Prelude Therapeutics Shares Findings from Its Myeloproliferative Neoplasm Programs at the 2025 ASH Annual Meeting

12/06/2025 – 11:00 AM

First disclosure of PRT12396, a JAK2V617F‑selective JH2 inhibitor demonstrating disease‑modifying potential in myeloproliferative neoplasms.

PRT12396 has completed GLP toxicology studies and is on track for IND filing in Q1 2026.

First disclosure of a mutant calreticulin (mCALR)‑targeted degrader antibody conjugate with a novel CDK9 degrader payload.

JAK2V617F and mCALR are the primary driver mutations responsible for disease progression and poor prognosis in most MPN patients.

WILMINGTON, Del., Dec. 6, 2025 (GLOBE NEWSWIRE) — Prelude Therapeutics Incorporated (Nasdaq: PRLD), a precision‑oncology company, unveiled early preclinical data on its mutant‑selective JAK2V617F inhibitor and on mutant CALR‑directed degrader antibody conjugates at the 67th American Society of Hematology Annual Meeting in Orlando, Florida.

CEO Kris Vaddi, Ph.D., said, “Since the discovery of JAK2V617F two decades ago, the field has sought an inhibitor that spares wild‑type JAK2. Our lead candidate, PRT12396, achieves this selectivity and outperforms ruxolitinib in multiple disease models, potentially overcoming dose‑limiting toxicities seen with current therapies. We aim to enter the clinic in early 2026.”

He added, “Mutant CALR is the second most common driver in MPNs. A CALR‑directed antibody has already shown benefit in patients, and our degrader antibody conjugate platform builds on that by delivering a potent CDK9 degrader directly to CALR‑mutant cells, offering a differentiated, potentially more efficacious approach.”

The oral presentation titled “Discovery and preclinical characterization of orally bioavailable JAK2V617F‑selective JH2 inhibitors with disease‑modification potential in myeloproliferative neoplasms” detailed how PRT12396 inhibited mutant JAK2 signaling while leaving wild‑type cytokine pathways intact. In mouse models of polycythemia vera, essential thrombocythemia, and myelofibrosis, the compound produced greater reductions in spleen size and mutant allele burden than ruxolitinib. Toxicology studies under GLP conditions showed favorable safety, with minimal impact on hematologic parameters.

GLP toxicology is complete, and the company plans to file an IND and launch a Phase 1 trial in Q1 2026. The JAK2V617F program is governed by an exclusive option agreement with Incyte, signed in November 2025.

In a second oral presentation, “Discovery of first‑in‑class calreticulin‑targeted precision antibody‑drug conjugates delivering a CDK9 degrader payload for CALR‑mutated MPNs,” Prelude showcased mutant CALR × CDK9 DACs that selectively internalize into CALR‑mutant clones, degrade CDK9, and trigger apoptosis. The DACs achieved deep mutant‑selective killing across multiple CALR‑mutant cell lines, primary patient samples, and hematopoietic stem and progenitor cells, while sparing normal hematopoietic cells. In vivo efficacy was demonstrated in xenograft models, supporting a disease‑modifying strategy.

JAK2V617F drives disease in roughly 95% of polycythemia vera, 60% of essential thrombocythemia, and 55% of myelofibrosis patients. Targeting the mutant‑specific JH2 pocket offers a mechanistic route to reduce mutant allele burden, potentially altering disease trajectory. Mutant CALR appears in about 25‑35% of myelofibrosis and essential thrombocythemia patients and represents a neoantigen amenable to antibody‑based therapy.

Prelude’s pipeline also includes selective KAT6A degraders, reinforcing the company’s broader focus on targeted protein degradation technologies. By integrating small‑molecule allosteric inhibition with antibody‑directed degradation, Prelude positions itself at the intersection of precision oncology and next‑generation therapeutics.

For more information, visit Prelude’s website.