Phase 1 PRT12396 mutant-selective JAK2V617F inhibitor (allosteric JH2 “pseudokinase” inhibitor) in PV/MF

Prelude Therapeutics is running a first-in-human, open-label, multi-center Phase 1 dose-escalation/expansion study testing PRT12396, an oral, twice-daily small molecule designed to selectively inhibit the JAK2 V617F mutant by binding an allosteric pocket in the JAK2 JH2 (pseudokinase) domain. The goal is to define safety/tolerability, pharmacokinetics, maximum tolerated dose, and recommended dose(s) for expansion, while looking for early signs of clinical activity in high-risk polycythemia vera and intermediate/high-risk myelofibrosis with JAK2 V617F. A key scientific angle is the mutant-selective approach, aiming to suppress the disease-driving clone (and potentially reduce mutant allele burden) rather than broadly inhibiting JAK signaling in normal hematopoiesis. This JAK2V617F program is tied to an exclusive option agreement with Incyte, highlighting commercial interest in a potentially more precise next-generation JAK2 strategy. Today’s care for PV is phlebotomy and cytoreduction (often hydroxyurea) plus aspirin, with ruxolitinib used for hydroxyurea-intolerant/resistant patients; for MF, care commonly includes JAK inhibitors such as ruxolitinib or fedratinib for symptom/spleen control, with transplant for select candidates—so this trial probes whether a mutation-targeted JAK2 inhibitor can improve depth of response and tolerability versus current pathway-level inhibition.