ZE74-0282 / Eilean Therap - LARVOL DELTA

ZE74-0282 is a novel JH2 domain JAK2 inhibitor with promising pre-clinical activity in JAK2 V617F mutant diseases (ASH 2025) - "Current available JAK2 inhibitortherapies such as ruxolitinib and fedratinib target the JH1 domain and provide symptomatic relief but arelimited by non-selective JAK inhibition and disruption of WT JAK2 signaling. ZE74-282 is a first-in-class, JH2 domain specific JAK2 inhibitor with potent and selectiveactivity against mutant JAK2V617F while preserving normal JAK2-mediated function. Compared with JH1directed JAK2 inhibitors ZE74-2882 offers a superior therapeutic index in preclinical models,pharmacology suggesting twice daily dosing, and exceptional "drug properties" with ADME studiescompleted to date. These findings support its further development as a potentially disease-modifyingtherapy for JAK2 V617F mutated diseases."

Preclinical • Essential Thrombocythemia • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis • ASXL1

Eilean Therapeutics to Present First-in-Class, Wild-Type-Sparing JAK2-JH2/V617F Inhibitor ZE74-0282 at ASH 2025 and Initiate Clinical Studies in December 2025 (PRNewswire) - "Picomolar potency and > 500-fold selectivity for JAK2 V617F JH2 versus WT JAK2 JH2 in cellular assays; 100× selective inhibition of pSTAT5 phosphorylation and proliferation in BaF3 JAK2 V617F and SET-2 JAK2 V617F cells, with minimal effect on WT cells; Nanomolar potency in selectively reducing pSTAT5 in myeloid cells from human JAK2 V617F⁺ MPN whole-blood assays, with no effect on lymphoid cells—confirming wild-type sparing. In contrast, ruxolitinib suppressed signaling across both lineages; Selective inhibition of colony formation from JAK2 V617F/ASXL1-mutant progenitors, without affecting WT JAK2 progenitors, in murine colony-forming assays....Eilean Therapeutics plans to initiate its first-in-human clinical study of ZE74-0282 in December 2025."

JAK2V617F • New trial • Preclinical • Myeloproliferative Neoplasm