Novel Calreticulin-Mutation-Targeting Antibody Safe, Effective for High-Risk ET

For patients with high-risk essential thrombocythemia (ET) that has withstood prior therapy, the novel agent INCA33989 offers well-tolerated and effective management. This was the key takeaway from dose escalation study data presented at the 2025 European Hematology Association (EHA) Congress in Milan, Italy.¹

John Mascarenhas, MD, from the Icahn School of Medicine at Mount Sinai in New York City was first author for the study. He also presented the data in person during the late-breaking oral session of the Congress.²

“Current treatments aim at controlling blood counts in order to prevent vascular complications and improve symptoms but are limited in many cases to toxicity and/or poor activity and do not target the driver mutation,” Dr. Mascarenhas explained during his presentation about the need for the agent.²

INCA33989 is a first-in-class, human IgG1 monoclonal antibody that targets exon 9 mutations in calreticulin. Two phase 1, first-in-human, open-label multicenter studies, INCA33989-101 and INCA33989-102, are underway to evaluate this agent for the management of ET and myelofibrosis, both as monotherapy and in combination with ruxolitinib. The data presented at the EHA Congress were preliminary dose escalation data, specifically of monotherapy in patients with high-risk ET.¹

The enrolled patients were aged 60 years and older, had pathogenic calreticulin mutations, and had platelet counts greater than 450 x 10⁹/L. ET in these patients had withstood prior therapies, or the patients had intolerance to such treatments. The patients also had histories of thrombosis, extreme thrombocytosis, or major bleeding.¹

By the data cutoff of February 14, 2025, there were 41 patients enrolled in the cohort, 56% of whom were women. The cohort had a median age of 60 years, a median platelet count of 933 x 10⁹/L, and a median baseline calreticulin mutation variant allele frequency (VAF) of 0.32. Type-1, type-2, and other type calreticulin mutations were present in 56%, 26%, and 18% of the cohort, respectively.¹

Patients in the cohort received intravenous INCA33989 every 2 weeks at a range of doses from 24 mg to 2500 mg. The cohort had a median exposure of 20 weeks. No dose-limiting toxicities were encountered, and no maximum tolerated dose was reached; 98% of the patients remained on treatment.¹

The primary endpoints for the study were safety and tolerability. Regarding treatment-emergent adverse events (TEAE), 81% of patients across all dose cohorts of the study experienced a TEAE. The most common were fatigue and upper respiratory tract infection, affecting 27% and 17% of patients, respectively, and all grade 2 or lower in severity. TEAEs of grade 3 or worse severity affected 22% of patients, the most common of which was elevated transient lipase without clinically evident pancreatitis, occurring in 5% of patients. Anemia developed in 15% of patients and neutropenia in 12%, with one case of neutropenia having grade 3 severity. No thrombocytopenia was reported in any patient.¹

Specifically, in the 24 mg dose intravenous INCA33989 patient sub-cohort, two patients had serious TEAEs. One experienced a transient, asymptomatic lipase increase, and the other presented with visceral venous thrombosis, followed by melena, which occurred after initiation of anticoagulants. The latter patient discontinued treatment and was the only patient in the study to do so. The study had no dose reductions or infusion interruptions due to a TEAE.¹

Efficacy in the study was evaluated based on hematologic response in the patients. A response was defined in patients as either a complete response (CR) of achieving a platelet count of less than 400 x 10⁹/L, or a partial response (PR) of platelet count less than 600 x 10⁹/L together with a leukocyte count of less than 10 x 10⁹/L.¹

“It is most impressive at doses above 400, in which you see normalization and durable normalization of the platelet count,” Dr. Mascarenhas noted during his presentation.²

Across all dose cohorts in the study in total, 66% of patients achieved CR, and the best overall response rate, defined as CR plus PR, was 79%. A CR was achieved after 4 weeks, or two doses, by 57% of evaluable patients. In 68% of evaluable patients, a CR or PR was sustained for at least 8 weeks.¹

A reduction in calreticulin mutation VAF from baseline occurred in 88% of all evaluable patients in the study. A reduction in calreticulin mutation VAF from baseline of greater than 20% was achieved by 50% of all evaluable patients in the study. Eight patients in the study achieved a greater than 50% VAF reduction after 12 weeks of treatment.¹

“These findings support the potential of nine-eight-nine, a mutant-specific targeted therapy, to provide durable hematologic responses and modify the disease in patients with mutant CALR ET,” Dr. Mascarenhas said at the closing of his presentation.²

One question was raised from the audience about whether the study assessed for any acquired or increased secondary mutations in the treated patients. Dr. Mascarenhas responded that the analyses of such mutations in the study are ongoing.²