MEN1703

P2, N=178, Recruiting, Ryvu Therapeutics SA | Not yet recruiting --> Recruiting

We also show that MEN1703 downregulates stromal cytokines that promote cytokine-mediated resistance of AML blast cells to FLT3 inhibition. These results demonstrate the importance of the combination approach to overcome microenvironment-mediated resistance to FLT3 inhibitors.

P2, N=178, Not yet recruiting, Ryvu Therapeutics SA

P1/2, N=73, Completed, Menarini Group | Active, not recruiting --> Completed | Trial completion date: Sep 2022 --> May 2023 | Trial primary completion date: Sep 2022 --> May 2023

Our data suggest that PIMs support pro-tumoral and immunosuppressive phenotype of cHL-TAMs. Since PIM activity is required for RS cell survival and immune escape, these kinases are rational targets for therapy in cHL, suggesting the use of PIM inhibitors, such as MEN1703, as a possible therapeutic approach .

The higher efficacy of this combination in-vivo and compared to monotherapy could be related to a very potent concomitant inhibition of FLT3 and PIM kinases affecting upregulated FLT3 signaling pathway in-vivo as demonstrated by the reduction of phosphorylation of downstream effector proteins, such as pS6. Overall, these experiments have demonstrated the antitumor potential of concomitant inhibition of FLT3 and PIM kinases which could drive a novel therapeutic strategy in AML.

To assess role of PIMs in TAMs RS-M were treated with a dual pan-PIM/FLT3 inhibitor MEN1703 and subjected to transcriptional biochemical and immunophenotype analyses...This suppressive effect was alleviated in cocultures with the PIM inhibitor-treated RS-M.Our data suggest that PIMs support pro-tumoral and immunosuppressive phenotype of cHL-TAMs. Since PIM activity is required for RS cell survival and immune escape these kinases are rational targets for therapy in cHL.

SEL24/MEN1703 had a manageable safety profile and single-agent activity in adult patients with R/R IDHm AML and may be a feasible therapeutic option in this difficult-to-treat population.

SEL24/MEN1703 had a manageable safety profi le and single-agent activity in adult patients with R/R IDHm AML and may be a feasible therapeutic option in this diffi cult-to-treat population.

P1/2, N=68, Active, not recruiting, Menarini Group | Recruiting --> Active, not recruiting

Conclusion Preliminary results in the IDH m cohort confirm that SEL24/MEN1703, a first-in-class, orally available, dual PIM/FLT3 inhibitor, has a manageable safety profile and single-agent activity in patients with R/R IDH m AML. Updated results will be presented at the congress.

Preliminary results in the IDHm cohort confirm that SEL24/MEN1703, a first in class, orally available, dual PIM/FLT3 inhibitor, has a manageable safety profile and single-agent activity in pts with R/R IDHm AML. Updated results will be presented at the congress.

Figure 1. pS6 (%pS6*MFI) assessment in peripheral blast cells at screening and at C1D14-4H in CE patients treated at RD of 125 mg.

Treatment of DLBCL cells with SEL24/MEN1703, a pan PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies.

P1/2, N=68, Recruiting, Menarini Group | N=47 --> 68 | Trial completion date: Oct 2021 --> Sep 2022 | Trial primary completion date: Oct 2021 --> Sep 2022

A total of 3 out of 6 pts with IDH mutations treated at doses ≥75 mg achieved CR/CRi, including a CR in a patient with IDH2 mutant AML relapsed on Enasidenib. Conclusion SEL24/MEN1703 confirmed a manageable safety profile at RD and showed preliminary single agent efficacy in R/R AML, particularly clustering in pts with IDH mutant disease either naïve or previously exposed to IDH inhibitors. These results warrant further investigation of SEL24/MEN1703 in AML, with potential focus in the IDH mutated subset.

R-CHOP immunochemotherapy remains standard frontline therapy for newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients...As expected, in SEL24/MEN1703-treated cells, MYC occupancy at the MS4A1 promoter markedly decreased...We also demonstrate that PIM inhibition exhibits pleiotropic effects that combine direct cytotoxicity with increased surface CD20 levels and increased susceptibility to anti-CD20 antibody-based therapies. Study supported by Foundation for Polish Science (POIR.04.04.00-00-5C84/17-00), Polish National Science Centre (2016/22/M/NZ5/00668 and 2017/26/D/NZ5/00561) and Ministry of Science and Higher Education in Poland (iONCO) grants.