On November 2, 2023 Ryvu Therapeutics [WSE:RVU], a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported 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) (Free ASH Whitepaper) Annual Meeting & Exposition, which is being held on December 9 –12, 2023 in San Diego, California (Press release, Ryvu Therapeutics, NOV 2, 2023, View Source [SID1234636828]).

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"At this year’s ASH (Free ASH Whitepaper) 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.