Early Data Show INCA033989 Activity in Calreticulin-Driven Myelofibrosis

New early-phase data presented at the 2025 American Society of Hematology Annual Meeting suggest that INCA033989, a first-in-class antibody targeting mutant calreticulin, may have activity in patients with myeloproliferative neoplasms whose disease has limited treatment options.

The findings come from two phase 1 studies evaluating the investigational therapy alone and in combination with Jakafi (ruxolitinib) in patients with calreticulin-mutated myelofibrosis, including those who were resistant to or unable to receive Janus kinase inhibitor treatment, according to a news release from Incyte.

“These positive study results reinforce our confidence in INCA033989’s transformative potential, both as a targeted monotherapy and combination therapy for myelofibrosis, building on the positive results previously reported in essential thrombocythemia (ET),” Dr. Pablo J. Cagnoni, president and head of research and development, Incyte, said in the news release. “Our goal is to bring new targeted treatment options to patients across the MPN disease spectrum. In line with this commitment, we plan to initiate a registrational program evaluating INCA033989 for the treatment of patients with myelofibrosis in 2026.”

In a preliminary analysis with a data cutoff of Sept. 25, 2025, INCA033989 was evaluated in patients with myelofibrosis for spleen volume reduction, symptom changes, anemia response and reductions in mutant calreticulin levels.

In the monotherapy arm, patients treated with INCA033989 experienced spleen volume reductions, anemia responses and symptom improvements across the evaluated dose range. At week 24, 41.7% (15 of 36) of evaluable patients achieved a spleen volume reduction of at least 25% and 33.3% (12 of 36) achieved a reduction of at least 35%. Among patients who had not previously received a Janus kinase inhibitor, 71.4% (five of seven) achieved a spleen volume reduction of at least 25% and 57.1% (four of seven) achieved a reduction of at least 35%. Among patients who were resistant or intolerant to Janus kinase inhibitor treatment, 34.5% (10 of 29) achieved a spleen volume reduction of at least 25% and 27.6% (eight of 29) achieved a reduction of at least 35%.

An anemia response occurred in 56% (14 of 25) of evaluable patients with anemia, including 40% (10 of 25) who achieved a major anemia response with INCA033989 treatment.

Symptom improvement was reported in 93.3% (42 of 45) of patients, and 60% (27 of 45) achieved a reduction of at least 50% in total symptom score as their best response. At Week 24, 39.4% (13 of 33) of patients achieved a reduction of at least 50% in total symptom score.

Reductions in mutant calreticulin variant allele frequency were observed in 89.4% (42 of 47) of patients with at least one post-baseline measurement, with 10.6% (five of 47) achieving a best reduction of at least 25%.

Most patients (76.5%; 39 of 51) had co-occurring mutations. Among response-eligible patients with co-occurring mutations, 40.5% (15 of 37) achieved either a spleen volume reduction of at least 35% or an anemia response. Single-cell analyses showed reductions in calreticulin-mutant clones, including in patients with high clonal complexity and high-risk mutations, regardless of the presence of additional variants.

In the combination arm evaluating INCA033989 given with Jakafi, patients with myelofibrosis also experienced spleen volume reductions and symptom improvements across the evaluated dose range.

At Week 24, 50% (six of 12) of evaluable patients achieved a spleen volume reduction of at least 25%, and 25% (three of 12) achieved a reduction of at least 35%. Among 14 evaluable patients, 86% had stable anemia, and one patient with non–transfusion-dependent anemia achieved a major anemia response.

Symptom improvement was reported in 81.3% (13 of 16) of patients treated with the combination. At Week 24, 33.3% (three of nine) of evaluable patients achieved a reduction of at least 50% in total symptom score.

“Widely regarded as the most aggressive type of MPN – a group of rare, chronic blood cancers – myelofibrosis is characterized by bone marrow fibrosis, anemia and splenomegaly, which can lead to debilitating symptoms and increased mortality,” Dr. John Mascarenhas, professor of Medicine at the Icahn School of Medicine at Mt. Sinai and Director, Center of Excellence for Blood Cancers and Myeloid Disorders, The Tisch Cancer Institute, said in the news release.

He continued, “The phase 1 data evaluating INCA033989 alone and in combination with [Jakafi] offer compelling proof-of-concept for a differentiated, targeted treatment approach in myelofibrosis. The early signals observed suggest the potential to meaningfully influence the myelofibrosis disease course, and I look forward to seeing this therapy advance in future clinical studies.”

Reference

1. “Incyte Announces New Positive Data For INCA033989, Its First-In-Class MutCALR-Targeted Monoclonal Antibody, In Patients With Myelofibrosis Presented At ASH 2025.” News Release Incyte.

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