Ryvu Therapeutics announced new data demonstrating clinical and preclinical activity of its selective CDK8/19 inhibitor RVU120 and its selective PIM/FLT3 inhibitor SEL24 (MEN1703) at the 64thAmerican Society of Hematology (ASH) Annual Meeting & Exposition, which is being held on December 10–13, 2022, in New Orleans, Louisiana. Phase 1b Interim Efficacy and Safety Results on RVU120 as of a cut-off date of November 11, 2022: 16 relapsed/refractory (R/R) acute myeloid leukemia (AML) and 3 high-risk myelodysplastic syndrome (HR-MDS) patients with a median of 3 prior lines of therapy have been treated with RVU120 at doses between 75 and 110 mg; Clinical activity was demonstrated in 9 out of 16 evaluable patients, all of them with molecular markers preclinically predicted to respond to CDK8 inhibition; One AML patient achieved a complete response; 4 patients demonstrated blast reductions; 4 patients showed erythroid and/or platelet responses; RVU120 was generally well tolerated at all doses; Most frequent adverse events were nausea/vomiting, worsening of thrombocytopenia grade 3 to 4, and febrile neutropenia; After the data cut-off for the poster, dose escalation has continued, and the 110 mg dose cohort has now been fully enrolled. In total, 22 patients have been enrolled in the study through December 7, 2022.
Additionally, the on-target activity of RVU120 was evaluated in AML and HR-MDS patient samples by measuring changes in pSTAT5 levels. As of the cut-off date, the inhibition of pSTAT5 reached >50% in some patients, a threshold, that may be sufficient for robust efficacy in certain groups of super-responder patients. Combined results from the ongoing dose-escalation trials (in 10-135 mg dose range) in AML/HR-MDS and solid tumor patients indicate that pSTAT5 inhibition is dose-dependent. Ryvu licensee, Menarini Group, and academic collaborators presented new data on SEL24 (MEN1703), a first-in-class, oral, dual type I PIM/FLT3 inhibitor. Combination therapy of SEL24 (MEN1703) with gilteritinib, a highly potent and selective oral FLT3 inhibitor, induces strong tumor regression and complete responses in vivo, demonstrating the potential of concomitant FLT3 and PIM inhibition kinases in AML. SEL24 (MEN1703)-induced PIM inhibition, and the mechanism of action was also demonstrated in vitro in multiple myeloma (MM), classical Hodgkin lymphoma-tumor-associated macrophages (cHL-TAMs), and diffuse large B-cell lymphoma (DLBCL) models. In multiple myeloma preclinical models, SEL24 (MEN1703) induces cytotoxicity of MM cell lines, disrupts MM endothelial cell vessel formation, and decreases the activity of several pathways essential for myeloma cell survival. This study demonstrates the promising therapeutic potential of SEL24 (MEN1703) in MM and reveals the underlying mechanism of PIM inhibition. Indeed PIM-dependent oncogenic signaling pathways were also inhibited following SEL24 (MEN1703) treatment of MM cells.