Results demonstrate a favorable safety profile for INCA033989 as a monotherapy and in combination with ruxolitinib – no dose limiting toxicities were reported and a maximum tolerated dose was not reached

Incyte announced new clinical data from two Phase 1 studies evaluating the safety, tolerability and efficacy of INCA033989, a first-in-class mutant calreticulin (mutCALR)-targeted monoclonal antibody, for patients with mutCALR-expressing myeloproliferative neoplasms (MPNs). These preliminary results are from the dose escalation portion of the studies evaluating INCA033989 as a monotherapy in patients with myelofibrosis (MF) harboring a CALR mutation who are resistant, intolerant to or ineligible for JAK inhibitor treatment, and INCA033989 in combination with ruxolitinib (Jakafi®) in patients who experienced a suboptimal response to ruxolitinib monotherapy. These data are being featured in oral presentations (Session 634, Publication #484; Session 631, Publication #71) at the 2025 American Society of Hematology (ASH) Annual Meeting in Orlando.

“These positive study results reinforce our confidence in INCA033989’s transformative potential, both as a targeted monotherapy and combination therapy for MF…” said Pablo J. Cagnoni, M.D., President & Head of Research & Development, IncyteShare

“These positive study results reinforce our confidence in INCA033989’s transformative potential, both as a targeted monotherapy and combination therapy for MF, building on the positive results previously reported in essential thrombocythemia (ET),” said Pablo J. Cagnoni, M.D., President and Head of Research and Development, Incyte. “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 MF in 2026.”

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The preliminary analysis (data cut off September 25, 2025) evaluated the safety and efficacy of INCA033989 in patients with MF as measured by spleen volume reduction ≥25% (SVR25) and ≥35% (SVR35), change in MPN-Symptom Assessment Form (SAF), total symptom score (TSS), anemia response and mutCALR variant allele frequency (VAF) reduction.

In the monotherapy arm of the trials, patients with MF treated with INCA033989 (dose range 24 to 2,500 mg) experienced rapid and robust spleen and anemia responses and symptom improvements. Specifically:

  • At Week 24, 41.7% (15/36) of all evaluable MF patients achieved SVR25, and 33.3% (12/36) achieved SVR35. Among MF patients not previously treated with a JAK inhibitor, 71.4% (5/7) achieved SVR25 and 57.1% (4/7) achieved SVR35. Among those resistant or intolerant to JAK inhibitor treatment, 34.5% (10/29) and 27.6% (8/29) achieved SVR25 and SVR35 at Week 24, respectively.
  • Anemia response occurred in more than half (56%; 14/25) of evaluable anemic MF patients, with 40% (10/25) of patients achieving a major response with INCA033989 treatment.
  • Nearly all MF patients treated with INCA033989 (93.3%; 42/45) experienced improved symptoms, with 60% (27/45) achieving a ≥50% reduction in TSS (TSS50) as best response. At Week 24, 39.4% (13/33) of patients achieved a TSS50.
  • Most patients (89.4%; 42/47) with ≥1 post-baseline VAF measurement experienced a reduction in mutCALR VAF, and 10.6% (5/47) achieved a ≥25% best reduction in VAF.
  • Most patients (76.5%; 39/51) in the studies had co-occurring mutations. Of those, 40.5% (15/37) of response eligible patients achieved SVR35 or an anemia response. Single-cell analyses in MF patients with high clonal complexity, including high-risk mutations, showed consistent reductions in all CALR-mutant clones, regardless of the presence of co-occurring variants.

Similarly, in the INCA033989 (dose range 70 to 2,500 mg) and ruxolitinib combination arm of the trials, most MF patients experienced spleen volume reductions and symptom improvements:

  • At Week 24, half (50%; 6/12) of all evaluable MF patients achieved SVR25 and 25% (3/12) achieved SVR35.
  • Among the 14 evaluable patients, 86% had stable anemia and one (1) patient with non-transfusion dependent anemia had a major anemia response.
  • The majority of MF patients (81.3%; 13/16) treated with INCA033989 in combination with ruxolitinib experienced symptom improvement, and 33.3% (3/9) achieved TSS50 at Week 24.

Additionally, exploratory analyses in a subset of MF patients from the studies showed that INCA033989 reduced circulating mutCALR-positive hematopoietic stem and progenitor cells (HSPC) and mutCALR-positive platelet producing cells called megakaryocytes (MK) in the bone marrow, and improved marrow architecture, as measured by increased wild type (mutCALR-negative) MK. Among evaluable anemic MF patients (n=12), erythroid progenitor cells (CD71+ by IHC) in the bone marrow increased, correlating with hemoglobin increase and clinical anemia response. Together, these findings demonstrate the disease-modifying activity of INCA033989 in patients with mutCALR-expressing MF.

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INCA033989 was well-tolerated, both as a monotherapy and in combination with ruxolitinib, in patients with MF who were resistant or intolerant to prior JAK inhibitor therapy or ineligible for JAK inhibitor treatment, with no dose-limiting toxicities observed.

  • In the monotherapy arm (n=52), 86.5% (45) of patients were still receiving treatment and 13.5% (7) discontinued treatment. Only two (2) patients discontinued treatment due to treatment-emergent adverse events (TEAEs). Two (2) dose and three (3) infusion interruptions due to TEAEs were reported, and a maximum tolerated dose was not reached (dose range 24 to 2,500 mg). Fifty (50) patients across the monotherapy dose cohorts reported a TEAE, 30 of which were deemed treatment related.
    • The most common TEAEs (>20%) were anemia, fatigue, thrombocytopenia, arthralgia, AST elevations, cough, diarrhea, headache, leukopenia, nausea and pruiritis – nearly all were Grade 1. Sixteen (16) patients had Grade ≥3 TEAEs, with neutropenia being the most frequent (9.6%).
  • In the combination therapy arm (n=20), 85.0% (17) patients were still receiving treatment and 15.0% (3) discontinued treatment. Only two patients discontinued treatment due to TEAEs. One (1) dose and one (1) infusion interruption due to TEAEs were reported, and a maximum tolerated dose was not reached (dose range 70 to 2,500 mg). Twenty (20) patients across the combination therapy dose cohorts reported a TEAE, 13 of which were deemed treatment related.
    • The most common TEAEs (>20%) were anemia, thrombocytopenia, ALT increase, diarrhea and fatigue. Eleven (11) patients experienced Grade ≥3 TEAEs, with anemia (30%) being the most frequent.

“Widely regarded as the most aggressive type of MPN – a group of rare, chronic blood cancers – MF is characterized by bone marrow fibrosis, anemia and splenomegaly, which can lead to debilitating symptoms and increased mortality,” said John Mascarenhas, M.D., 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. “The Phase 1 data evaluating INCA033989 alone and in combination with ruxolitinib offer compelling proof-of-concept for a differentiated, targeted treatment approach in MF. The early signals observed suggest the potential to meaningfully influence the MF disease course, and I look forward to seeing this therapy advance in future clinical studies.”

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Source- businesswire