Incyte’s INCA033989 Delivers Durable Responses in CALR-Mutated MPNs at EHA 2026 First-in-Class Targeting of mutCALR

Incyte presented updated Phase 1 data at the European Hematology Association (EHA) 2026 Congress showing that INCA033989, a first-in-class mutant calreticulin (mutCALR)-targeted monoclonal antibody, delivered durable clinical and molecular responses in patients with myelofibrosis (MF) and essential thrombocythemia (ET). The findings support its potential to modify disease biology in CALR-mutated myeloproliferative neoplasms (MPNs), where no approved mutation-specific therapies currently exist.

CALR mutations drive uncontrolled blood cell production and account for approximately 25% to 35% of MF and ET cases. INCA033989 selectively targets mutCALR-expressing cells while sparing healthy cells, offering a potential disease-modifying approach.

Molecular and Clinical Activity

Across both studies (NCT05936359, NCT06034002), reductions in mutCALR variant allele frequency (VAF) correlated with clinical responses. Investigators also observed reductions in mutCALR-positive hematopoietic stem and progenitor cells, suggesting activity against disease-initiating clones.

Durable Efficacy in Myelofibrosis

In MF, INCA033989 demonstrated clinical activity as both a monotherapy and in combination with ruxolitinib.

Among patients receiving monotherapy, 55% achieved a best spleen volume reduction of at least 25% (SVR25) and 39% achieved SVR35. At Week 24, 27% maintained SVR35 responses. Symptom improvement was substantial, with 53% of patients achieving at least a 50% reduction in total symptom score (TSS50).

The therapy also showed encouraging activity against anemia. Sixty percent of evaluable anemic patients achieved an anemia response, including 52% who achieved a major anemia response.

Molecular activity remained consistent, with 89% of patients experiencing reductions in mutCALR VAF regardless of prior JAK inhibitor exposure, mutation subtype, or high molecular risk status.

Among patients with a suboptimal response to ruxolitinib, combination treatment with INCA033989 produced SVR35 responses in 30% and TSS50 responses in 31% at Week 24.

Rapid Responses in Essential Thrombocythemia

In ET patients resistant or intolerant to prior cytoreductive therapy, INCA033989 produced rapid and durable hematologic control.

Overall, 87% of patients achieved a complete or partial hematologic response, while 70% achieved complete hematologic response (CHR). The median time to durable CHR was approximately 2.1 weeks.

Strong molecular activity accompanied these responses. Among patients who achieved CHR and underwent molecular assessment, 73% also achieved at least a 25% reduction in mutCALR VAF.

Safety and Tolerability

INCA033989 demonstrated a favorable and manageable safety profile across both disease settings. No dose-limiting toxicities were observed, and a maximum tolerated dose was not reached.

Grade 3 or higher cytopenias occurred in 6% of ET patients, while Grade 3 or higher adverse events were reported in 19% overall. No Grade 3 thrombocytopenia events were observed, and most participants remained on therapy at the data cutoff.

 Regulatory Path Forward

The U.S. Food and Drug Administration granted Breakthrough Therapy designation to INCA033989 in November 2025 for patients with Type 1 CALR-mutated ET who are resistant or intolerant to prior cytoreductive therapy.

Incyte plans to initiate the pivotal Phase 3 EXCALIBUR-ET2 study (NCT07623200) in mid-2026 and is advancing registrational discussions in MF.

If confirmed in Phase 3 studies, INCA033989 could become the first targeted therapy for CALR-mutated MPNs and establish a disease-modifying treatment approach in both ET and MF.

Reference

Incyte Announces New Positive Data at EHA 2026 Showed INCA033989 Achieved Rapid, Robust and Sustained Clinical and Molecular Responses and Was Well Tolerated in Patients with Myelofibrosis and Essential Thrombocythemia | Incyte