Preclinical data presented at ASH showed that Prelude Therapeutics’ JAK2V617F-selective JH2 inhibitor PRT12396 inhibited mutant JAK2 signaling while preserving wild-type cytokine pathways, delivered activity across multiple MPN models superior to ruxolitinib, selectively suppressed JAK2V617F stem and progenitor proliferation in vitro and in vivo, and produced minimal hematologic impact in toxicology studies. The company has completed GLP tox and targets an IND and Phase 1 start in Q1 2026. Prelude also disclosed preclinical results from a mutant calreticulin (mCALR)-targeted degrader antibody conjugate that delivers a CDK9 degrader payload, showing mutant-selective cytotoxicity across cell lines, HSPCs, and primary cultures with in vivo efficacy and sparing of healthy hematopoietic cells.
The core development is a two-track push in MPNs: an oral, mutant-selective JAK2 allosteric inhibitor designed to reduce allele burden without the cytopenias associated with wild-type JAK inhibition, and a first-in-class mCALR-directed degrader antibody conjugate intended to deepen disease modification by targeting a validated neoantigen. Prelude’s JAK2V617F program sits under an exclusive option with Incyte, while the mCALR program leverages the company’s protein degradation payload chemistry inside an ADC-like format.
Strategically, this is a bid to move MPN therapy beyond symptom and spleen control and toward clonal eradication or durable modification. Targeting the JH2 deep pocket to spare wild-type function addresses the long-standing toxicity ceiling for JAK inhibitors that limits dosing intensity and combinations. Pairing that with a payloaded antibody against mCALR signals an intent to segment the MPN population by driver mutation and prosecute parallel registrational paths. The Incyte option is notable: the ruxolitinib franchise faces pressure from new entrants and combination strategies, and a mutant-selective asset could hedge lifecycle risk or enable differentiated combinations if the safety profile holds up clinically.
For sites and CROs, this portfolio points to trials that are operationally familiar yet analytically demanding. JAK2V617F and CALR testing are standard in MF, ET, and PV, easing molecular screening, but sponsors will likely prioritize allele burden reduction, fibrosis grade shifts, and molecular responses as decision-driving endpoints, necessitating centralized NGS, standardized pathology reads, and tight PK/PD integration. If mutant selectivity translates, cytopenia management may be less burdensome than with current JAK inhibitors, potentially broadening eligibility and reducing dose interruptions. The mCALR DAC introduces ADC-like operational requirements: conjugate-specific CMC, stability tracking, specialized bioanalytical assays for degrader payloads, and careful monitoring for transcriptional toxicities associated with CDK9 targeting, even with tumor-restricted delivery. Vendors supporting degradation pharmacology, translational biomarker panels, and modeling of allelic dynamics will be central.
Near term, watch for IND acceptance, starting-dose rationale, and first-in-human design choices that reveal regulatory intent: early molecular response and allele burden kinetics as co-primary or key secondary endpoints would indicate a push toward disease-modifying claims. Safety readouts in the initial dose-escalation—particularly hematologic tolerability and cytokine signaling preservation—will determine whether combinations with existing JAK inhibitors or BET/transforming agents are viable. For the mCALR program, manufacturability and payload consistency are gating risks, alongside the need to calibrate dosing that captures degrader pharmacology without off-target transcriptional suppression. Competitive tension is building around mutation-selective JAK2 concepts and mCALR-directed biologics; the decisive advantage will be clean clinical differentiation on cytopenias, depth of molecular remission, and operational simplicity. The inflection to watch is whether Incyte exercises its option, which would accelerate site activation through established MPN networks and shape the combination and commercialization roadmap.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
