INCA033989 / Incyte - LARVOL DELTA

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

Safety and efficacy of the mutant calreticulin-specific monoclonal antibody INCA033989 as monotherapy or in combination with ruxolitinib in patients (pts) with myelofibrosis (MF): Preliminary results from dose escalation of two global Phase 1 studies (ASH 2025) - P1 | "As monotherapy in pts with MF intolerant, resistant or ineligible for JAKi tx, and incombination with rux, 989 was well-tolerated with no DLTs and few tx discontinuations. Promising spleenand anemia responses and symptom improvements occurred in both cohorts despite advanced diseaseand limited follow-up. VAF reductions and single cell analyses further support the potential disease-modifying impact of 989."

Clinical • Combination therapy • Monotherapy • P1 data • B Cell Lymphoma • Dental Disorders • Diffuse Large B Cell Lymphoma • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Leukopenia • Lymphoma • Mantle Cell Lymphoma • Musculoskeletal Pain • Myelofibrosis • Myeloproliferative Neoplasm • Neutropenia • Non-Hodgkin’s Lymphoma • Rheumatology • Stomatitis • Thrombocytopenia • CALR

Molecular characterization of patients (pts) with myeloproliferative neoplasms treated with INCA033989 demonstrates selective targeting of CALR mutant hematopoietic cells (ASH 2025) - P1 | "Pts with MF had higher mutCALR VAF than pts with ET and were more likely to have co-occurring somatic mutations at enrollment. Correlation between clinical response and post-treatmentVAF reduction was observed in both ET and MF, with more frequent MRs achieved in ET. Post-treatmentMR occurred over a range of baseline VAFs, which included patients with co-occurring variant(s)."

Clinical • Essential Thrombocythemia • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis • ASXL1 • CALR • TET2

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 (Businesswire) - "Nearly all (90%) of essential thrombocythemia (ET) patients treated with INCA033989 at the higher dose achieved a hematologic response (HR) with 83.3% achieving a complete HR. Molecular responses were frequent, rapid, durable and correlated with hematologic responses; a reduction in mutCALR variant allele frequency (VAF) from baseline occurred in 96.2% of patients with ≥1 post-baseline VAF measurement. Exploratory analyses from the clinical studies show potential direct disease-modifying activity of INCA033989."

CALR • P1 data • Essential Thrombocythemia

Incyte Announces New Positive Data for INCA033989, its First-In-Class mutCALR-Targeted Monoclonal Antibody, in Patients with Myelofibrosis Presented at ASH 2025 (Businesswire) - "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....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."

CALR • P1 data • Myelofibrosis

The Company plans to initiate a Phase 3 program evaluating INCA033989 in essential thrombocythemia (ET) patients with all types of CALR mutations in mid-2026, following alignment with regulators (Businesswire) - "Incyte plans to develop INCA033989 for patients with Type 1 and non-Type 1 CALR mutations..."

CALR • New P3 trial • Essential Thrombocythemia • Myeloproliferative Neoplasm

Incyte…announced that 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, for the treatment of patients with essential thrombocythemia (ET) harboring a Type 1 CALR mutation (Businesswire) - "The FDA Breakthrough Therapy Designation was supported by the early Phase 1 data evaluating INCA033989 in ET patients with a Type 1 CALR mutation available at the time of submission. The preliminary Phase 1 data were presented earlier this year at the 2025 European Hematology Association (EHA) Congress."

Breakthrough therapy • CALR • Essential Thrombocythemia

Preliminary Safety and Efficacy of the Novel, First in Class, Mutant Calreticulin-Specific Monoclonal Antibody INCA033989 in Patients With Essential Thrombocythemia (ET) (MPN 2025) - No abstract available

Clinical • Essential Thrombocythemia • Hematological Disorders • Myeloproliferative Neoplasm • Thrombocytosis • CALR

Challenges in the Evolving Role of Calreticulin as a Promising Target for Precision Medicine in Myeloproliferative Neoplasms. (PubMed, Cancers (Basel)) - "Early-phase clinical trials with fully human anti-CALR monoclonal antibodies (e.g., INCA033989) have shown very promising hematologic and molecular responses with manageable toxicity...At the same time, the complexity of CALR-driven disease raises key questions, including whether anti-CALR therapies can shift treatment goals beyond thrombotic risk reduction, how best to monitor clonal burden, and how to address immune escape. In this review, we highlight the latest therapeutic advances in CALR-mutated MPNs while outlining the critical unmet needs that will shape the future of care for these patients."

CALR • IO biomarker • Journal • Review • Hematological Disorders • Myeloproliferative Neoplasm • Oncology • ABL1 • CALR

INCA033989, a first-in-class mutant calreticulin (mutCALR)-targeted monoclonal antibody, will be showcased in three presentations, including new Phase 1 monotherapy and combination data in myelofibrosis (MF), updated data in essential thrombocythemia (ET) and translational data demonstrating disease modifying activity in both ET and MF. (Incyte Press Release)

Clinical data • Essential Thrombocythemia • Myelofibrosis • Myeloproliferative Neoplasm

Pharmacologic management of et: established therapies and emerging agents. (PubMed, Expert Opin Pharmacother) - "Key trials include the phase 2 LSD1 inhibitor bomedemstat trial showing significant platelet-count reduction and mutation-burden improvement the phase 3 SURPASS-ET trial comparing ropeginterferon alfa-2b versus anagrelide, ongoing investigations of JAK - STAT pathway modulators, and emerging data on the anti-calreticulin (CALR) monoclonal antibody INCA033989, which selectively targets mutCALR progenitors to suppress malignant hematopoiesis while sparing normal hematopoiesis. Drawing on recent clinical trials, expert consensus, and emerging data presented at hematology meetings (2018-2025), we highlight established cytoreductive strategies - hydroxyurea, interferon-α (including pegylated formulations), and anagrelide - and evaluate emerging targeted agents. Future advances in ET management hinge on integrating molecular risk stratification into treatment algorithms, optimizing combination regimens to deepen molecular remissions, and prioritizing agents with favorable..."

Journal • Review • Tumor mutational burden • Hematological Disorders • Myeloproliferative Neoplasm • Oncology • CALR • TMB

Results from the Phase 1 trial evaluating INCA033989, an investigational mutant calreticulin (mutCALR) selective monoclonal antibody, in mutCALR positive patients with myelofibrosis (MF) are expected in the second half of 2025 (Businesswire)

P1 data • Myelofibrosis • Myeloproliferative Neoplasm

The Company announced a strategic partnership with Enable Injections, Inc., to develop and commercialize specific assets in Incyte’s portfolio, including INCA033989, with Enable’s enFuse on-body delivery system (Businesswire) - "Under the terms of the agreement, Incyte will obtain a worldwide, exclusive license to use the enFuse technology with INCA033989 in essential thrombocythemia (ET) and MF, with the potential to expand to additional assets and indications."

Licensing / partnership • Essential Thrombocythemia • Myelofibrosis

Novel Therapies in Essential Thrombocythemia and Polycythemia Vera (SOHO 2025) - P1, P1/2, P2, P3 | "In PV, recommended cytoreductive options include hydroxyurea, pegIGN, ropeginterferon-alpha-2b (ropeginterferon), and ruxolitinib...A novel fully human IgG1 monoclonal antibody against mutant CALR (INCA033989) has demonstrated promising preclinical activity...Another phase 1 trial evaluating JNJ-88549968, a novel bispecific antibody that binds to both mutant CALR and T cells to enhance cytotoxicity, 10 is also enrolling both CALR -mutated ET and MF patients (NCT06150157)...12 A phase 2 trial of bomedemstat in high-risk ET patients who were resistant or intolerant to hydroxyurea demonstrated that 94% (34/36) of patients met hematologic response criteria after a median of 8 weeks, with stable hemoglobin levels and improved white blood cell counts...Novel Therapies in Polycythemia Vera Rusfertide and Hepcidin Mimetics Maintenance of a hematocrit <45% is a core aspect of PV therapy, which can be accomplished with a combination of therapeutic phlebotomy..."

IO biomarker • Chronic Myeloid Leukemia • Essential Thrombocythemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • CALR • JAK2 • KLK7 • MPL • TMPRSS6

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

QIAGEN and Incyte Announce Precision Medicine Collaboration to Develop Companion Diagnostics for Patients With Mutant CALR-expressing Myeloproliferative Neoplasms (MPNs) (Businesswire) - "QIAGEN N.V...and Incyte...announced a new global collaboration to develop a novel diagnostic panel to support Incyte’s extensive portfolio of investigational therapies for patients with myeloproliferative neoplasms (MPNs), a group of rare blood cancers, including Incyte’s monoclonal antibody INCA033989, targeting mutant calreticulin (mutCALR), which is being developed in myelofibrosis (MF) and essential thrombocythemia (ET). Under the terms of the Master Collaboration Agreement with Incyte, QIAGEN will develop a multimodal panel using next-generation sequencing (NGS) technology for detecting clinically relevant gene alterations in hematological malignancies."

Diagnostic • Licensing / partnership • Essential Thrombocythemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Positive Late-Breaking Data for Incyte’s First-in-Class mutCALR-targeted therapy INCA033989 in Essential Thrombocythemia Presented at EHA2025 (Yahoo Finance) - P1 | N=230 | NCT06034002 | P1 | N=225 | NCT05936359 | Sponsor: Sponsor: Incyte Corporation | "Results as of April 4, 2025, showed rapid and durable normalization of platelet counts across all dose levels, with a trend toward improved responses in higher doses (>400 mg), in patients with ET treated with INCA033989. Notably, 86% of patients at doses 400 mg and above achieved a complete or partial hematologic response, with the majority (82%) of patients achieving complete response. Eighty-nine (89) percent of evaluable patients (34/38) showed a reduction in mutCALR VAF from baseline....Additional data from the INCA033989 study in patients with myelofibrosis will be submitted for presentation at a future medical meeting. Discussions with regulatory authorities are planned with the goal to initiate a Phase 3 study by early 2026."

Late-breaking abstract • New P3 trial • P1 data • Essential Thrombocythemia

Incyte Announces Multiple Presentations, Including New Late-Breaking Data for its mutCALR-Directed Monoclonal Antibody (INCA033989), Accepted for Presentation at EHA 2025 (Businesswire) - "Late-breaking oral presentation will highlight new data from a trial of INCA033989, an anti-mutant calreticulin (mutCALR)-directed monoclonal antibody, in patients with essential thrombocythemia (ET); Incyte to host an in-person analyst and investor event highlighting the mutCALR data at EHA on Sunday, June 15, 2025, from 6:00 - 7:30 a.m. EDT (12:00 - 1:30 p.m. CEST)."

Clinical data • Chronic Graft versus Host Disease • Essential Thrombocythemia • Follicular Lymphoma • Marginal Zone Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm

A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P1 | N=230 | Recruiting | Sponsor: Incyte Corporation | N=140 ➔ 230

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

Incyte Reports 2024 Fourth Quarter and Year-End Financial Results, Provides 2025 Financial Guidance and Highlights 2025 R&D Milestones (Businesswire) - "Key Recent Company Updates: In December 2024, Incyte shared additional data from its BET inhibitor (INCB057643) in patients with relapsed or refractory myelofibrosis and other advanced myeloid neoplasms at the 2024 ASH Annual Meeting....Incyte plans to initiate a Phase 3 monotherapy study in the post Jakafi patient population in 2025. In December 2024, the supplemental Biologics License Application (sBLA) submission for retifanlimab (Zynyz) in advanced/metastatic squamous cell anal carcinoma was filed with the FDA with approval anticipated in the second half of 2025....The Phase 1 studies evaluating mutCALR in myelofibrosis (MF) and essential thrombocythemia (ET) and JAK2V617Fi in MF are ongoing and enrolling patients. Initial proof of concept data for both studies are anticipated in 2025."

FDA approval • FDA filing • New P3 trial • P1 data • Anal Carcinoma • Essential Thrombocythemia • Myelofibrosis • Squamous Cell Carcinoma

INCA033989: the first shot on goal for MPNs? (PubMed, Blood) - "In this issue of Blood, Reis et al1 identify a monoclonal antibody, INCA033989, that selectively targets mutant calreticulin (mutCALR) in myeloproliferative neoplasms (MPNs), inhibiting its oncogenic activity without affecting normal hematopoiesis."

Journal • Hematological Disorders • Myeloproliferative Neoplasm • Oncology • CALR

Incyte Reports 2024 Third Quarter Financial Results and Provides Updates on Key Clinical Programs (Businesswire) - "Additional Pipeline Updates: A bioequivalence study of ruxolitinib extended-release (XR) is enrolling. The data are anticipated in the first half of 2025....Trials of ruxolitinib twice daily (BID) with BETi and zilurgisertib are ongoing. Additional data for BETi and zilurgisertib are anticipated in the fourth quarter of 2024. The Phase 1 studies evaluating mCALR and JAK2V617Fi are ongoing and enrolling patients. Initial data for both studies are anticipated in 2025."

Clinical data • P1 data • Myelofibrosis • Myeloproliferative Neoplasm

Selective targeting of mutated calreticulin by the monoclonal antibody INCA033989 inhibits oncogenic function of MPN. (PubMed, Blood) - "INCA033989 reduced the pathogenic self-renewal of mutCALR-positive disease-initiating cells in both primary and secondary transplantations, illustrating its disease-modifying potential. In summary, we describe a novel mutCALR-targeted therapy for MPNs, a monoclonal antibody that selectively inhibits the oncogenic function of MPN cells without interfering with normal hematopoiesis."

Journal • Hematological Disorders • Myeloproliferative Neoplasm • Oncology • Thrombocytosis • Transplantation • CALR • CD34

Incyte Reports 2024 Second Quarter Financial Results and Provides Updates on Key Clinical Programs (Businesswire) - "Jakafi: Net product revenues for the second quarter 2024 of $706 million (+3% Y/Y): Paid demand increased 9% in the second quarter of 2024 versus the same quarter in the prior year, with growth across all indications. Year over year net product revenue growth was lower than paid demand growth due to higher channel inventory levels at the end of the second quarter of 2023 versus the same period of 2024. Channel inventory at the end of the second quarter of 2024 was within the normal range....The Phase 1 studies evaluating mCALR and JAK2V617Fi are ongoing and enrolling patients. Initial data for both studies is anticipated in 2025."

P1 data • Sales • Graft versus Host Disease • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera

EFFICACY OF INCA033989 IN CHRONIC AND ADVANCED FORMS OF CALRDEL52 AND CALRINS5 MYELOPROLIFERATIVE NEOPLASMS (MPN) MODELS (EHA 2024) - "Together, our results show INCA efficiently targets CALRdel52 and CALRins5 cells in chronic and advancedforms of MPNs, demonstrating therapeutic potential and warranting further investigation."

Clinical • Metastases • Acute Myelogenous Leukemia • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • Thrombocytosis • CALR • CD34 • HSP90AA1