INCA33989, a first-in-class mutant CALR-specific monoclonal antibody for ET: Phase I results

Essential thrombocythemia (ET) is characterized by elevated platelet counts, thrombotic risk, and potential transformation to myelofibrosis or acute myeloid leukemia. Patients with ET carrying mutations in the calreticulin gene (mutCALR) have poorer outcomes and a higher risk of transformation compared with those harboring JAK2V617F mutations. Current therapies for ET are not tailored to specific mutations, and are often limited due to toxicity and suboptimal efficacy.

INCA33989 is a novel, first-in-class, high-affinity, fully human IgG1 monoclonal antibody that represents a new mechanism of action in ET by selectively targeting mutant CALR in complex with the thrombopoietin receptor (also known as myeloproliferative leukemia protein) to inhibit cell signaling and proliferation. Preliminary results from the ongoing phase I studies, INCA33989-101 (NCT05936359) and INCA33989-102 (NCT06034002), were presented by John Mascarenhas at the 2025 European Hematology Association (EHA) Congress. 

These open-label, dose-escalation studies evaluated the safety, pharmacokinetics, and efficacy of INCA33989 in patients with high-risk ET harboring CALR exon 9 mutations and prior intolerance or resistance to ≥1 line of cytoreductive therapy.¹

Key learnings

No DLTs were observed at any dose, and MTD was not reached. TEAEs occurred in 85.7% of patients (n = 49), the majority of which were Grades 1–2; Grade ≥3 TEAEs occurred in 26.5%. One patient discontinued due to visceral venous thrombosis at the 24 mg dose.

Normalization of platelet counts occurred rapidly and was sustained in most patients; thrombocytopenia was not observed, and ≥400 mg doses resulted in higher normalization rates. Of 31 patients that enrolled with concomitant cytoreductive therapy, 65% of patients discontinued it and remained on study.

OR was achieved in 86% of patients treated with ≥400 mg dose, including 82% with CR. Responses occurred early and were maintained with a median duration of exposure of 26 weeks.

Peripheral blood mutCALR VAF reduction was observed in 89% of evaluable patients; 47% and 21% had >20% and >50% best reduction in VAF, respectively. All molecular responders achieved a hematologic response, supporting the potential of INCA33989 as a well-tolerated, mutation-specific therapy for the treatment of patients with mutCALR ET.