Ryvu Therapeutics, a clinical-stage drug discovery and development company focused on novel small molecule therapies for oncology, will present significant clinical and preclinical data from its pipeline at two major scientific conferences: the 2024 American Association for Cancer Research (AACR) Annual Meeting in April and the European Hematology Association (EHA) Congress in June.
The presentations will highlight progress across the company's portfolio, with particular emphasis on RVU120, a selective CDK8/19 kinase inhibitor, and several synthetic lethality programs targeting specific genetic vulnerabilities in cancer.
RVU120 Shows Promising Clinical Activity in Hematologic Malignancies
Updated data from the Phase I trial of RVU120 in patients with relapsed/refractory acute myeloid leukemia (r/r AML) or high-risk myelodysplastic syndromes (HR-MDS) demonstrate encouraging results. Among 29 evaluable patients (out of 38 total dosed), 15 experienced clinical benefit with red blood cell transfusion independence and/or blast reduction.
Notably, a complete remission (CR) was achieved in a patient with NPM1 and DNMT3A mutations, while three patients with HR-MDS achieved marrow CRs. The data support a recommended Phase II dose of 250mg, with relevant target inhibition observed at doses of 110 mg or higher.
"RVU120 has demonstrated clinical activity as a single agent in 15 of 29 evaluable patients with AML and HR-MDS at tolerated doses," said Dr. Hendrik Nogai, Chief Medical Officer at Ryvu Therapeutics. "Furthermore, our preclinical data demonstrate the synergistic potential of RVU120 in combination with venetoclax, representing a promising strategy against resistance in AML."
Expanding Development with Four Phase II Studies
Based on these encouraging results, Ryvu has outlined an ambitious development plan for RVU120 that includes four Phase II studies:
- The RIVER-52 study: RVU120 as monotherapy in patients with genetically defined AML or HR-MDS
- The RIVER-81 study: RVU120 in combination with venetoclax in patients with r/r AML
- The POTAMI-61 study: RVU120 in patients with myelofibrosis
- The REMARK study: An investigator-initiated trial in patients with low-risk MDS
Synergistic Combinations Show Promise in Preclinical Models
Preclinical data to be presented at both conferences highlight the potential of RVU120 in combination therapies. Research conducted in collaboration with Prof. Raajit Rampal's group from Memorial Sloan Kettering Cancer Center demonstrates synergistic effects when combining RVU120 with ruxolitinib, a JAK1/2 inhibitor, for the treatment of myeloproliferative neoplasms (MPN).
The combination resulted in significant reductions in disease manifestations, including splenomegaly, white blood cell counts, fibrosis scoring, and hematopoiesis compared to vehicle or ruxolitinib alone. These findings suggest that dual inhibition of JAK1/2 and CDK8/19 could represent a novel therapeutic strategy in MPNs, particularly myelofibrosis.
Similarly, preclinical studies show synergistic potential when combining RVU120 with venetoclax in AML models, including the ability to potentially overcome resistance to venetoclax treatment. The Phase II RIVER-81 study is currently investigating this combination in patients with AML.
Advancing Synthetic Lethality Programs
Beyond RVU120, Ryvu will present updated preclinical data from its synthetic lethality pipeline at the AACR Annual Meeting. These programs exploit specific genetic vulnerabilities in cancer cells to develop targeted therapies.
"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," said Krzysztof Brzózka, Ph.D., Chief Scientific Officer of Ryvu Therapeutics. "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."
PRMT5 Inhibitors for MTAP-Deleted Cancers
Co-deletion of MTAP occurs in approximately 10-15% of all human tumors, including non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma. These cancers typically have poor prognoses, highlighting a significant unmet medical need.
Ryvu has developed potentially best-in-class MTA-cooperative PRMT5 inhibitors that show favorable drug-like properties and effective PRMT5 inhibition dependent on MTA binding. These compounds demonstrate high target engagement in cells and selective potency in MTAP-deleted cell lines, with favorable pharmacokinetic profiles allowing for oral administration.
WRN Inhibitors for Microsatellite Unstable Tumors
Another promising program in Ryvu's synthetic lethality pipeline focuses on WRN inhibitors for the treatment of microsatellite unstable (MSI-H) tumors. This instability, resulting from deficiency in DNA mismatch repair mechanisms, is prevalent in 10-30% of colorectal, gastric, endometrial, and ovarian cancers.
Structure-based optimization has enabled the rapid development of a compound library with novel intellectual property, demonstrating target engagement in cells and selective potency over other RecQ family members. In vivo studies have confirmed efficacy in xenograft MSI-H cancer models, providing pharmacological proof-of-concept for the synthetic lethal effect of these inhibitors.
Innovative Platform for Target Discovery
Ryvu will also present its cutting-edge drug discovery platform that uniquely combines high throughput capabilities with precision and translational impact. The platform leverages primary cells, including human stem cell-derived model cells, patient-derived xenografts, and clinical samples to identify synthetic lethal targets specific to oncogenic pathways.
By integrating CRISPR/Cas9 technology, phenotypic screening, RNA-seq, and whole-exome sequencing, the platform enables rapid identification of molecular vulnerabilities. Initial results from engineered intestinal primary models representing frequently altered genes in colorectal cancer, including KRAS G12D mutation, will be presented.
Partner Programs Show Progress
Ryvu's partner Menarini will present data on MEN1703 (SEL24), a dual PIM/FLT3 kinase inhibitor licensed from Ryvu. The data demonstrate promising anti-tumor activity in preclinical models of myelofibrosis both as a single agent and in combination with ruxolitinib.
MEN1703 exhibited in vitro activity at clinically relevant concentrations, and the combination with ruxolitinib showed synergistic effects. Molecular analyses confirmed the inhibition of downstream targets of PIM, supporting the therapeutic potential of MEN1703 in myelofibrosis treatment strategies.
Looking Forward
With multiple clinical and preclinical programs advancing, Ryvu Therapeutics is positioned at the forefront of developing novel targeted therapies for cancer. The company's dual focus on CDK8/19 inhibition and synthetic lethality provides a diverse pipeline addressing significant unmet needs in oncology.
"We are excited to present our latest data at these prestigious conferences, showcasing our significant progress in advancing novel small molecule therapies for oncology," said Dr. Brzózka. "Our discovery platform continues to produce novel precision medicine targets and drugs, and we are proud to highlight platform data with broader applicability across cancers."
As Ryvu's programs progress through clinical development, the company aims to transform treatment options for patients with difficult-to-treat cancers through innovative, targeted approaches based on deep understanding of cancer biology.
