WILMINGTON, DE — First clinical data for INCA033989, a novel monoclonal antibody from Incyte (Nasdaq: INCY) targeting CALR-mutant myeloproliferative neoplasms (MPNs), were presented at the European Hematology Association (EHA) Congress 2025. The findings highlight both the safety and the potential disease-modifying capabilities of the agent in treating high-risk essential thrombocythemia (ET).
The Phase 1/2 studies focused on patients with CALR-mutant ET who were resistant to or intolerant of prior cytoreductive therapies. Receiving INCA033989 demonstrated robust results, with 86% of patients at doses of 400 mg and above achieving a partial or complete hematologic response, while 82% achieved complete normalization of platelet counts.
According to Dr. Pablo J. Cagnoni, President and Head of Research and Development at Incyte, “The late-breaking data presented highlight the impact of INCA033989, a novel agent that selectively targets mutant CALR, to inhibit and eliminate cancer-causing cells in patients with essential thrombocythemia. These findings, and the further development of INCA033989, offer the potential to significantly transform the treatment of patients with CALR-mutant myeloproliferative neoplasms.”
Key Findings
- Efficacy: 89% of evaluable patients saw a reduction in the CALR mutation allele frequency in their blood, with 21% achieving a partial molecular response after just three treatment cycles. Platelet counts normalized across all dose levels, with stronger responses observed at higher doses.
- Disease Modification: INCA033989 showed a clear capacity to selectively inhibit mutant CALR cells while promoting the recovery of healthy blood cells. Bone marrow analyses confirmed the agent reduced disease-driving megakaryocytes and supported the restoration of normal hematopoiesis.
- Safety: The therapy was well-tolerated across all tested doses, with no dose-limiting toxicities reported. Common adverse events, such as fatigue and upper respiratory tract infections, were mostly mild (Grade ≤2), and no treatment interruptions occurred.
Dr. John Mascarenhas of the Icahn School of Medicine at Mount Sinai commented on the breakthrough potential of this therapy. “mutCALR is the second most common oncogenic driver of MPNs, yet the therapeutic landscape lacks a targeted agent for mutCALR-expressing MPNs. These data support the hypothesis that INCA033989 not only normalizes platelet counts and provides durable hematologic responses but could also induce molecular responses that may alter the natural history of the disease.”
Broader Implications
Essential thrombocythemia, a chronic condition currently managed with therapies aimed at symptom relief and vascular complication prevention, represents an unmet need for more targeted and tolerable treatments. INCA033989’s ability to selectively address CALR-mutant cells and promote healthy blood production offers a significant advancement for patients. Discussions with regulatory authorities are planned, with a Phase 3 trial for the therapy anticipated in early 2026.
With its promising early results, INCA033989 sets the stage to redefine the treatment of CALR-mutant MPNs, providing hope for improved outcomes and potentially altering the course of these challenging diseases.
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