romaciclib (RVU120) / Ryvu Therap - LARVOL DELTA

Remark: A phase II, open-label, multicenter study of orally administered romaciclib (RVU120) for the treatment of anemia in patients with lower-risk myelodysplastic neoplasms (LR-MDS) (ASH 2025) - P2 | "Hereceived three prior lines of therapy with ESA, luspatercept, and lenalidomide. Despite the preliminary nature of the data, initial signs of clinical activity of romaciclib in patients with LR-MDS were observed. Ongoing analyses in the study aim at describing the clinical and molecular changesduring treatment with romaciclib, at identifying the optimal dose and schedule as well as potentialpredictors of response."

Clinical • P2 data • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CD34 • SF3B1

Preliminary results from RIVER-81, a phase 2 study of romaciclib (RVU120) + venetoclax in patients with acute myeloid leukemia failing first-line venetoclax + hypomethylating agent (HMA) (ASH 2025) - P1, P2 | "Romaciclib in combination with VEN shows promising anti-leukemic activity in a subset of patients withhistorically poor prognosis. The observed CR/CRi responses suggest that romaciclib may help overcomeVEN resistance. The current data support continuation of the study."

Clinical • IO biomarker • P2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Congestive Heart Failure • Febrile Neutropenia • Heart Failure • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Pneumonia • Respiratory Diseases • Septic Shock • ASXL1 • BCL2 • BCL2L1 • CDK9 • IL6 • MCL1 • NRAS • STAT5 • TP53

An open-label, Phase I/II clinical trial of romaciclib (RVU120) as monotherapy and in combination with ruxolitinib in patients with intermediate or high-risk, primary or secondary myelofibrosis (POTAMI-61) (ASH 2025) - P2 | "Reduction ofBM fibrosis was seen after 12 weeks of treatment in a patient who failed prior lines of RUX andfedratinib; reduction of TSS of >50% was not observed in these 6 patients after 12 weeks.The most common AEs were nausea and vomiting, reported in 52% and 43% of patients, respectively.Majority of AEs were G1-2. Initial signs of clinical activity were observed, as demonstrated by SVR, TSSimprovements, and BM fibrosis reduction in some patients while data continue to mature. Initialevidence from POTAMI-61 study supports further investigation of romaciclib in patients with MF."

Clinical • Combination therapy • Monotherapy • P1/2 data • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Thrombocytopenia

Mediator Kinase/CDK8 Inhibition As a Strategy to Improve FLT3 Inhibitor Activity in Acute Myeloid Leukemia (ASH 2023) - "RAS mutations also decrease efficacy of the BCL2 inhibitor venetoclax now widely used in AML, suggesting an anti-apoptotic influence of MAPK signaling...Using GSEA we found that gilteritinib stimulated adaptive interferon/inflammatory gene signatures at 16h drug treatment, but this response was restrained by addition of SEL120...We speculate this latter effect may in part alter an AML cell's differentiation state to sensitize cells to apoptosis, though further study to explore this hypothesis is needed. Our in vitro and in vivo efficacy data further validated combined FLT3i/CDK8i as a promising investigational strategy to pre-empt or overcome MAPK-mediated FLT3 TKI resistance."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Inflammation • Leukemia • Oncology • FLT3 • IRF8 • NRAS • SPI1

CDK8 Inhibition Represses Monocyte-like Gene Expression in Acute Myeloid Leukemia Cells and Antagonizes In Vivo Resistance to FLT3 Inhibition (ASH 2024) - "Both screens identified the Mediator complex/CDK8 as regulators of gilteritinib resistance that can be co-targeted by SEL120, a small-molecule CDK8 inhibitor. This activity may stem in part from preventing AML cell activation of inflammatory and monocyte-like gene expression that may otherwise promote cell survival. Further exploration is warranted to determine whether repression of this gene signature by CDK8 inhibition could also reduce resistance to venetoclax and other targeted AML therapies."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2A1 • CD68 • FLT3 • IDH1 • IDH2 • ITGAM • MCL1 • NRAS • PTPRC • SPI1 • TLR4

River-81: A Multicenter, Open-Label, Dose-Finding Clinical Trial to Assess Safety, PK, PD, Clinical Efficacy of RVU120 in Combination with Venetoclax in Patients with AML Failing Prior Venetoclax Plus Hypomethylating Agent Therapy (ASH 2024) - P1, P2 | "Preclinical research testing the combination of RVU120 with Ven across a broad panel of AML cell lines demonstrated drug synergy in cell lines representing 2 out of 4 distinct Ven resistant clusters, according to Mohanty et al., bioRxiv, 2024. The ongoing analysis of transcriptomic profiles and treatment-induced changes will be presented in the poster to enable further patient stratification in the RIVER-81 study.Conclusions : •Preliminary evidence of activity in a Ven-refractory AML population comes from the first evaluable patient treated in cohort 2 of RIVER-81 trial that achieved a CRi in Cycle 1.•In the studies population, infections occur frequently with poor outcome.•The safety and tolerability of RVU120 in combination with Ven allows further exploration.•The current data warrant continuation of enrollment into the study."

Clinical • Combination therapy • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Infectious Disease • Inflammation • CDK9 • DNMT3A • MCL1

Trial in Progress: An Open-Label Clinical Trial of RVU120 As Monotherapy and in Combination with Ruxolitinib in Patients with Intermediate or High-Risk, Primary or Secondary Myelofibrosis (POTAMI-61) (ASH 2024) - P2 | "Ruxolitinib (RUX) is JAK1/2 inhibitor used to treat MF and hydroxyurea-resistant/intolerant polycythemia vera. Cohorts 1 and 2 will enroll the same patient populations as in part A. In cohort 3, patients with untreated primary or secondary MF may be enrolled. Part A will start recruiting patients in Poland and Italy.Recruitment for this study will begin in September 2024."

Clinical • Combination therapy • Monotherapy • Anemia • Bone Marrow Transplantation • Cardiovascular • Fibrosis • Hematological Disorders • Hepatology • Immunology • Myelofibrosis • Oncology • Polycythemia Vera • Thrombocytopenia

ASXL1 Mutations in AML Are Associated with a Distinct Epigenetic State Which Highlights Vulnerabilities to Specific Epigenetic-Targeted Agents (ASH 2024) - "Notably, compared to parental cells, OCIAML3 ASXL1 Y591* cells exhibited reduced sensitivity to standard anti-AML chemotherapeutic agents, including cytarabine, etoposide and daunorubicin...Our findings also demonstrate and confirm that mtASXL1-expressing AML cells exhibited increased sensitivity to BETi (pelabresib or birabresib)...Importantly, in the NSG mice engrafted with luciferized OCIAML3 ASXL1 Y591*, monotherapy with NEO2734 (5 mg/kg QD), pelabresib (30 mg/kg QD) or SEL120-34A (40 mg/kg QD), compared to vehicle control, significantly reduced AML burden. Collectively these findings highlight previously uncharacterized biologic effects of the presence of mtASXL1 and support the rationale for further evaluating AML therapies incorporating BETi, HAT-BETi or inhibitor of mediator kinase."

Acute Myelogenous Leukemia • Hematological Malignancies • Immunology • Oncology • Targeted Protein Degradation • ASXL1 • AURKA • BAP1 • BRD4 • CD14 • CDK9 • E2F1 • FZD5 • HOXA9 • MEIS1 • MYC • NDUFA2 • PLK1 • SPI1 • TCF7L2

Preclinical and Clinical Evidence for Erythroid-Stimulating Activity of RVU120 CDK8/19 Inhibitor in AML and MDS (ASH 2023) - P1 | "The presented results provide clinical and preclinical evidence for RVU120 as a candidate for a novel erythroid stimulating agent. Treatment with RVU120 could be a promising addition to the current treatment options for patients with lower-risk MDS who are transfusion-dependent and failing first-line therapies."

Preclinical • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • CD34 • CDK9 • DNMT3A • ERG • GATA1 • GYPA • IFNG • NPM1 • STAT5 • TFRC • TGFB1

Targeting CDK8/CDK19 to Disrupt Leukemic Stem Cell-like Population in Acute Myeloid Leukemia: Exploring RVU120 As a Promising Frontline Therapy (ASH 2023) - P1 | "Moreover, single-cell studies offer insights into its inhibitory effects on LSC-enriched populations and capacity for inducing differentiation. Overall, these results support RVU120 as a frontline candidate in AML therapy, countering therapeutic failure caused by persistent LSCs."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD123 • CD14 • CD34 • CD38 • CDK9 • IL3RA • STAT5 • THY1

Novel Clinically Useful Inhibitor of Mediator Complex, RVU120, Relives Differentiation Block in MDS/AML (ASH 2023) - P1 | "We investigated the expression of mediator complex components in a large database of MDS CD34+ marrow samples and age-matched controls. Our findings revealed that MED12, a critical component of the mediator complex, was significantly overexpressed in MDS samples from refractory anemia with excess blasts (RAEB), a higher risk subset of MDS(p=0.018) (Fig A). Furthermore, we observed that this overexpression of MED12 was associated with a higher rate of transformation to AML."

Clinical • Acute Myelogenous Leukemia • Anemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD34 • CDK9 • GYPA • MED12 • STAT5 • TFRC

Safety and Efficacy Results from CLI120-001 a Phase 1 Study in RR-AML and HR-MDS: Update from Higher Dose Levels (ASH 2023) - P1 | "In the ongoing phase 1 trial, RVU120 shows clinical activity in both AML and HR-MDS, inducing RBC transfusion independence and blast reduction with a tolerable safety profile. Clearance of BM blasts including a formal CR were observed in patients treated at different dose levels. Relevant target inhibition is achieved from 110 mg onwards with expected higher pSTAT 5 inhibition with further dose escalation."

Clinical • P1 data • Acute Myelogenous Leukemia • Fibrosis • Hematological Disorders • Immunology • Neutropenia • Oncology • FLT3 • NPM1 • STAT5 • TP53

River-52: A Multicenter, Open-Label Clinical Trial of RVU120 in Patients with Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia (ASH 2024) - P1, P2 | "The majority of AEs are of grade 1 or 2. Preliminary pharmacokinetic data showed systemic exposure consistent with that seen in previous RVU120 studies, sufficient for robust target engagement.Conclusions : While the study is ongoing, preliminary results of RIVER-52 study demonstrate that RVU120 monotherapy has an acceptable safety profile, encouraging antileukemic activity, and emerging biologic activity consistent with the proposed mechanism of action in pts with R/R acute leukemia harboring NPM1 alterations."

Clinical • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • DNMT3A • NPM1

ROVER-01: RVU120 Rollover Study (clinicaltrials.gov) - P2 | N=10 | Not yet recruiting | Sponsor: Ryvu Therapeutics SA | Initiation date: Aug 2025 ➔ Dec 2025

Trial initiation date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor

Ryvu presented one oral presentation and four posters from the RVU120 program at EHA 2025. The following data update is expected in Q4 2025. (Ryvu Therapeutics Press Release)

Clinical data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • Myelofibrosis

Ryvu Therapeutics…announces its involvement in the MEDWAY project with a new non-commercial academic Phase I study to evaluate the CDK8/19 inhibitor RVU120 in combination with everolimus in children with recurrent or progressive Group 3 or 4 medulloblastoma. (Biotech Newswire) - "The MEDWAY project will be executed by the Children’s Memorial Health Institute (IPCZD) under the grant awarded in the Medical Research Agency call (ABM/2024/2) for non-commercial clinical trials and research experiments in oncology...The total grant awarded to IPCZD amounts to PLN 40,151,060.47...The first shipment of the drug is expected in Q2 2026. The MEDWAY project is expected to run from July 1, 2025, to June 30, 2033 with the potential for earlier completion."

Financing • New P1 trial • Medulloblastoma

ASXL1 Mutations in AML Are Associated With a Distinct Epigenetic State That Results in Vulnerabilities to Epigenetic-Targeted Agents (SOHO 2025) - " Notably, compared with parental cells, OCIAML3 ASXL1 Y591* cells exhibited reduced sensitivity to chemotherapeutic agents, including cytarabine, etoposide, and daunorubicin. In contrast, mtASXL1-expressing AML cells exhibited increased sensitivity to bromodomain and extraterminal inhibitors (BETi; pelabresib or birabresib)... These findings highlight that rationally targeted agents including NEO2734, pelabresib, and SEL120 or their combinations can potentially exert significant anti-AML efficacy against AML cells with mtASXL1."

Acute Myelogenous Leukemia • Hematological Malignancies • Oncology • ASXL1 • BAP1 • BCL9L • DVL1 • HOXA9 • MEIS1 • MYC • SPI1 • TCF7L2 • WNT5B • WNT7B

AN OPEN-LABEL CLINICAL TRIAL OF RVU120 AS MONOTHERAPY AND IN COMBINATION WITH RUXOLITINIB IN PATIENTS WITH INTERMEDIATE OR HIGH-RISK, PRIMARY OR SECONDARY MYELOFIBROSIS (POTAMI-61). (EHA 2025) - "RVU120 when used as a single agent or in combination with RUX was found to be tolerated by MF patients. Initial signs of clinical activity have been observed after a median follow-up of 4 weeks. Initial data of POTAMI-61 warrant further exploration of RVU120 in MF patients."

Clinical • Combination therapy • Monotherapy • Fatigue • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Oncology

PRELIMINARY RESULTS FROM RIVER-81, A PHASE 2 STUDY OF RVU120+VEN IN PATIENTS WITH AML FAILING FIRST LINE VEN+HMA (EHA 2025) - P1, P2 | "Background: First-line venetoclax (VEN) in combination with hypomethylating agents (HMA) is the standard of care for elderly AML patients unfit for intensive chemotherapy. RVU120 in combination with VEN shows preliminary anti-leukemic activity in a subset of patients with a historically poor prognosis. The observed CR/CRi responses suggest that RVU120 may help overcome VEN resistance. Enrollment in this study is continuing, including further dose optimization."

Clinical • IO biomarker • P2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Oncology • ASXL1 • BCL2 • BCL2L1 • CDK9 • MCL1 • NRAS • TP53

RIVER-52: A MULTICENTER, OPEN-LABEL CLINICAL TRIAL OF RVU120 IN PATIENTS WITH RELAPSED OR REFRACTORY HIGH-RISK MYELODYSPLASTIC SYNDROME OR ACUTE MYELOID LEUKEMIA (EHA 2025) - P1 | "RVU120 continued to show an acceptable safety profile at the dose of 250 mg QOD. Nausea, vomiting and infectious complications were among the most frequent events, consistent with prior findings from Phase 1. Due to the absence of complete responses in the observed patient populations or sufficient evidence of anti-tumor or clinical activity, the protocol defined criteria to open Part 2 were not met and the study was subsequently stopped."

Clinical • Acute Myelogenous Leukemia • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Hepatology • Infectious Disease • Leukemia • Liver Failure • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Septic Shock • DNMT3A • NPM1

OVERCOMING VENETOCLAX RESISTANCE: SYNERGISTIC POTENTIAL OF RVU120, A CDK8/CDK19 INHIBITOR, IN COMBINATION TREATMENT. (EHA 2025) - P2 | "RVU120+VEN also revealed its superiority in eradicating LSC-like cells within the AML hierarchical model, compared to standard VEN and azacitidine treatment (Pakulska et al., EHA 2024). Preclinical data demonstrate that RVU120 in combination with VEN is highly effective and has a strong capacity to overcome resistance to venetoclax. The underlying mechanism involves the downregulation of key pathways known to drive resistance to VEN. Altogether, these data support the ongoing Phase II RIVER-81 (NCT06191263) clinical trial and may improve patient stratification for RVU120+VEN therapy."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CDK9 • IL6 • MCL1 • STAT3 • TGFB1

RVU120 ENHANCES ERYTHROID POTENTIAL IN MDS PATIENT-DERIVED CELLS: PRECLINICAL MECHANISTIC INSIGHTS INTO CDK8/CDK19 INHIBITION AND POTENTIAL PATIENT STRATIFICATION (EHA 2025) - P1, P2 | "This study demonstrates that RVU120 significantly enhances erythropoiesis in MDS primary cells. RVU120 shows efficacy at clinically relevant and lower doses, supporting its potential as a therapeutic strategy for MDS. Transcriptomic analysis confirms the mechanism of CDK8/CDK19 inhibition, highlighting its role in modulating erythroid differentiation."

Preclinical • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ASXL1 • CD34 • CDK9 • GATA1

ROVER-01: RVU120 Rollover Study (clinicaltrials.gov) - P2 | N=10 | Not yet recruiting | Sponsor: Ryvu Therapeutics SA

New P2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor

REMARK_001: RVU120 for Treatment of Anemia in Patients With Lower-risk Myelodysplastic Neoplasms (clinicaltrials.gov) - P2 | N=41 | Active, not recruiting | Sponsor: GCP-Service International West GmbH | Recruiting ➔ Active, not recruiting

Enrollment closed • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

RIVER-52: Safety and Efficacy of RVU120 for Treatment of Relapsed/Refractory AML (clinicaltrials.gov) - P2 | N=94 | Active, not recruiting | Sponsor: Ryvu Therapeutics SA | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology