Positive Late-Breaking Data for Incyte’s First-in-Class mutCALR-targeted therapy INCA033989 in Essential Thrombocythemia Presented at EHA2025

Incyte (Nasdaq:INCY) today announced the first clinical data from two studies evaluating the safety, tolerability and efficacy of INCA033989, a novel, first in class, Incyte-discovered, targeted monoclonal antibody in patients with mutant calreticulin (mutCALR)-expressing myeloproliferative neoplasms (MPNs). These data – featured today in the Late-Breaking Oral Session (#LB4002) at the European Hematology Association 2025 (EHA2025) Congress in Milan, Italy – focus on the dose escalation portion of the studies in patients with high risk essential thrombocythemia (ET) who are resistant/intolerant to prior cytoreductive therapy.

The studies evaluated the safety and efficacy of INCA033989 in patients with ET as measured by hematologic response and reduction in mutCALR variant allele frequency (VAF).

Results as of April 4, 2025, showed rapid and durable normalization of platelet counts across all dose levels, with a trend toward improved responses in higher doses (>400 mg), in patients with ET treated with INCA033989. Notably, 86% of patients at doses 400 mg and above achieved a complete or partial hematologic response, with the majority (82%) of patients achieving complete response. Eighty-nine (89) percent of evaluable patients (34/38) showed a reduction in mutCALR VAF from baseline. A partial molecular response (>50% VAF reduction) was observed in 21% of evaluable patients (8/38) after only 3 cycles of treatment.

An exploratory study using single-cell DNA (scDNA) sequencing showed that INCA033989 directly targets and reduces cells carrying mutCALR. This reduction was seen in early blood-forming (CD34-positive) cells and cells in the myeloid-erythroid (ME) lineage. At the same time, there was a clear increase in healthy (wild-type CALR) cells, suggesting that the treatment supports the return of normal blood production. Bone marrow biopsies further confirmed these effects showing fewer megakaryocytes with mutCALR protein and a notable increase in megakaryocytes without mutCALR protein. Together, these findings demonstrate the selectivity of INCA033989, allowing for normalization of healthy hematopoiesis and disease modification.