FDA Grants Breakthrough Designation to INCA-33989 in Essential Thrombocythemia

The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to INCA033989, a first-in-class mutant calreticulin (mutCALR)-targeted monoclonal antibody intended for the treatment of patients with essential thrombocythemia (ET) with a Type 1 CALR mutation who are resistant or intolerant to at least one cytoreductive therapy.

The development was announced in a news release issued by Incyte, the biopharmaceutical company which developed INCA033989.

ET is a rare chronic blood cancer characterized by the production of too many platelets in the bone marrow and falls under the umbrella of myeloproliferative neoplasms, or MPNs.

According to the news release, CALR mutations are the second most common oncogenic driver mutation and are observed in 25% of patients with ET. A 52-bp deletion is another known Type 1 mutation and it occurs in 55% of patients with a CALR mutation; this mutation is associated with the highest risk of transformation to myelofibrosis among all ET patients.

“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 ET patients, who today have limited treatment options,” said Dr. Pablo J. Cagnoni, president and head of Research and Development at Incyte, in a statement included in the news release. “The designation allows us to expedite the development pathway for INCA033989 in patients with Type 1 mutations. Looking ahead, we plan to initiate a phase 3 program evaluating INCA033989 in [patients with] ET with all types of CALR mutations in mid-2026, following alignment with regulators in the first half of next year.”

According to the news release, the FDA breakthrough therapy designation was supported by early phase 1 data evaluating INCA033989 in patients with ET with a Type 1 CALR mutation, with preliminary findings having been presented earlier this year at the 2025 European Hematology Association Congress.

As stated in the news release, the study has shown that INCA033989 was well-tolerated and the drug demonstrated rapid and durable normalization of platelet counts across evaluated doses, with greater responses seen at higher doses among patients with both mutation types.

Data presented earlier this month at the 2025 American Society of Hematology Annual Meeting in Orlando showed that 90% of patients with ET treated with higher-dose INCA033989 achieved a hematological response, with 83.3% achieving a complete hematological response. Molecular responses were frequent, rapid, durable, and correlated with hematological responses. Results also demonstrated a favorable toxicity profile, with no dose-limiting toxicities reported and the maximum tolerated dose not reached.

"Approximately 25% to 35% of patients [with ET] have mutCALR-expressing ET, yet current treatments are broadly myelosuppressive, not mutant targeted and have limited efficacy in reducing mutCALR allele frequency,” Dr. John Mascarenhas said in a prior news release on the topic. “These emerging data suggest that INCA033989 could offer a novel treatment approach by selectively targeting mutCALR in a way that enables rapid and durable hematologic responses, while maintaining safety and tolerability for ET patients who are resistant or intolerant to prior cytoreductive therapy. I’m encouraged by these findings and the potential for INCA033989 to redefine treatment paradigms for patients with ET."

Mascarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai and director of the Center of Excellence for Blood Cancers and Myeloid Disorders at the Tisch Cancer Institute.

Overall, there are plans to develop INCA033989 for patients with Type 1 and non-Type 1 CALR mutations and, after discussions with regulatory agencies, plans to initiate a registrational program evaluating patients with ET with a Type 1 or non-Type 1 CALR mutation who are resistant or intolerant to at least one cytoreductive therapy in the first half of next year.

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References

1. “Incyte’s First-in-Class mutCALR-Targeted Monoclonal Antibody, INCA033989, Granted Breakthrough Therapy Designation” by U.S. FDA. News release; Dec. 7, 2025.
2. “Incyte Presents Updated Positive Data at ASH 2025 Reinforcing the Potential of INCA033989, its First-in-Class mutCALR-Targeted Monoclonal Antibody, in Patients with Essential Thrombocythemia,” by Incyte. News release; Dec. 7, 2025.