STAT5A

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

Clinical activity observed in 50% of evaluable patients with relapsed/refractory acute myeloid leukemia (r/r AML) or high-risk myelodysplastic syndromes (HR-MDS) treated with RVU120 monotherapy, including a complete response. Treatment continues to show a favorable safety pro 50-70% target engagement achieved at a dose of 250 mg. The published clinical and non-clinical data strongly support RVU120’s Phase II development plans presented in October. A webinar discussing the data presented at the ASH 2023 conference will take place on Sunday, December 10, at 11:00 PM (PST) / Monday, December 11, at 8:00 AM (CET).Registration is available at: ryvu.clickmeeting.com/ryvu-ash-2023-results/register. KRAKOW, Poland, Dec. 11, 2023 (GLOBE NEWSWIRE) -- Ryvu Therapeutics [WSE:RVU], a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, presents clinical and preclinical data on RVU120, a selective CDK8/19 inhibitor, at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, which is held on December 9-12, 2023, in San Diego, California. “The results from the CLI120-001 (RIVER-51) study of RVU120 in patients with r/r-AML and HR-MDS continue to improve over time. RVU120 monotherapy shows signs of clinical activity in 50% of evaluable patients, including a complete response, multiple clinically significant blast reductions, hematologic improvements, and reduction of bone marrow fibrosis. In particular, early signs of efficacy were observed in patients with NPM1 mutation, DNMT3a mutation, and in those with HR-MDS,” said Hendrik Nogai, M.D., Chief Medical Officer of Ryvu Therapeutics. “We are pleased with the 50-70% target engagement achieved at 250 mg dose, which, based on our preclinical data, is anticipated to result in robust antileukemic efficacy in selected settings.” Dr. Nogai continued: “Given the observed hematologic improvements, particularly the early signs of erythroid responses in seven patients, we believe that RVU120 holds the potential to be a novel erythropoiesis-stimulating agent for patients with LR-MDS and myelofibrosis. Furthermore, the non-clinical study supports RVU120's development as a frontline targeted therapy in AML, as evidenced by its cytotoxic and differentiating effects on well-characterized leukemic stem cell-like populations. Based on these encouraging results, we plan to initiate Phase II studies in patients with AML, HR-MDS, LR-MDS, and myelofibrosis.” Posters highlights featured at the Meeting: Abstract Title: “Safety and Efficacy Results from CLI120-001 a Phase 1 Study in RR-AML and HRMDS: Update from Higher Dose Levels” Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II Session date and time: Sunday, December 10, 2023, 6:00 PM - 8:00 PM PST Poster Number: 2913 Updated Phase I data on RVU120 at higher dose levels in patients with relapsed/refractory (r/r) acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (HR-MDS) demonstrate clinical activity with a favorable safety profile. As of the data cut-off on November 10, 2023, 38 patients (34 with AML and four with HR-MDS) have been treated in the trial at doses up to 250 mg. Of the 28 evaluable patients, 14 showed clinically relevant benefits, including eight blast reductions to <5% in the bone marrow. Among these, there was one complete response, three marrow complete responses, and four clinically relevant BM blast reductions. Five additional patients achieved transfusion independence, and one achieved an absolute difference of >4 RBC units compared to the baseline, following Cheson 2006 criteria. One patient received a transplant after nearly four months of treatment. The first evaluable patient at 250 mg showed significant blast reduction (64%) at the end of cycle 2. Doses up to 250 mg have shown a favorable safety profile, with 50-70% target engagement achieved at a dose of 250 mg. Abstract Title: “Preclinical and Clinical Evidence for Erythroid-Stimulating Activity of RVU120 CDK8/19 Inhibitor in AML and MDS” Session Name: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster II Session date and time: Sunday, December 10, 2023, 6:00 PM - 8:00 PM PST Poster Number: 2800 RVU120-induced erythroid differentiation was studied in primary malignant stem cells from MDS patients and in a stem cell model. To date, early signs of erythroid response, at the molecular level measured by increased erythroid surface markers CD71 and/or CD235a expression, were observed in seven evaluable patients in the ongoing Phase Ib. Four out of seven patients had a clinically relevant hematological response. Transcriptomic analyses of bone marrow cells in patients treated with RVU120 showed specific induction of gene expression programs leading to the maturation of erythroid cells in two out of four patients, who also exhibited clinical hematologic improvement. These clinical and preclinical data support further development of RV120 as a novel erythroid stimulating agent. Treatment with RVU120 could be a promising treatment option for patients with lower-risk MDS who are transfusion-dependent and failing previous lines of treatment. Abstract Title: “Novel Clinically Useful Inhibitor of Mediator Complex, RVU120, Relieves Differentiation Block in MDS/AML” Session Name: 636. Myelodysplastic Syndromes—Basic and Translational: Poster II Session date and time: Sunday, December 10, 2023, 6:00 PM - 8:00 PM PST Poster Number: 3225 Data demonstrate RVU120’s potential for erythroid-stimulating activity in CD34+ primary samples of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Treatment with RVU120 in MDS and AML models, including patient-derived sample cultures, resulted in increased erythroid differentiation, as evidenced by increased expression of erythroid surface markers. Additionally, inhibition of CKD8/19 led to transcriptional silencing in MDS-L cells. Notably, RVU120 also inhibits phosphorylation of STAT5 and STAT1, which may represent the underlying mechanism of action. These results provide supporting rationale for further development of RVU120 for transfusion-dependent MDS/AML patients. Posters are available on Ryvu corporate website. Additionally, the two posters listed below will be made public on December 11, 2023, at 9:00 AM PST/18:00 CET. Abstract Title: “Targeting CDK8/CDK19 to Disrupt Leukemic Stem Cell-like Population in Acute Myeloid Leukemia: Exploring RVU120 As a Promising Frontline Therapy” Session Name: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster III Session date and time: Monday, December 11, 2023, 2023, 6:00 PM - 8:00 PM PST Poster Number: 4175 Abstract Title: “Mediator Kinase/CDK8 Inhibition as a Strategy to Improve FLT3 Inhibitor Activity in Acute Myeloid Leukemia” Session Name: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster III Session date and time: Monday, December 11, 2023, 6:00 PM-8:00 PM PST Poster Number: 4173 Investor Event Ryvu will host a webinar on Sunday, December 10, at 11:00 PM PST / Monday, December 11, at 8:00 AM CET, to discuss the data presented at the ASH Annual Meeting. To join the webcast, please register here: ryvu.clickmeeting.com/ryvu-ash-2023-results/register. 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 are RVU120 — a selective CDK8/CDK19 kinase inhibitor with potential for the treatment of hematological malignancies and solid tumors, currently in phase Ib clinical development for the treatment of acute myeloid leukemia and myelodysplastic syndromes, and phase I/II for the treatment of r/r metastatic or advanced solid tumors — and SEL24 (MEN1703), 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, Exelixis, Menarini, and Merck. 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 . Contacts: Investors John Fraunces LifeSci Advisors +1 917-355-2395 jfraunces@lifesciadvisors.com Corporate Natalia Baranowska Ryvu Therapeutics +48 784 069 418 natalia.baranowska@ryvu.com

- Pioneering compounds believed to be the first orally administered reversible inhibitors to bind to and inhibit the SH2 domain potently and selectively - Proprietary STAT3 inhibitors are differentiated in several ways from alternative approaches, including potency, selectivity, reversibility and oral bioavailability Recludix Pharma, a leader in platform approaches to discover inhibitors of challenging targets for inflammatory disease and cancer, announced that in a presentation given today titled “Drugging the Undruggable,” Recludix’s senior vice president of biology, Paul Smith, Ph.D., discussed the first application of the company’s platform capabilities to target the Src Homology 2 (SH2) domain, as well as reviewed preclinical data on an early STAT3 inhibitor that was internally discovered through the platform. The presentation is available on the company’s website under the section titled “Events.” “We have had tremendous success in developing oral STAT inhibitors by targeting the SH2 domain, which has been previously considered undruggable,” said Nancy Whiting, PharmD, CEO of Recludix. “In this presentation, we highlight data from one of our earlier STAT3 discovery compounds showing its highly selective STAT3 inhibition with demonstrated potency in biochemical and cellular assays. We have continued to refine our lead STAT3 inhibitors and are in the final stages of confirming a STAT3 development candidate to move into clinical testing. We believe this could be a first- and best-in-class approach to selectively inhibit Th17-driven inflammatory diseases, such as psoriasis, rheumatoid arthritis, ulcerative colitis and Crohn's disease.” Recludix has generated potent and selective small molecule STAT3 inhibitors for Th17-driven inflammation. In T cell functional assays, Recludix’s STAT3 inhibitor potently and selectively impaired the Th17 phenotype, while still enabling the T cell to continue to perform robustly against viruses, bacteria, extracellular pathogens, and parasites. This is in contrast to the family of JAK or TYK2 inhibitors, which can be associated with changes in immune surveillance and hematopoiesis, leading to dose limiting safety concerns. Data demonstrate that targeting STAT3 spares interferon-driven anti-viral gene transcription and avoids STAT5 signaling, which is important for hematologic homeostasis and is differentiated from JAK/TYK2 inhibition. In a preclinical model of multiple sclerosis, proof-of-concept was established that STAT3 inhibition modulates in vivo Th17 diseases as measured by mean clinical score compared to vehicle control, exhibiting greater preclinical disease control than the JAK inhibitor baricitinib. Activity for STAT3 was found to be dose-dependent in both prophylactic and therapeutic preclinical models. Selective STAT3 inhibition was also evaluated in an imiquimod-induced (Th17-dependent) model of psoriasis which demonstrated that STAT3 inhibition modulates disease as measured by the PASI score and skin thickness, and it does so comparably to a supra-maximal efficacious dose of the JAK inhibitor tofacitinib (30 mg/kg). 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 replace 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 and founding scientific team members of Seagen and Blueprint Medicines. 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 https://recludixpharma.com. The content above comes from the network. if any infringement, please contact us to modify.