Paper Details

ABSTRACT

Background:

Polycythemia vera (PV) and myelofibrosis (MF) are myeloproliferative neoplasms frequently driven by the Janus Kinase 2 (JAK2) V617F mutation, resulting in constitutive JAK-STAT signaling, abnormal hematopoiesis, and significant symptom burden. Although approved JAK inhibitors improve symptoms and splenomegaly, they lack mutant selectivity, are dose-limited by cytopenias and immunosuppression, and do not meaningfully modify disease course. Furthermore, many patients experience loss of response or disease progression despite ongoing JAK inhibitor treatment, highlighting the need for therapies that target oncogenic JAK2 signaling more effectively. PRT12396 is a JAK2 V617F mutant-selective JAK homology 2 (JH2) allosteric inhibitor that interacts directly with the structural phenylalanine-triad motif and has demonstrated potent and selective inhibition of mutant signaling, reduction of splenomegaly, and favorable hematologic effects in preclinical models. Recent preclinical studies further showed that JAK2 V617F mutated SET2 cells chronically cultured with ruxolitinib to model adaptive persistence showed comparable PRT12396 potency to naïve cells by viability assay, with suppression of elevated pJAK2 and pSTAT5. These findings support JAK-STAT pathway inhibition by PRT12396 independent of ruxolitinib persistence status, providing additional rationale for clinical evaluation in patients with PV and MF.

Aims:

The primary objectives of PRT12396-01 are to evaluate the safety and tolerability of PRT12396, determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE), and recommended dose for expansion (RDE). Secondary objectives include assessment of preliminary efficacy in PV and MF, pharmacokinetics (PK), and patient-reported outcomes including symptom burden. Exploratory objectives include pharmacodynamic and biomarker analyses, including changes in JAK2 V617F variant allele frequency and downstream signaling.

Methods:

This first-in-human, multicenter, open-label, Phase 1 study is enrolling patients with high-risk PV (Group A) or intermediate-1, intermediate-2, or high-risk primary MF, post-PV MF, or post-essential thrombocythemia MF (Group B). Eligible patients must have a documented JAK2 V617F mutation and disease that is refractory, have lost response to or are intolerant to prior standard therapies, including JAK inhibitors for MF.

The study consists of two parts. Part 1 is a parallel dose-escalation phase in PV and MF cohorts using a Bayesian optimal interval design. PRT12396 is administered orally twice daily in 28-day cycles across parallel escalating dose levels to evaluate safety and dose-limiting toxicities during Cycle 1 and to define the MTD and/or maximum administered dose. Part 2 comprises two dose-expansion cohorts, a PV cohort and an MF cohort, each enrolling approximately 20 patients at the selected RDE(s) to further assess safety, efficacy, and PK. Key efficacy endpoints include hematologic response and hematocrit control without phlebotomy in PV, spleen volume reduction and transfusion independence in MF, and changes in symptom burden in PV and MF, measured by MPN-SAF TSS and PGIC. Treatment continues until disease progression, unacceptable toxicity, or loss of clinical benefit.

Conclusions:

The potent and excellent preclinical activity of PRT12396 in ruxolitinib-persistent models forms the basis of further evaluation in patients with myeloproliferative neoplasms including those with prior JAK inhibitor exposure. This Phase 1 study will characterize the safety, tolerability, and optimal dosing of PRT12396 and provide initial clinical and biologic evidence supporting selective JAK2 V617F inhibition as a novel therapeutic strategy with disease-modifying potential in patients with PV and MF, including those previously treated with JAK inhibitors. The study is open and actively enrolling eligible patients. ClinicalTrials.gov identifier: NCT07469891.