romaciclib (RVU120) / Ryvu Therap - LARVOL DELTA

POTAMI-61: RVU120 in Patients With Intermediate or High-risk, Primary or Secondary Myelofibrosis (clinicaltrials.gov) - P2 | N=36 | Terminated | Sponsor: Ryvu Therapeutics SA | N=230 ➔ 36 | Trial completion date: Oct 2027 ➔ Jun 2026 | Recruiting ➔ Terminated; Sponsor decision

Enrollment change • Monotherapy • Trial completion date • Trial termination • Myelofibrosis

ROVER-01: RVU120 Rollover Study (clinicaltrials.gov) - P2 | N=14 | Enrolling by invitation | Sponsor: Ryvu Therapeutics SA | Trial completion date: Aug 2026 ➔ Dec 2026 | Trial primary completion date: Aug 2026 ➔ Dec 2026

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

RIVER-81: Safety and Efficacy of RVU120 Combined With Venetoclax for Treatment of Relapsed/Refractory AML (clinicaltrials.gov) - P2 | N=98 | Recruiting | Sponsor: Ryvu Therapeutics SA | Trial completion date: Sep 2026 ➔ Aug 2027 | Trial primary completion date: Feb 2026 ➔ Aug 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

RIVER-52: Safety and Efficacy of RVU120 for Treatment of Relapsed/Refractory AML (clinicaltrials.gov) - P2 | N=62 | Terminated | Sponsor: Ryvu Therapeutics SA | N=94 ➔ 62 | Active, not recruiting ➔ Terminated; Sponsor decision

Enrollment change • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

RIVER-52: RVU120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=51 | Terminated | Sponsor: Ryvu Therapeutics SA | N=112 ➔ 51 | Active, not recruiting ➔ Terminated; RPD2 has been identified

Enrollment change • First-in-human • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

RVU120-SOL-021: RVU120 (SEL120) in Patients With Relapse/Refractory Metastatic or Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=66 | Terminated | Sponsor: Ryvu Therapeutics SA | N=120 ➔ 66 | Trial completion date: May 2025 ➔ Oct 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2025 ➔ Oct 2025; Sponsor decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

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

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

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

Integrated Multi-Omics and Interactome Analysis of CDK8 Inhibition Reveals Erythroid Differentiation Programs and Therapeutic Synergy with BET Blockade in AML. (PubMed, Cells) - "CDK8, a kinase component of the Mediator complex, regulates oncogenic transcription, and the selective CDK8/CDK19 inhibitor RVU120 (Romaciclib) targets AML cells with CD34+/pSTAT5-high LSC-like characteristics; however, the epigenetic and transcriptional consequences of CDK8 blockade and actionable combinatorial strategies remain incompletely defined. CDK8 combined with Pelabresib acted synergistically in MOLM-16 cells and two of three PDX models. These findings identify CDK8 as a transcriptional node of LSC-associated programs and provide a mechanistic rationale for combined CDK8-BET inhibition in molecularly defined AML subsets, which will require validation in functional LSC assays and primary specimens."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD3 • CD34 • CD38 • CDK9 • RUVBL1 • STAT5

ROVER-01: RVU120 Rollover Study (clinicaltrials.gov) - P2 | N=14 | Enrolling by invitation | Sponsor: Ryvu Therapeutics SA | Not yet recruiting ➔ Enrolling by invitation | N=10 ➔ 14

Enrollment change • Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor

Targeting CDK8 dually enhances paclitaxel antitumor efficacy and alleviates chemotherapy-induced peripheral neuropathy in breast cancer. (PubMed, Front Pharmacol) - "CDK8 is a dual target linking chemoresistance and neurotoxicity. Inhibiting CDK8 with romaciclib may improve paclitaxel therapy while reducing its side effects."

Journal • Breast Cancer • Neuralgia • Oncology • Pain • Peripheral Neuropathic Pain • Solid Tumor • CDK9

POTAMI-61: Clinical trial testing an investigational drug RVU120 for myelofibrosis (myeloproliferative neoplasm, MPN) (clinicaltrialsregister.eu) - P1/2 | N=83 | Active, not recruiting | Sponsor: Ryvu Therapeutics S.A. | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

ROMACICLIB (RVU120), A SELECTIVE CDK8/19 INHIBITOR, AS MONOTHERAPY OR IN COMBINATION WITH RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS: UPDATED RESULTS FROM THE PHASE II POTAMI-61 STUDY (EHA 2026) - P2 | "Summary/Conclusion Romaciclib, administered as monotherapy or combined with RUX, demonstrates a manageable safety profile in patients with MF without significant treatment-related cytopenias. Prolonged exposure, spleen volume reductions, including in patients with high molecular risk mutations, and favorable hematologic tolerability support continued clinical development and further evaluation in expansion cohorts."

Clinical • Combination therapy • Monotherapy • P2 data • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Myelofibrosis • Neutropenia • Thrombocytopenia • ASXL1

UPDATED FINDINGS FROM THE PHASE 2 RIVER-81 STUDY OF ROMACICLIB (RVU120) COMBINED WITH VENETOCLAX IN ACUTE MYELOID LEUKEMIA AFTER FIRST-LINE VENETOCLAX AND HYPOMETHYLATING AGENT FAILURE (EHA 2026) - P1, P2 | "The 150 mg QD regimen achieved the most consistent responses and was selected for expansion based on integrated safety, PK, and efficacy findings. These data support continued clinical development of this combination in a population with limited therapeutic options."

Clinical • P2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Thrombocytopenia • CDK9 • IL6 • STAT3 • STAT5

ROVER-01: RVU120 Rollover Study (clinicaltrials.gov) - P2 | N=29 | Not yet recruiting | Sponsor: Ryvu Therapeutics SA | N=20 ➔ 29

Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor

ROVER-01: RVU120 Rollover Study (clinicaltrials.gov) - P2 | N=10 | Not yet recruiting | Sponsor: Ryvu Therapeutics SA | N=29 ➔ 10

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

Phase I study of CDK8 inhibitor RVU120 in combination with everolimus in children with recurrent or progressive Group 3 or 4 medulloblastoma; MEDWAY (clinicaltrialsregister.eu) - P1 | N=48 | Not yet recruiting | Sponsor: Instytut Pomnik Centrum Zdrowia Dziecka

New P1 trial • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor

FGFR3 altered bladder cancer exhibits a lineage-dependent vulnerability (AACR 2024) - "Moreover, the synergy in FGFR3-mutant cells was superior to that of SHP2 inhibitor SHP099 or the ERK inhibitor BVD-523...By contrast, Sel120+Erdafitinib induced complete responses in 8/10 mice compared to 6/10 mice for SHP099+Erdafitinib...Our results suggest an immediate and promising benefit in combining either CDK8/19 or SHP2 inhibitors with Erdafitinib in treating patients with FGFR3 alteration driven bladder cancers. Furthermore, we identified a strategy in targeting lineage modulators as sensitizers to existing therapies."

Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • FGFR3 • GATA3 • PPARG

Combination JAK1/2 and CDK8/19 inhibition demonstrates enhanced efficacy in myeloproliferative neoplasms (AACR 2024) - "Ruxolitinib (RUX) is a JAK1/2 inhibitor used to treat myelofibrosis (MF) and hydroxyurea-resistant/intolerant polycythemia vera. Further, in vivo treatment with RVU120/RUX+RVU120 resulted in significant reductions of disease manifestation (splenomegaly, WBC, fibrosis scoring, hematopoiesis) when compared to VEH/RUX. These data nominate JAK1/2 and CDK8/19 inhibition as a potential novel therapeutic strategy in MPNs; further work on nascent RNA expression and cytokine profiles will potentially elucidate additional mechanisms of action."

Clinical • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • JAK1 • JAK2 • STAT5

Targeting CDK8: A translatable therapeutic approach for fusion-positive aRMS (AACR 2024) - "CDK8 expression is notably elevated in aRMS tumors compared to other pediatric tumors, and aRMS cell lines exhibit significantly higher CDK8 protein levels than non-transformed primary skeletal muscle cells.We next validated these in silico results through the application of shRNA knockdown, CRISPR knockout, and the use of CDK8 kinase inhibitory small molecules, including BI-1347, SEL-120-34A, and JH-XII-178, which demonstrated on-target activity as assessed by STAT1Ser727 phosphorylation...We discovered that loss of CDK8 led to gain of chromatin accessibility and the upregulation of hallmark genes involved in myogenesis, such as MYH3, MYOG, MEF2C, and MYBPH, as well as alteration of PAX3-FOXO1 gene expression programs. We next validated this differentiation phenotype both in vitro through detection of increased myogenin staining by immunofluorescence and in vivo by visualization of myofibrils in the xenograft tumors and increased myoglobin quantified by qRT-PCR after..."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FOXO1 • MB • MEF2C • MYBPH • MYH3 • Myogenin • PAX3

ROVER-01: RVU120 Rollover Study (clinicaltrialsregister.eu) - P1/2 | N=20 | Recruiting | Sponsor: Ryvu Therapeutics S.A.

New P1/2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor

Romaciclib, a CDK8/CDK19 inhibitor, can overcome venetoclax resistance through a combinatorial strategy. (PubMed, bioRxiv) - P2 | "These findings prove the highly synergistic mechanism of action of RVU120+VEN combination and the potential to overcome primary/acquired VEN resistance in relapse/refractory AML disease. Altogether, the presented results support ongoing clinical studies evaluating romaciclib and VEN in VEN/HMA-refractory patients ( NCT06191263 ) and provide a basis for future exploration as a frontline therapy in VEN-naïve patients."

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

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