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Scientists at Cincinnati Children's lead deepest dive yet into the mechanics of blood cell development. They found new treasure. CINCINNATI , March 21, 2024 /PRNewswire/ -- Thanks to an unusual application of game theory and machine learning technology, a large team of scientists led by experts at Cincinnati Children's has published the world's most detailed "atlas" of the many types of stem cells and early progenitors involved in producing human blood from diverse donors. Continue Reading A large team of scientists led by experts at Cincinnati Children’s has published the world’s most detailed “atlas” of the many types of stem cells and early progenitors involved in producing human blood from diverse donors. The team has identified more than 80 distinct subsets of hematopoietic stem and progenitor cells (HSPCs) – early-stage cells that kick off production of mature red cells, white cells and other elements of our complex blood system. Details were published March 21, 2024, in Nature Immunology. "We believe our highly focused capture strategy of the earliest HSPCs, intermediate cell states plus stromal populations, and the most abundant end states provides the deepest view of bone marrow stem and progenitor compartments described to date," the co-authors state. The study was led by co-first authors Xuan Zhang, PhD, and Baobao Song, PhD, and co-corresponding authors Nathan Salomonis, PhD, and H. Leighton Grimes, PhD, all researchers with Cincinnati Children's. Overall, the study includes 26 co-authors from four academic medical centers and two biotech companies. Leukemia implications and more This complex research project involved using multiple advanced genomic research tools and computational methods to build detailed genomic and proteomic profiles of more than 300,000 bone marrow cells collected from a diverse mix of donors spanning race and sex. Cincinnati Children's is committed to promoting inclusivity and addressing population diversity in scientific studies as part of their ongoing mission. In addition to meticulous single-cell RNA sequencing work and matching flow cytometry, analyzing the massive data set required innovative use of machine learning technology and dipping into game theory to perform key statistical analyses. Some of the research tools the team used, including two software tools scTriangulate and pyIninityFlow, were developed at Cincinnati Children's. Among the team's key findings: Mixing a new "cocktail" of 132 antibodies that can target surface proteins on HSPCs and related cells. Testing demonstrated that the new mix outperforms commercial products for profiling human bone marrow cells. Identifying 89 clusters by a novel integration of gene expression and surface proteins helped reveal new stem/progenitor cell populations. Strategies and markers for isolating novel cell populations. First, two novel surface markers C5L2 and TSPAN33 to identify cells entering transitional states between progenitor status and becoming a mature neutrophil. Second, distinct staging of human red blood cell formation called erythroblasts with CD326 and CD235a. New online computational tools to predict the cellular origins and possible causes of cancers such as acute myeloid leukemia (AML). "Our analysis uncovers previously hidden cell states, such as the most primitive stem cells, by combining information from diverse prior atlases, surface markers and genes, and new advances in machine learning," Salomonis says. One of the most immediate potential applications of the new stem cell atlas centers on how treatment centers monitor patients receiving therapies for leukemia. "For example, some people develop resistance to Venotoclax with azacytidine (a chemotherapy that was approved in 2018 as a first line therapy for AML)," Grimes says. "In some cases, the therapy-resistant disease appears to be driven by a "monocytic" form of leukemia stem cell (m-LSC) rather than a more "primitive" form (p-LSC). With an atlas like this, it becomes more possible to determine which types of cancer stem cells are present in the AML, and that information could then inform how a clinician might adjust a treatment regimen." The new study reports finding 69 antibodies within 23 cell states that may represent attractive biomarkers for clinical monitoring of people with AML. While the development of the new stem cell atlas is an essential start, much more research and development will be needed to integrate the new data about blood cell formation into medical care, Grimes says. Making the tool available The co-authors predict that the new digital bone marrow atlas will accelerate the discovery of more cellular and molecular regulators of blood diseases. To support such efforts, the research team is making its data and tools widely available to the research community. While the Nature Immunology article has been made open access, full detail and access to this advanced digital resource, including data viewers, methods, raw data and code, are available at . About the study In addition to the first and corresponding authors, contributing co-authors from Cincinnati Children's include Guangyuan Li, Dan Schnell, Kairavee Thakkar, Michal Kouril, Kang Jin, Stuart Hay, and Sidharth Sen, all with the Division of Biomedical Informatics; plus Kyle Ferchen, Bailee Kain, David Bernardicius, Siyuan Ma, and Sierra Bennett, all with the Division of Immunobiology. Data acquisition for this study included support from the Research Flow Cytometry Core and the DNA Sequencing and Genotyping Core at Cincinnati Children's. Contributors also included scientists from the Yale School of Medicine, University of Pittsburgh, University of Colorado School of Medicine, San Diego-based BioLegend Inc., and Massachusetts based Curiox Biosystems, Inc. Funding sources for this work include several grants from the National Institutes of Health, especially an RC2 grant from the NIDDK, complemented by an NIDDK Cooperative Centers of Excellence in Hematology grant, a Specialized Center of Research (SCOR) grant from the Leukemia & Lymphoma Society, and the US Department of Veterans Affairs. SOURCE Cincinnati Children's Hospital Medical Center

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

Updated data from the Phase I trial of RVU120 in relapsed/refractory acute myeloid leukemia (r/r AML) or high-risk myelodysplastic syndromes (HR-MDS) demonstrate clinically relevant benefit in 50% of evaluable patients Preclinical data support RVU120 as a novel agent for the treatment of patients with lower-risk MDS (LR-MDS) and show cytotoxic and differentiating effects on leukemic stem cells The published data strongly supports the RVU120 Phase II development plans presented in October KRAKOW, Poland, Nov. 2, 2023 /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, today announced that clinical and preclinical data on RVU120, a selective CDK8/19 inhibitor, will be presented on four posters at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, which is being held on December 9 –12, 2023 in San Diego, California. "At this year's ASH conference, we are pleased to present updated clinical and preclinical data that highlight the potential of RVU120 to address hematologic malignancies," said Hendrik Nogai, M.D., Chief Medical Officer of Ryvu Therapeutics. "RVU120 continues to show single-agent clinical activity in patients with AML and HR-MDS, along with a tolerable safety profile. Notably, several patients achieved a reduction of blasts in the bone marrow including one complete response. We also observed hematologic improvement supporting RVU120's further development as a treatment for patients with LR-MDS and myelofibrosis. In addition, evidence that RVU120 has cytotoxic and differentiating effects on leukemic stem cells highlight its potential as frontline therapy in AML." Based on these data and in line with prior guidance, Ryvu's development plan for RVU120 includes initiation of Phase II studies in AML/HR-MDS as a monotherapy and in combination, in myelofibrosis, and an investigator-initiated trial in LR-MDS. Initiation of Ryvu-sponsored studies in AML is planned in Q4 2023, and in the LR-MDS and myelofibrosis studies in H1 2024. "Our internal Clinical Committee and a global network of external experts have thoroughly assessed the clinical and preclinical results of RVU120, and have recognized its significant potential in the treatment of multiple hematological diseases. This recognition is a crucial element in the recently presented RVU120 development plans," added Hendrik Nogai. Details on the poster presentations are as follows: Abstract Title: "Safety and Efficacy Results from CLI120-001 a Phase 1 Study in RR-AML and HR-MDS: 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 higher dose level Phase I data on RVU120 in patients with relapsed/refractory (r/r) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) demonstrate clinical activity with a tolerable safety profile. 12 of 24 evaluable patients showed clinically relevant benefit, including four blast reductions to <5% in the bone marrow: one complete response and three marrow complete responses in patients with HR-MDS. Three additional patients treated across different dose levels experienced a sustained BM blast reduction, and five patients achieved hematologic improvements. Dose-escalation data continues to demonstrate relevant target inhibition at doses of 110 mg and higher. 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, erythroid improvement has been observed in five evaluable patients in the ongoing Phase Ib study. Bulk RNA-seq analysis confirmed broad transcriptomic changes in the bone marrow (BM) of selected patients after treatment compared to the pre-dose baseline levels. Robust induction of genes involved in erythroblast differentiation and hemoglobin metabolism genes were observed in two AML with myelodysplasia-related changes (AML-MRC) and two AML patients. These clinical and preclinical data strongly support the further development of RVU120 as a novel agent for patients with LR-MDS who are transfusion-dependent and failing first-line therapy. 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, 6:00 PM - 8:00 PM PST Poster Number: 4175 Leukemic stem cells (LSC) are a small subset of AML cells that can resist therapy and cause relapse. To achieve a cure for patients, it is essential to eliminate LSCs. In preclinical models, RVU120 displayed cytotoxic and differentiating effects on well-characterized LSC populations. Single-cell studies further revealed RVU120's ability to inhibit LSC-enriched populations and induce differentiation. In summary, RVU120 emerges as a frontline candidate in AML treatment, addressing therapeutic failures caused by persistent LSCs. 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 the potential of inhibiting overexpressed mediator complex proteins, including CDK8, to address differentiation blocks and resulting anemias in MDS/AML. Treatment of primary cells in bone marrow collected from MDS and AML patients with RVU120 led to increased erythroid differentiation, as evidenced by changes in the expression of erythroid differentiation markers, including increased CD71 and Glycophorin A expression. These studies provide supportive evidence for RVU120 as a drug candidate in transfusion-dependent MDS/AML patients. 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 I 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 . SOURCE Ryvu Therapeutics