Prelude Therapeutics Opens First-in-Human Study of Mutant-Selective JAK2 Inhibitor PRT12396 in Myeloproliferative Neoplasms
Prelude Therapeutics Incorporated (Nasdaq: PRLD) has registered a Phase 1 clinical trial for PRT12396, a first-in-class, oral, allosteric inhibitor that selectively targets the JAK2 V617F mutation through the JH2 pseudokinase domain. The PRT12396 clinical trial, which received FDA IND clearance in February 2026, will enroll adults with high-risk polycythemia vera and myelofibrosis — two chronic myeloproliferative neoplasms driven predominantly by constitutive JAK-STAT signaling. PRT12396 enters clinical development as the second known JAK2 V617F JH2-domain inhibitor to reach first-in-human testing, following Eilean Therapeutics' ZE74-0282, which began dosing in December 2025. Incyte Corporation holds an exclusive option to acquire the PRT12396 program globally.
The open-label, multi-center study (NCT07469891) plans to enroll approximately 100 participants across two sequential parts: dose escalation (Part 1) to identify the maximum tolerated dose and recommended dose for expansion, followed by dose expansion (Part 2) in separate polycythemia vera and myelofibrosis cohorts. PRT12396 is administered as an oral capsule twice daily. Primary endpoints center on safety: incidence of dose-limiting toxicities assessed during a four-week first cycle, incidence and severity of treatment-emergent adverse events graded per NCI CTCAE v6.0, adverse events leading to dose modification or discontinuation, and determination of the MTD. Secondary endpoints include pharmacokinetic parameters (Cmax, AUC, T1/2, clearance, accumulation, steady-state trough concentrations), hematologic response rate and duration of response in polycythemia vera participants, spleen volume reduction and symptom burden (MPN-SAF TSS, PGI-C) in myelofibrosis participants, and changes in hemoglobin, platelet count, and transfusion independence in the myelofibrosis cohort. Eligible patients must be aged 18 or older with ECOG performance status 0–2, a confirmed diagnosis per WHO 2016 or ICC/WHO 2022 criteria, and a documented JAK2 V617F mutation. The trial excludes patients with prior systemic therapy for their MPN, prior allogeneic transplant, or concurrent use of strong CYP3A4 modulators. The estimated primary completion date is Q2 2028.
The biological rationale for PRT12396 rests on the structural consequences of the JAK2 V617F point mutation. In normal physiology, the JH2 pseudokinase domain exerts autoinhibitory control over the adjacent JH1 catalytic kinase domain. The V617F substitution disrupts this regulation, producing ligand-independent JAK-STAT activation that drives clonal expansion of myeloid progenitors. Approved JAK inhibitors — ruxolitinib, fedratinib, pacritinib, momelotinib — bind the JH1 ATP-binding pocket and inhibit both wild-type and mutant JAK2 indiscriminately, which controls symptoms and splenomegaly but causes dose-limiting cytopenias and achieves limited reduction in mutant allele burden. PRT12396 binds instead to the JH2 domain at the site of the V617F mutation, restoring autoinhibition selectively in mutant cells. Preclinical data presented at ASH 2025 showed that PRT12396 suppressed JAK2 V617F-dependent proliferation in multiple MPN models while sparing normal hematopoiesis, with minimal hematologic toxicity compared to ruxolitinib. Structural and functional studies have established the feasibility of selectively uncoupling mutant JAK2 activation from normal cytokine signaling by modulating the JH2 αC helix. Earlier work on other mutant-selective compounds such as LY2784544 and ZT55 provided proof-of-principle that targeting V617F selectively could suppress MPN pathogenesis.