INCA033989 / Incyte - LARVOL DELTA

MUTANT CALRETICULIN–SPECIFIC MONOCLONAL ANTIBODY, INCA033989, IS WELL TOLERATED AND ACHIEVES ROBUST SPLEEN, ANEMIA, AND MOLECULAR RESPONSES IN PATIENTS (PTS) WITH MYELOFIBROSIS (MF) (EHA 2026) - P1 | "Aims To evaluate safety and efficacy of INCA033989 monotherapy (MF mono) or combined with ruxolitinib (rux; MF combo). Robust spleen, symptom and anemia responses are observed and correlate with reductions in mut CALR cell populations. These data support the planned initiation of phase 3 trials in pts with MF."

Clinical • First-in-human • Anemia • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Neutropenia • Thrombocytopenia • CALR • CD34

INCA33989 is a novel, first in class, mutant calreticulin-specific monoclonal antibody that demonstrates safety and efficacy in patients with essential thrombocythemia (ET) (EHA 2025) - P1 | "INCA33989-101 (NCT05936359) and -102 (NCT06034002) are phase 1, first-in-human, multicenter, open-label studies evaluating INCA33989 in patients with ET or myelofibrosis (monotherapy or in combination with ruxolitinib). INCA33989 monotherapy in ET patients who were resistant/intolerant to prior therapy was well-tolerated with no DLTs, and 98% of patients remain on treatment. Rapid and durable normalization of blood counts and reduction of mutCALR VAF was observed in most patients, and the potential for disease modification was evidenced by 25% of patients achieving an early PMR."

Clinical • Late-breaking abstract • Anemia • Cardiovascular • Essential Thrombocythemia • Fatigue • Hematological Disorders • Infectious Disease • Myelofibrosis • Myeloproliferative Neoplasm • Neutropenia • Pancreatitis • Respiratory Diseases • Thrombocytopenia • Thrombocytosis • Thrombosis • CALR

Mutant Calreticulin-Specific Monoclonal Antibody, INCA033989, is Well Tolerated and Achieves Robust Spleen, Anemia, and Molecular Responses in Patients With Myelofibrosis (SOHO 2026) - P1 | "INCA033989 alone or with ruxolitinib showed favorable safety in patients with MF relapsed/resistant/intolerant/ineligible for JAK inhibitor treatment, or suboptimal response to ruxolitinib. Robust spleen, symptom, and anemia responses were observed and correlated with mutCALR reduction. AE: adverse event; DLT: dose-limiting toxicity; IgG: immunoglobulin; IWG-ELN: International Working Group–European LeukemiaNet; JAK: Janus kinase; MF: myelofibrosis; MPN-SAF: Myeloproliferative Neoplasm Symptom Assessment Form; MTD: maximum tolerated dose; mutCALR: calreticulin mutations; SV: spleen volume; TEAE: treatment-emergent adverse event; TSS: total symptom score; VAF: variant allele frequency."

Clinical • Essential Thrombocythemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CALR

MUTANT CALRETICULIN–SPECIFIC MONOCLONAL ANTIBODY, INCA033989, IS WELL TOLERATED AND ACHIEVES RAPID AND SUSTAINED HEMATOLOGIC AND MOLECULAR RESPONSES IN PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA (ET) (EHA 2026) - P1 | "The most frequent prior cytoreductive tx were hydroxycarbamide (84%), anagrelide (31%), and interferons (32%). Most pts had a rapid, durable CHR that correlated with a reduction in mut CALR VAF. These data support the planned initiation of phase 3 trials in pts with ET."

Clinical • First-in-human • Cardiovascular • Essential Thrombocythemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis • Thrombosis • CALR

Mutant Calreticulin-Specific Monoclonal Antibody, INCA033989, is Well Tolerated and Achieves Rapid and Sustained Hematologic and Molecular Responses in Patients With Essential Thrombocythemia (SOHO 2026) - P1 | "INCA033989 demonstrated favorable safety and efficacy in patients with mutCALR ET resistant/intolerant to cytoreductive treatment. Most patients achieved rapid, durable CHR correlating with decreased mutCALR VAF. DLT: dose-limiting toxicity, ET: essential thrombocythemia, MTD: maximum tolerated dose."

Clinical • Essential Thrombocythemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CALR

Mutant Calreticulin-Specific Monoclonal Antibody INCA033989 Produces Molecular Responses That Correlate With Clinical Responses in Patients With Myelofibrosis (SOHO 2026) - P1 | "Spleen and anemia responses were comparable regardless of co-occurring somatic mutations being present, suggesting that clonal complexity does not limit treatment response. Despite modest mutCALR VAF reduction via peripheral blood NGS, the observed rapid reduction of mutCALR HSPCs supports disease-modifying INCA033989 activity. ASXL1: ASXL transcriptional regulator 1, EZH2: enhancer of zeste 2 polycomb repressive complex 2 subunit, Fc: fragment crystallizable region, HSPCs: hematopoietic stem and progenitor cells, IgG1: immunoglobulin G1, mAb: monoclonal antibody, NGS: next-generation sequencing, TET2: tet methylcytosine dioxygenase 2, VAF: variant allele frequency."

Clinical • First-in-human • Essential Thrombocythemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • ASXL1 • CALR • EZH2 • TET2

INCA 33989-101: A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P1 | N=160 | Active, not recruiting | Sponsor: Incyte Corporation | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Essential Thrombocythemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CALR

EXCALIBUR-ET2: A Phase 3 Study of INCA033989 Versus Best Available Therapy in Participants With Essential Thrombocythemia (clinicaltrials.gov) - P3 | N=426 | Recruiting | Sponsor: Incyte Corporation | Not yet recruiting ➔ Recruiting

CALR • Enrollment open • Essential Thrombocythemia • Hematological Disorders • Myeloproliferative Neoplasm • Thrombocytosis

Emerging agents and regimens for myeloproliferative neoplasms: updates from ASH 2025 Annual Meeting. (PubMed, Exp Hematol Oncol) - "At ASH 2025 Annual Meeting, multiple investigational strategies aimed to address these limitations, including clone-directed targeting (INCA033989), phlebotomy-sparing physiologic therapy (rusfertide), and epigenetic disease-modifying combinations (pelabresib). We summarized the latest updates on these emerging agents and regimens for MPNs from the 2025 ASH Annual Meeting."

Journal • Genetic Disorders • Hematological Disorders • Myeloproliferative Neoplasm • Oncology

The registrational Phase 3 study (EXCALIBUR-ET2), evaluating INCA033989 in mutCALR positive patients with ET who are resistant or intolerant to at least one prior cytoreductive therapy was initiated in mid-2026. (Businesswire)

Trial status • Essential Thrombocythemia

Data from the Phase 1 cohort evaluating INCA033989 as a monotherapy and in combination with ruxolitinib in treatment naïve MF patients are anticipated in the second half of 2026. (Businesswire)

P1 data • Myelofibrosis

A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of INCA033989 Following Subcutaneous or Intravenous Administration in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=126 | Recruiting | Sponsor: Incyte Corporation | Active, not recruiting ➔ Recruiting | N=72 ➔ 126

Enrollment change • Enrollment open

EXCALIBUR-ET2: A Phase 3 Study of INCA033989 Versus Best Available Therapy in Participants With Essential Thrombocythemia (clinicaltrials.gov) - P3 | N=426 | Not yet recruiting | Sponsor: Incyte Corporation

CALR • New P3 trial • Essential Thrombocythemia • Hematological Disorders • Myeloproliferative Neoplasm • Thrombocytosis

MUTANT CALRETICULIN-SPECIFIC MONOCLONAL ANTIBODY, INCA033989, PRODUCES CLONAL MOLECULAR RESPONSES THAT CORRELATE WITH CLINICAL RESPONSES IN PATIENTS WITH MYELOFIBROSIS (EHA 2026) - P1 | "Summary/Conclusion In pts with MF, comparable spleen and anemia responses were observed regardless of the presence of co-occurring somatic mutations, indicating that clonal complexity does not limit clinical response to INCA03989 treatment. In addition, single-cell immunophenotyping and genotyping data demonstrated a rapid reduction of mut CALR HSPCs in the majority of pts, despite modest mut CALR VAF reduction via bulk NGS, supporting the disease-modifying activity of INCA033989."

Clinical • First-in-human • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis • ASXL1 • CALR • TET2

Results in Patients with Essential Thrombocythemia (Businesswire) - "These findings are being presented...at the European Hematology Association (EHA) 2026 Congress....Across doses, 70% (80/114) of patients achieved a complete hematologic response (CHR, platelet count ≤400 × 109/L and leukocytes 12 weeks) CHR at 750 mg and above; and 50% of patients with non–Type 1 mutCALR achieved a durable CHR/PHR at 2500 mg. The median time to onset of durable CHR was 2.1 weeks....A reduction in mutCALR megakaryocytes was seen in both Type 1 and non-Type 1 patients treated with INCA033989."

CALR • P1 data • Essential Thrombocythemia

Results in Patients with Myelofibrosis (MF):...Monotherapy (Businesswire) - "These findings are being presented...at the European Hematology Association (EHA) 2026 Congress....INCA033989 monotherapy demonstrated durable clinical benefit, with clinically meaningful improvements across spleen volume, symptoms and anemia across both JAK R/R/I and JAK ineligible patients....Rapid and robust spleen volume reductions were observed in patients, with 55% (38/69) and 39% (27/69) of patients achieving the best SVR25 and SVR35 reduction, respectively. At Week 24, 27% (17/62) patients achieved SVR35, including 47% (8/17) JAK ineligible and 20% (9/45) JAK R/R/I....At Week 24, 32% of patients achieved TSS50, including 29% and 33% of JAK ineligible and JAK R/R/I patients, respectively."

P1 data • Anemia • Myelofibrosis

Results in Patients with Myelofibrosis (MF):…Combination therapy (Businesswire) - "These findings are being presented...at the European Hematology Association (EHA) 2026 Congress....INCA033989 demonstrated additive, multi-domain clinical activity in patients when administered in combination with ruxolitinib. SVR: At Week 24, 55% (11/20) and 30% (6/20) of patients achieved SVR25 and SVR35, respectively. Symptom Improvement: 31% (5/16) of patients achieved TSS50 at Week 24. Anemia: Anemia response occurred in 35% (6/17) of evaluable anemic patients. INCA033989 in combination with ruxolitinib was generally well-tolerated, with 76% (16) of patients remaining on treatment at the time of the data cut off."

P1 data • Myelofibrosis

A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of INCA033989 Following Subcutaneous or Intravenous Administration in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=72 | Active, not recruiting | Sponsor: Incyte Corporation | Trial completion date: May 2026 ➔ Oct 2026 | Trial primary completion date: May 2026 ➔ Oct 2026

Trial completion date • Trial primary completion date

Incyte Announces More Than 20 Abstracts Accepted for Presentation at the European Hematology Association (EHA) 2026 Congress (Businesswire) - "Data from pivotal Phase 3 frontMIND trial evaluating tafasitamab (Monjuvi/Minjuvi) in first-line diffuse large b-cell lymphoma (DLBCL) selected for prestigious Plenary Abstracts Session; Oral and poster presentations to feature new data for INCA033989, an anti-mutant calreticulin (mutCALR)-directed monoclonal antibody, in patients with myeloproliferative neoplasms (MPNs)."

CALR • JAK2V617F • P1 data • P3 data • Preclinical • Chronic Myeloid Leukemia • Diffuse Large B Cell Lymphoma • Essential Thrombocythemia • Follicular Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm

Key Business Updates (Incyte Press Release) - "The Company is on track to initiate a Phase 3 registrational study evaluating INCA033989 in mutCALR positive patients with essential thrombocythemia (ET) who are resistant or intolerant to at least one prior cytoreductive therapy in mid-2026 following a successful end-of-phase meeting with the U.S. Food and Drug Administration (FDA) in the first quarter of 2026; Updated data from the ongoing Phase 1 trial in second-line ET and myelofibrosis (MF) patients are anticipated in mid-2026. Data from the cohort evaluating INCA033989 and INCA033989 in combination with ruxolitinib in treatment naïve MF patients are anticipated in the second half of 2026....The Company plans to initiate a Phase 1 study evaluating INCA033989 as a SC administration in mutCALR positive patients mid-year 2026."

CALR • New P1 trial • New P3 trial • P1 data • Essential Thrombocythemia • Myelofibrosis • Myeloproliferative Neoplasm

A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of INCA033989 Following Subcutaneous or Intravenous Administration in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=72 | Active, not recruiting | Sponsor: Incyte Corporation | Recruiting ➔ Active, not recruiting

Enrollment closed

A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of INCA033989 Following Subcutaneous or Intravenous Administration in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=72 | Recruiting | Sponsor: Incyte Corporation | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of INCA033989 Following Subcutaneous or Intravenous Administration in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=72 | Not yet recruiting | Sponsor: Incyte Corporation

New P1 trial

Key Business Updates (Businesswire) - "INCA033989 (mutCALR)...Based on the promising results, the Company plans to initiate registrational programs in ET and MF in mid-2026 and in the second half of 2026, respectively...Results from the Phase 1 trial evaluating INCB160058 in MPN patients with a JAK2V617F mutation are anticipated in the second half of 2026...The initiation of a Phase 3 study evaluating INCB123667 in first-line maintenance ovarian cancer is anticipated in 2026."

CALR • JAK2V617F • New trial • P1 data • Platinum resistant • Trial status • Essential Thrombocythemia • Myelofibrosis • Myeloproliferative Neoplasm • Ovarian Cancer

Safety and efficacy of INCA033989, a novel first in class mutant calreticulin-specific monoclonal antibody, in patients with essential thrombocythemia (ASH 2025) - P1 | "Pts received 989 intravenously every 2 weeks; concomitant hydroxyurea (HU) or anagrelide was permitted. In pts with ET with resistance/intolerance to prior ET tx, 989 monotherapy was well toleratedwith no DLTs and 94% of pts remaining on tx. Rapid and sustained normalization of blood counts wasobserved with most pts achieving CHR as best hematologic response. Rapid reduction of mutCALR VAF inmost pts, improvement of MK hyperplasia, and shift from mutated to normal hematopoiesis supportsthe disease modification potential of 989 for pts with mutCALR ET."

Clinical • Acute Myelogenous Leukemia • Essential Thrombocythemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Hemophilia • Infectious Disease • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Neutropenia • Respiratory Diseases • Thrombocytopenia • Thrombocytosis • Thrombosis • CALR • ITGB3