INCA033989 Demonstrates Promising Activity in mutCALR-Driven MPNs

An investigative inhibitor of mutated calreticulin (mutCALR) is showing promising ability to restore normal hematopoiesis in patients who have either essential thrombocythemia (ET) or myelofibrosis (MF), according to new research presented at the American Society of Hematology 2025 annual meeting.1 Use of INCA033989, also known as 989, led to hematologic responses in 41 of 51 patients (80%) who have ET and an evaluable anemia response in 21 of 59 patients (36%) who have MF.

The agent is currently being evaluated in 2 phase 1 first-in-human trials (NCT05936359 and NCT06034002), both as monotherapy and in combination with ruxolitinib.2,3

“ET and MF are driven by mutCALR in approximately 30% of patients and result in substantial morbidity and mortality,” study authors wrote. “INCA033989, a novel, fully human, Fc-silenced, IgG1 monoclonal antibody, selectively inhibits oncogenic signaling and proliferation of cells expressing mutCALR and thrombopoietin receptor.”

They used 3 methods for clinicogenomics and histological analyses: next-generation sequencing (NGS), single-cell multi-omic analysis, and immunohistochemistry. For NGS, the panel evaluated 37 genes associated with myeloid malignancies, with molecular response defined as a 20% reduction in mutCAL. The multi-omic analysis assessed 47 cell surface proteins and 37 genes. IHC used a mutCALR-specific antibody on bone marrow biopsies. The data cutoff was May 2025.

Restoring hematopoiesis in patients with essential thrombocythemia and myelofibrosis may be possible thanks to the new calreticulin inhibitor currently under investigation. | Image Credit: © luchschenF-stock.adobe.com

Among the study population, patients with mutCALR Type 1, mutCALR Type 2, and mutCALR Type-other represented 55%, 29%, and 16%, respectively, of the patients with ET and 58%, 24%, and 19% of the patients with MF. There was an equivalent range of mean mutCALR variant allele frequency (VAF) at enrollment, with 0.33 (range, 0.12-0.75) seen in the ET cohort and 0.38 (0.30-0.85) seen in the MF cohort.

Of the 5 patients with a VAF above 0.5, all had Type-2 mutations.

The study found a strong correlation between mutCALR measures seen in the bone marrow and the peripheral blood samples (r2 = 0.97), with nondriver somatic mutations seen in 33% of the patients with ET and 83% of the patients with MF. Corresponding co-occurring variants per patient ranged from 0 to 3 for the ET cohort and 0 to 9 for the MF cohort. TET2 and ASXL1, TET2, and EZH2 were the most frequently mutated genes, respectively.

Of the 39 patients with longitudinal VAF data in the ET cohort, mutCALR was reduced in 37 patients (95%), with 22 (56%) achieving molecular response. For the 16 patients who achieved International Working Group/European LeukemiaNet–defined durable peripheral blood count remission, 14 (88%) achieved molecular response.

Of the 17 patients with an evaluable spleen response from the MF cohort, 10 (37%) had experienced a 25% spleen volume reduction by week 24 of treatment, with all also having a VAF reduction and 5 (50%) achieving molecular response. Also in the MF cohort, 12 of the 21 patients (57%) achieved a minor or major anemia response, with all also seeing a VAF reduction and 4 (33%) achieving molecular response.

Other results show selective reductions in mutCALR+ hemopoietic stem/progenitor cells (HSPCs) by the end of treatment cycle 3 among patients in both cohorts, as well as decreased density of total megakaryocytes (MKs).

“A rapid and selective reduction in mutCALR+ HSPCs and MKs was observed within 4 months of 989 treatment and correlated with clinical responses,” the investigators concluded, “suggestive of potential disease modification and recovery of normal hematopoiesis.”

References

1. Psaila B, Nangalia J, Gotlib J, et al. Molecular characterization of patients (pts) with myeloproliferative neoplasms treated with INCA033989 demonstrates selective targeting of CALR mutant hematopoietic cells. Presented at: American Society of Hematology; December 6-9, 2025; Orlando, FL. Publication 71.
2. A study to evaluate INCA033989 administered as a monotherapy or in combination with ruxolitinib in participants with myeloproliferative neoplasms.ClinicalTrials.gov. Updated November 18, 2025. Accessed December 8, 2025. https://clinicaltrials.gov/study/NCT05936359
3. A study to evaluate INCA033989 administered as a monotherapy or in combination with ruxolitinib in participants with myeloproliferative neoplasms. ClinicalTrials.gov. Updated October 30, 2025. Accessed December 8, 2025. https://clinicaltrials.gov/study/NCT06034002