On December 1, 2020 Ryvu Therapeutics (WSE: RVU), a clinical-stage biopharmaceutical company developing novel small molecule therapies that address emerging targets in oncology, reported the positive results of the pharmacodynamic assay demonstrating target engagement in the dose escalation part of the DIAMOND-01 trial (CLI24-001; clinicaltrials.gov identifier NCT03008187), a study investigating SEL24/MEN1703, a first-in-class, orally available, dual PIM/FLT3 inhibitor as single agent in acute myeloid leukemia (AML) (Press release, Ryvu Therapeutics, DEC 1, 2020, View Source [SID1234572066]).
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The poster entitled "SEL24/MEN1703 provides PIM/FLT3 Downstream Pathway Inhibition in Acute Myeloid Leukemia (AML) Blast Cells: Results of the Pharmacodynamic (PD) Assay in the Dose Escalation Part of First-in-Human DIAMOND Trial" will be presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, which will take place virtually on December 5-8.
"We are very happy to see SEL24/MEN1703 progressing through clinical development. The positive preliminary data from the dose escalation phase of DIAMOND-01 trial shows a manageable safety profile, signs of efficacy and a meaningful target engagement in peripheral blood and bone marrow blast cells of AML patients treated with SEL24/MEN1703," said Setareh Shamsili, MD, PhD, Chief Medical Officer of Ryvu Therapeutics. "At the same time, we are delighted to see that further research performed on PIM kinases inhibition as a potential therapeutic strategy in other hematologic malignancies – such as diffused large B-cell lymphoma and multiple myeloma – is ongoing in cooperation with our global development partner and trial sponsor Menarini and our academic partners, and results show promising potential for targeting PIM kinases in other hemato-oncology indications. Together with Menarini, we are fully focused on delivering the most effective and safe treatment options to cancer patients worldwide."
DIAMOND-01 is the First-in-Human, Phase I/II dose escalation and cohort expansion trial of SEL24/MEN1703, in-licensed from Ryvu Therapeutics by Menarini, in AML. The study has completed the dose escalation part showing a manageable safety profile up to the recommended dose of 125 mg/day, with initial evidence of anti-leukemic activity in a single agent setting.
The objective of the pharmacodynamic assessment was to investigate the degree of target engagement achieved at different doses of SEL24/MEN1703, by evaluating the phosphorylation of S6 (pS6), a downstream effector of the PIM/FLT3 signaling pathway. In addition, the correlation between pS6 levels and the anti-leukemic effect of SEL24/MEN1703 was assessed in samples collected from patients enrolled in the dose escalation part of the DIAMOND-01 trial. The quantitative assessment of pS6 at a single-cell level was performed both on peripheral blood (PB) and bone marrow (BM) blast cells samples.
The results of this assay confirmed that meaningful target engagement has been achieved, both in PB and BM blast cells, in patients treated with SEL24/MEN1703 at 100 mg/day (one dose level below the recommended dose) and at 125 mg/day. Moreover, preliminary data suggest that the PIM/FLT3 pathway inhibition might be associated with blast count reduction, particularly in those patients showing high phosphorylation of S6 at baseline.
Longitudinal monitoring of PD will be continued in the cohort expansion part of the DIAMOND-01 trial, which is currently recruiting patients with relapsed or refractory AML in both the EU and the US.
Two additional posters regarding the potential therapeutic effect of PIM kinases inhibition – in both cases carried out using SEL24/MEN1703 – in other hematological cancers, namely diffuse large B-cell lymphoma and multiple myeloma, will also be published at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition; :
– "Inhibition of PIM Kinases in Diffuse Large B-Cell Lymphoma Cells Targets MYC-Dependent Transcriptional Program, Increases CD20 Expression and Augments the Efficacy of Anti-CD20 Antibodies," characterizing a PIM-MYC regulatory circuit promoting DLBCL growth and resistance to anti-CD20 antibody, as well as demonstrating that PIM inhibition exhibits pleiotropic effects that combine direct cytotoxicity with increased surface CD20 levels and increased susceptibility to anti-CD20 antibody-based therapies;
– "PIM Kinase Inhibition Decreases the Proangiogenic Properties of Multiple Myeloma Cells and Affects the Metabolic State of the Vascular Endothelium," which demonstrates that PIM inhibition induces MM cell death and abolishes important tumor cell-ECs interactions. In addition, research shows that PIM3 is overexpressed in MM tumor endothelial cells and PIM inhibition disrupts the activation state in in vitro cultured ECs. Hence, targeting PIM kinases may represent an efficient approach to induce tumor cell death and to block angiogenesis in MM.