC). By leveraging human stem cell derived model cells (PDC), patient-derived xenografts (PDXs) and clinical samples we have created a groundbreaking approach to identify synthetic lethal (SL) targets specific to oncogenic pathways. We integrate CRISPR/Cas9 technology, phenotypic screening, RNA-seq, and whole-exome sequencing (WES), enabling rapid identification of molecular vulnerabilities. We present results obtained in engineered intestinal primary models which represent frequently altered genes in CRC, including KRAS G12D mutation. Notably, our use of normal hISCs facilitates the identification of genes essential only for transformed cells, amplifying the precision tumor targeting of our novel discoveries. Beyond CRC, our platform could extend to personalized medicine approaches in various cancer types. By spearheading the identification of KRAS-specific SL inhibitors, we pave the way for novel, targeted therapies, offering hope to patients battling this heterogeneous malignancy and beyond. Abstract Title: "Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors." Session Name: Novel Antitumor Agents 4 Session date and time: Tuesday, April 9, 1:30 PM – 05:00 PM EST Poster Number: 5942 The synthetic lethality resulting from the inhibition of the WRN helicase protein has been observed in tumors characterized by high levels of microsatellite instability (MSI-H). This instability stems from a deficiency in the DNA mismatch repair (MMR) mechanisms, leading to the accumulation of DNA damage. This phenomenon is notably prevalent in 10-30% of colorectal, gastric, endometrial, and ovarian cancers. Structure-based optimization performed at Ryvu facilitated the rapid expansion and delivery of a compound library with novel intellectual property (IP), demonstrating target engagement in cells and selective potency over other RecQ family members. The pharmacokinetic properties of these compounds were favorable and allowed progressing to in vivo studies which confirmed efficacy of our compounds in xenograft MSI-H cancer models. These data provide pharmacological proof-of-concept for the synthetic lethal effect of our inhibitors and support WRN inhibition as a new, targeted oncological therapy. Abstract Title: "Combination JAK1/2 and CDK8/19 inhibition demonstrates enhanced efficacy in myeloproliferative neoplasms." Session Name: Targeted, Combination, and Differentiation Therapies Session date and time: Wednesday, April 10, 9:00 AM - 12:30 PM EST Poster Number: 7225 The presentation, prepared in collaboration with Prof. Raajit Rampal's group from Memorial Sloan Kettering Cancer Center, includes the assessment of RVU120, a highly selective and potent CDK8/19 inhibitor, both in monotherapy and combination with ruxolitinib (RUX), a JAK1/2 inhibitor, for the treatment of myeloproliferative neoplasms (MPN) and hydroxyurea-resistant/intolerant polycythemia vera (PV). The combination of RVU120 and RUX demonstrated biochemical synergy and differential inhibition of STAT5 phosphorylation in vitro. Further, in vivo treatment with RVU120/RUX+RVU120 resulted in significant reductions in disease manifestation (splenomegaly, WBC, fibrosis scoring, hematopoiesis) compared to VEH/RUX. These data suggest that JAK1/2 and CDK8/19 inhibition could be a potential novel therapeutic strategy in MPNs. Additional work on nascent RNA expression and cytokine profiles aims at elucidating the exact mechanism of synergy between tested compounds. Abstract Title: "MEN1703/SEL24 exhibits promising antitumoral activity in preclinical models of myelofibrosis both as single agent and combined with ruxolitinib." Session Name: Novel Antitumor Agents 2 Session date and time: Sunday April 7, 01:30 AM – 0500 PM EST Poster Number: 665 MEN1703 (SEL24) is an oral, first-in-class, dual PIM/FLT3 kinase inhibitor in development for hematologic malignancies. The presented study aims to investigate the efficacy of MEN1703 alone and in combination with the JAK inhibitor ruxolitinib (RUX) in preclinical models of myelofibrosis (MF) and to elucidate the underlying signaling pathways. MEN1703 demonstrated anti-tumoral efficacy in MF preclinical models, exhibiting in vitro activity at clinically relevant concentrations. Importantly, the combination of MEN1703 with the standard of care, RUX, exhibited synergistic effects, and molecular analyses confirmed the inhibition of downstream targets of PIM. The results support the therapeutic potential and relevance of MEN1703 in the treatment strategies for myelofibrosis. All abstracts are now available online and can be obtained from the conference site: About Ryvu Therapeutics Ryvu Therapeutics is a clinical-stage drug discovery and development company focused on novel small-molecule therapies that address emerging targets in oncology. Internally discovered pipeline candidates use diverse therapeutic mechanisms driven by emerging knowledge of cancer biology, including small molecules directed at kinase, synthetic lethality, and immuno-oncology targets. Ryvu's most advanced programs include RVU120, a selective CDK8/CDK19 kinase inhibitor with the potential to treat hematological malignancies and solid tumors, currently in Phase II development (i) as a monotherapy for the treatment of patients with relapsed/refractory acute myeloid leukemia (r/r AML) and high-risk myelodysplastic syndromes (HR-MDS) as well as (ii) in combination with venetoclax for the treatment of patients with r/r AML. Another clinical program, SEL24 (MEN1703), is a dual PIM/FLT3 kinase inhibitor licensed to the Menarini Group. Ryvu Therapeutics has signed multiple partnering and licensing deals with global companies, including BioNTech and Exelixis. The Company was founded in 2007 and is headquartered in Kraków, Poland. Ryvu is listed on the Warsaw Stock Exchange and is a component of the mWIG40 index. For more information, please see . SOURCE Ryvu Therapeutics