Precision Strike: Atavistik Unveils Mutant-Selective JAK2 Inhibitor

CAMBRIDGE, MA – December 04, 2025 – In a move poised to challenge the current standard of care for a group of chronic blood cancers, Atavistik Bio has announced it will present the discovery of a novel, highly selective inhibitor for myeloproliferative neoplasms (MPNs). The data, slated for debut at the prestigious 67th American Society of Hematology (ASH) Annual Meeting this weekend, details a precision-engineered compound designed to overcome the critical limitations of existing therapies, shifting the treatment paradigm from symptom management to genuine disease modification.

This announcement places the Cambridge-based biotech at the forefront of a major strategic pivot in oncology: the move towards allosteric inhibition. By targeting the specific genetic driver of the disease while sparing healthy cells, Atavistik’s approach could offer a powerful new weapon for patients with polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF).

The Allosteric Advantage: A Paradigm Shift from Pan-JAK Inhibition

For years, the treatment of MPNs has been dominated by pan-JAK inhibitors, most notably ruxolitinib. These drugs work by blocking the active site of the Janus kinase (JAK) family of enzymes, which play a central role in the signaling pathways that drive abnormal blood cell production. While effective at providing symptomatic relief, their broad mechanism is a double-edged sword. These inhibitors block both the mutated JAK2 V617F protein—the driver mutation in the vast majority of MPN cases—and the healthy, wild-type JAK2 protein essential for normal hematopoiesis, or blood cell formation.

This lack of selectivity leads to significant dose-limiting toxicities, including anemia and thrombocytopenia, and prevents clinicians from administering doses high enough to meaningfully reduce the mutant allele burden—the proportion of cells carrying the cancerous mutation. Consequently, current therapies manage the disease but rarely alter its long-term course or lead to deep, molecular remissions.

Atavistik Bio is tackling this challenge head-on with a fundamentally different strategy. Its new compounds are allosteric inhibitors, meaning they bind to a secondary, regulatory site on the JAK2 protein, not the highly conserved active site. This allosteric pocket is located on the pseudokinase JH2 domain, which is precisely where the V617F mutation occurs. This elegant approach, developed using the company's proprietary AMPS™ platform, allows the drug to selectively bind to and inhibit only the mutated form of the protein.

Preclinical data to be presented at ASH demonstrates the power of this design. Atavistik’s inhibitors show picomolar affinity for the JAK2 V617F mutant and over 100-fold selectivity against other JAK family kinases. In cell models, they potently shut down mutant-driven signaling while leaving wild-type JAK2 pathways untouched—a level of precision current therapies cannot match.

“Unlike pan-JAK inhibitors that broadly target JAK2 and can only manage symptoms of myeloproliferative neoplasms, our highly selective allosteric JAK2 V617F mutant-selective inhibitors have the potential to deliver durable responses and mitigate off-target hematological effects, offering a powerful disease-modifying benefit and addressing the unmet needs of this patient population,” said Marion Dorsch, Ph.D., President and Chief Scientific Officer at Atavistik Bio, in the company’s press release.

Redefining Patient Outcomes: Beyond Symptom Control

The clinical implications of this scientific innovation are profound. For patients living with MPNs, the prospect of a therapy that can not only alleviate symptoms but also attack the root cause of the disease is a significant leap forward. By selectively eradicating the mutant cell population, Atavistik's approach holds the potential to reduce the risk of disease progression, thrombotic events, and transformation to acute leukemia—the most feared complications of MPNs.

An effective mutant-selective inhibitor could, for the first time, make molecular remission a realistic goal for a broad swath of MPN patients. This would represent a shift from chronic management to potentially curative-intent therapy. Furthermore, by sparing wild-type JAK2, the therapy promises a much-improved safety and tolerability profile. Avoiding the hematological side effects that plague current treatments would not only enhance patient quality of life but also allow for more consistent and effective dosing, potentially leading to more durable responses.

This focus on disease modification aligns with a broader trend in oncology, where the ultimate goal is not just to extend survival but to restore health and eliminate the underlying cancer. If successful in the clinic, Atavistik’s program could set a new benchmark for what patients and physicians expect from an MPN therapy.

A Crowded Field of Innovators

Atavistik Bio is not operating in a vacuum. The clear unmet need and the compelling scientific rationale for mutant-selective JAK2 inhibition have drawn intense interest from competitors. The upcoming ASH meeting will serve as a key battleground, with several companies poised to unveil their own next-generation inhibitors. Eilean Therapeutics and Cogent Biosciences, for instance, are also presenting preclinical data on their respective wild-type-sparing JAK2 V617F inhibitors, with both signaling aggressive development timelines. Even industry giant Incyte, which markets the blockbuster pan-JAK inhibitor Jakafi, is presenting its own selective inhibitor, INCB160058.

This competitive flurry underscores the perceived value of cracking the code to selective JAK2 inhibition. The race is on to see which company can translate promising preclinical selectivity and potency into a safe and effective clinical candidate. Success will depend not only on the molecule's intrinsic properties but also on clinical trial design, regulatory strategy, and speed to market. For industry observers and investors, ASH 2025 will offer a crucial first look at how these competing programs stack up against one another.

Strategic Positioning and The Road Ahead

Despite the competition, Atavistik Bio appears well-positioned for the challenge. Launched in 2021 with a substantial $60 million Series A and an additional $40 million in 2023, the company is backed by top-tier life science investors, including The Column Group and Lux Capital. This strong financial footing provides the runway needed for capital-intensive clinical development.

Moreover, the JAK2 program is not the company’s only shot on goal. Atavistik is already advancing another allosteric inhibitor, ATV-1601, in a Phase 1 trial for solid tumors, demonstrating its platform’s capacity to generate multiple clinical-stage assets. A research collaboration with Pfizer, announced early in 2025, further validates the potential of its AMPS™ discovery engine and provides non-dilutive capital.

The preclinical data revealed for its JAK2 program represents a critical milestone, showcasing the power of its allosteric discovery platform. The next steps will be to advance a lead candidate through IND-enabling studies and into the clinic. The journey from a compelling preclinical profile to an approved drug is long and fraught with risk, but for Atavistik Bio, the path forward is clear. The upcoming clinical trials will be the ultimate test of whether this innovative scientific approach can truly redefine the treatment landscape for thousands of patients with myeloproliferative neoplasms.