INCA033989 Nets FDA Breakthrough Therapy Designation in CALR-Mutated R/R Essential Thrombocythemia

The first-in-class mutant calreticulin (CALR)–targeted monoclonal antibody INCA033989 has been granted breakthrough therapy designation by the FDA for the treatment of patients with essential thrombocythemia harboring a type 1 CALR mutation who are resistant or intolerant to at least 1 cytoreductive therapy.¹

Data from the phase 1 INCA033989-101 (NCT05936359) and INCA033989-102 (NCT06034002) trials supported the designation. Findings from the trials presented during the 2025 European Hematology Association Congress demonstrated that no dose-limiting toxicities (DLTs) were reported in patients treated across dose levels (n = 49) and the maximum tolerated dose was not reached.² At the data cutoff, most patients remained on treatment (98%) and the median duration of treatment exposure was 22.6 weeks (range, 0.6-69.2%). Updated results from the studies are planned to be presented during the 2025 ASH Annual Meeting.¹

“Incyte has long been committed to improving outcomes for patients with MPNs, and this Breakthrough Therapy designation underscores the potential of INCA033989 to be a novel therapy that could significantly transform the treatment of patients [with] essential thrombocythemia, who today have limited treatment options,” Pablo J. Cagnoni, MD, president and head of research and development at Incyte, stated in a news release. “The designation allows us to expedite the development pathway for INCA033989 in patients with type 1 mutations.”

How were these phase 1 studies designed?

The essential thrombocytopenia cohort of INCA033989-101 and INCA033989-102 trials enrolled patients with a diagnosis of essential thrombocytopenia per 2022 World Health Organization criteria.² Patients also needed to have disease harboring a CALR exon 9 mutation, documented resistance or intolerance to at least 1 previous line of cytoreductive therapy, a platelet count of more than 450 × 10⁹/L, and high-risk disease. High-risk disease was defined as being at least 60 years old, having a history of thrombosis, history of major bleeding without any clearly documented alternative explanation, or extreme thrombosis.

INCA033989-101 enrolled patients outside the US and INCA033989-102 was a US-only study. Patients received intravenous INCA033989 every 2 weeks at doses ranging from 24 mg to 2500 mg.

The primary end points were the incidences of DLTs and treatment-emergent adverse effects (TEAEs). Secondary end points included response rate per European LeukemiaNet criteria, symptom improvement per the Myeloproliferative Neoplasm Symptom Assessment Form total symptom score, changes in allele burden of mutant CALR, and pharmacokinetic measures.

What additional safety and efficacy data have been reported with INCA033989?

Additional findings from these studies showed that the best overall response rates among patients treated at the 24-mg to 250-mg dose levels were 80% and 86%, respectively. Respective complete response (CR) rates were 68% and 82% in patients who were treated in the 400-mg to 2500-mg dose range.

Most evaluable patients (89%; n = 34/38) achieved a reduction in the variant allele frequency (VAF) of mutant CALR. Forty-seven percent of these patients experienced a reduction of more than 20% of mutant CALR VAF, and 21% achieved a greater than 50% reduction. A reduction of at least 20% of mutant CALR VAF occurred within 6 cycles for all 18 responders, and all molecular responders achieved a hematological response of either a CR or a partial response.

Further safety data revealed that any-grade TEAEs occurred at a rate of 85.7%, including treatment-related (61.2%), grade 3 or higher (26.5%), and serious (6.1%) TEAEs. Treatment discontinuation (2.0%) and dose reduction (2.0%) due to TEAEs also occurred. Most TEAEs were grade 1 to 2 in severity and the most frequent grade 3 or higher TEAE was a transient increase in asymptomatic lipase levels (6.1%).

“Looking ahead, we plan to initiate a phase 3 program evaluating INCA033989 in patients [with] essential thrombocythemia with all types of CALR mutations in mid-2026, following alignment with regulators in the first half of next year,” Cagnoni noted in the news release.¹

References

1. Incyte’s first-in-class mutCALR-targeted monoclonal antibody, INCA033989, granted breakthrough therapy designation by U.S. FDA. News release. Incyte. December 7, 2025. Accessed December 8, 2025. https://incytecorp.gcs-web.com/news-releases/news-release-details/incytes-first-class-mutcalr-targeted-monoclonal-antibody
2. Mascarenhas J, Ali H, Yacoub A, et al. INCA33989 is a novel, first-in-class, mutant calreticulin-specific monoclonal antibody that demonstrates safety and efficacy in patients with essential thrombocythemia (ET). Presented at: 2025 European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract LB4002