RVU120 / Ryvu Therap - LARVOL DELTA

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

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

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

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

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

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

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

ASXL1 mutations in AML are associated with a distinct epigenetic state that results in vulnerabilities to epigenetic-targeted agents (AACR 2025) - "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 confirm the previously published discovery that the presence of mtASXL1 confers an increased sensitivity to BETi inhibitors, e.g., pelabresib or birabresib...Importantly, in the NSG mice engrafted with OCIAML3 ASXL1 Y591*, monotherapy with NEO2734, pelabresib or SEL120 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 mediator-kinase inhibitor."

Acute Myelogenous Leukemia • Hematological Malignancies • Oncology • ASXL1 • AURKA • BAP1 • CDK9 • E2F1 • EP300 • FZD5 • HOXA9 • MEIS1 • MYC • PLK1 • SPI1 • TCF7L2

Ryvu Therapeutics announces strategic reorganization to extend the cash runway for the development of RVU120 and the preclinical pipeline (PRNewswire) - "RVU120: emphasis on rapid study enrollment and quality data generation in 2025 - Three Phase II studies of RVU120 are in progress as planned: RIVER-81 (combination study with venetoclax in patients with AML), POTAMI-61 (monotherapy/combination study with ruxolitinib in patients with myelofibrosis) and REMARK (monotherapy study in patients with LR-MDS). The Phase II RIVER-52 study of RVU120 monotherapy in patients with AML or HR-MDS, will not enroll new patients to focus investment on the other RVU120 development paths. Currently enrolled patients will continue to receive treatment per protocol. The decision to progress RIVER-81 and suspend enrollment in RIVER-52 was based on data analysis and feedback from advisory boards in February 2025. The next data update for RVU120 is planned in Q2 2025. RVU305: IND/CTA-enabling studies are ongoing and planned to be completed in H2 2025."

Clinical data • Preclinical • Trial status • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • Myelofibrosis

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

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 | "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

RIVER-81: Phase II study of RVU120 in combination with venetoclax administered to patients with AML who are relapsed or refractory to prior therapy with venetoclax and a hypomethylating agent (PRNewswire) - P2 | N=98 | RIVER-81 (NCT06191263) | Sponsor: Ryvu Therapeutics SA | "In the RIVER-81 study...within eight patients treated with RVU120 at 250 mg (RP2D) that had at least one evaluable post-baseline assessment, one patient achieved a complete remission (CR), and another patient achieved a significant blast reduction. Part 1 of the study (combination dose escalation) was completed, and Part 2 is currently enrolling at the full doses of RVU120 (250 mg) and venetoclax (400 mg)."

P2 data • Acute Myelogenous Leukemia

RIVER-52: Phase II study of RVU120 as a single agent for the treatment of patients with genetically defined subtypes of AML (including NPM1 and DNMT3A mutations) and HR-MDS who have no alternative treatment options (PRNewswire) - P2 | N=94 | RIVER-52 (NCT06268574) | Sponsor: Ryvu Therapeutics SA | "In the RIVER-52 study...achieved a 50% blast reduction, while disease stabilizations and reduction of peripheral blasts were observed in patients in cohort 3 (DNMT3A mutation)...Enrollment in the study significantly accelerated in Q4 2024 and is expected to lead to key efficacy readouts in the coming months. Data from at least 10 patients in each cohorts 2-4 are expected in H1 2025...Ryvu plans to update stakeholders on the clinical progress of RVU120 in Q2 2025."

P2 data • Acute Myelogenous Leukemia

Ryvu Therapeutics provides an update on RVU120 Phase II program (PRNewswire) - "Ryvu Therapeutics...provided an update on clinical progress and data in the Phase II program RVU120, its fully-owned first-in-class dual CDK8/19 inhibitor, currently being developed to treat hematologic malignancies...Ryvu successfully launched all four RVU120 Phase II clinical studies planned for 2024: RIVER-52, RIVER-81, POTAMI-61 and REMARK - with all studies progressing on track toward key efficacy analyses in H1 2025...The Company estimates that across all four RVU120 Phase II studies, 113 sites will have been activated by the end of 2024...Ryvu anticipates dosing ~100 patients by year-end...Following the key efficacy data expected in H1 2025, Ryvu plans to update stakeholders on the clinical progress of RVU120 in Q2 2025."

P2 data • Trial status • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • Myelofibrosis

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 • Pain • Pneumonia • Respiratory Diseases • DNMT3A • NPM1

Ryvu Therapeutics Announces Dosing of the First Patient in the POTAMI-61 Phase II Study of RVU120 for the Treatment of Patients with Myelofibrosis (MF) (PRNewswire) - "In the POTAMI-61 study, patients will receive RVU120 until disease progression, withdrawal of consent or other reasons specified in the study protocol. The POTAMI-61 study consists of two parts. Part A of the study with a planned enrollment of approximately 20 patients will comprise two cohorts: 1) single-agent therapy with RVU120 in patients resistant or refractory to prior JAK inhibitor treatment or ineligible for JAK inhibitor treatment, and 2) RVU120 in combination with RUX in patients who experience a suboptimal response to prior JAK inhibitor treatment....Initially, Part A of the study will enroll patients at clinical sites in Poland and Italy. If the Ryvu Management Board decides to initiate Part B, the study will expand to include additional sites both in the EU and non-EU countries, totaling approximately 50 clinical sites worldwide."

Trial status • Myelofibrosis

Ryvu Therapeutics Reports 2024 Q3 Financial Results and Provides Corporate Update (PRNewswire) - "In Q1-Q3 2024, Ryvu recognized total operating revenues (including grants) of USD 18.6 million, compared to USD 11.9 million in Q1-Q3 2023; Ryvu reports an acceleration in patient enrollment for its RVU120 Phase II clinical studies, attributed in part to a significant increase in the number of activated clinical sites. As of October 31, a total of 66 sites have been activated in the most advanced RIVER-81 and RIVER-52 studies, and this number is expected to grow further by the end of the year; "

Commercial • Trial status • Acute Myelogenous Leukemia

RVU120-SOL-021: RVU120 (SEL120) in Patients with Relapse/Refractory Metastatic or Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=120 | Active, not recruiting | Sponsor: Ryvu Therapeutics SA | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors (EORTC-NCI-AACR 2024) - P1/2 | "RVU120 exhibits manageable safety profile at tested doses and schedules. TL size reductions were seen in 3 pts with AdCC. Available data warrant further clinical exploration of RVU120."

Clinical • Metastases • P1/2 data • Adenoid Cystic Carcinoma • Hematological Malignancies • Oncology • Solid Tumor • CDK9

Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors (PRNewswire) - P1/2 | N=120 | NCT05052255 | Sponsor: Ryvu Therapeutics SA | "No dose-limiting toxicities (DLTs) were observed, and most treatment-emergent adverse events (TEAEs) were mild to moderate, with nausea and vomiting being the most common. 6/8 patients with adenoid cystic carcinoma achieve a longer duration of treatment on RVU120 compared with their most recent prior line of therapy. A reduction of 20% of target lesions was observed in 2 patients with adenoid cystic carcinoma. The recommended phase 2 dose (RP2D) for the QOD schedule was identified as 250 mg and remains the primary dosing schedule in clinical studies, but a continuous dosing schedule was explored and could offer an alternative to patients: continuous every day administration (QD) of RVU120 at doses of 100 mg and 150 mg is considered safe and may improve tolerability of RVU120 compared with 250 mg every other day."

P1/2 data • Oncology • Solid Tumor

Ryvu Therapeutics to present clinical and preclinical data on RVU120, RVU305, and novel synthetic lethality programs at the 2024 EORTC-NCI-AACR Symposium (PRNewswire) - "Ryvu Therapeutics...will present four posters with clinical and preclinical data from RVU120 (CDK8/19 inhibitor), RVU305 (MTA-cooperative PRMT5 inhibitor), WRN and novel synthetic lethality programs at the 2024 EORTC-NCI-AACR Symposium (ENA), October 23-25, Barcelona, Spain."

Clinical data • Preclinical • Oncology • Solid Tumor

POTAMI-61: RVU120 in Patients with Intermediate or High-risk, Primary or Secondary Myelofibrosis (clinicaltrials.gov) - P2 | N=230 | Recruiting | Sponsor: Ryvu Therapeutics SA | Not yet recruiting ➔ Recruiting

Enrollment open • Myelofibrosis