Core Insights - Incyte announced updated clinical data for INCA033989, a first-in-class monoclonal antibody targeting mutant calreticulin (mutCALR) for treating myeloproliferative neoplasms (MPNs) [1][2] - The data presented at the 2025 ASH Annual Meeting highlight the drug's potential for disease modification in high-risk essential thrombocythemia (ET) patients with CALR mutations [2][7] Clinical Efficacy - The studies showed rapid and durable normalization of platelet counts in ET patients treated with INCA033989, with 90% of patients on higher doses (400 to 2,500 mg) achieving a hematologic response [3] - Among these, 83.3% achieved a complete hematologic response (CHR), with nearly half (46.4%) maintaining this response for at least 12 weeks [3] - In patients on lower doses (24 to 250 mg), 88% achieved a hematologic response, with 68% achieving CHR and 44% maintaining a durable CHR [3] Molecular Response - A significant reduction in mutCALR variant allele frequency (VAF) was observed, with 96.2% of patients showing a decrease from baseline [4] - Approximately 52% of patients achieved a 25% reduction in VAF, and nearly one-third (31%) achieved a 50% reduction [4] - These reductions were noted within three to six months and were more pronounced at higher doses of INCA033989 [4] Safety Profile - INCA033989 was well tolerated across all dose levels (24 to 2,500 mg), with no dose-limiting toxicities reported [6] - The most common treatment-emergent adverse events (TEAEs) included fatigue (30.9%), headache (27.3%), upper respiratory tract infection (27.3%), and anemia (20%) [6] - Only one patient discontinued treatment due to TEAEs, and a maximum tolerated dose was not reached [6] Regulatory Status - INCA033989 received Breakthrough Therapy designation from the FDA for treating ET patients with Type 1 CALR mutations who are resistant or intolerant to prior therapies [8] - Incyte plans to initiate a registrational program for both Type 1 and non-Type 1 CALR mutations in the first half of next year [8] Background on Essential Thrombocythemia - Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by elevated platelet counts and an increased risk of blood clots and bleeding [10] - Mutations in the CALR gene are responsible for 25-35% of ET cases, leading to abnormal blood cell production [10]

Core Insights - Incyte (INCY) has received FDA Breakthrough Therapy designation for its investigational monoclonal antibody INCA033989, aimed at treating essential thrombocythemia (ET) patients with Type 1 CALR mutations who are resistant or intolerant to at least one cytoreductive therapy [1][6][10] Group 1: FDA Breakthrough Therapy Designation - The FDA's Breakthrough Therapy designation accelerates the development and review of drugs for serious conditions, granted when early clinical evidence indicates significant improvement over existing treatments [2] - This designation provides enhanced guidance and support from senior FDA managers [2] Group 2: Clinical Data and Efficacy - Early phase I data for INCA033989 showed it was well tolerated and resulted in rapid and sustained normalization of platelet counts, with stronger responses at higher doses [3][6] - The treatment demonstrated robust clinical benefits in CALR-mutant myelofibrosis, both as a standalone therapy and in combination with Jakafi [7][8] Group 3: Patient Population and Disease Context - Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by excessive platelet production, with CALR mutations present in about 25% of ET patients [4] - The Type 1 CALR deletion is linked to a higher risk of progression to myelofibrosis among ET patients [4] Group 4: Future Development Plans - Incyte plans to initiate a registrational phase III program for INCA033989 in mid-2026, targeting both Type 1 and non-Type 1 CALR mutation patients [10][12]

Incyte Update Summary Company Overview - **Company**: Incyte Corporation - **Ticker**: NasdaqGS: INCY - **Event**: Update/Briefing on December 07, 2025 Industry Focus - **Industry**: Myeloproliferative Neoplasms (MPNs) - **Key Conditions**: Essential Thrombocythemia (ET), Myelofibrosis (MF) Core Points and Arguments 1. **Significance of INCA033989**: The company believes that INCA033989 has the potential to redefine the standard of care for patients with MPNs, aiming for not just symptomatic improvement but true disease eradication [2][5][32] 2. **Clinical Data Presentation**: Data presented includes results from the 989 program, focusing on its efficacy in patients with ET and MF, with emphasis on the ability to normalize hematopoiesis [1][2][3] 3. **Breakthrough Therapy Designation**: INCA033989 received Breakthrough Therapy Designation from the FDA for patients with essential thrombocythemia, indicating the potential for accelerated approval [6] 4. **Patient Demographics**: The majority of patients in the studies had CALR mutations, which are present in approximately 35% of MF patients [4][57] 5. **Efficacy Results**: - In the monotherapy cohort, 42% achieved SVR25 and 33% achieved SVR35 at week 24 [22][59] - 93% of patients experienced symptom improvement, with 60% achieving TSS50 [24][60] - Anemia responses were observed in 56% of patients, with 40% achieving a major response [61] 6. **Safety Profile**: INCA033989 was reported to be well tolerated, with no dose-limiting toxicities and a high retention rate of 86.5% in the study [19][31][58] 7. **Future Trials**: Plans to initiate a phase three trial for second-line ET and a second-line MF study in the second half of 2026, focusing on the IV administration of INCA033989 [63][64] Additional Important Content 1. **Mutant CALR Targeting**: The therapy specifically targets mutant CALR, which is a significant driver in MPNs, and aims to reduce the burden of the disease effectively [34][56] 2. **Molecular Characterization**: The presentation included detailed molecular characterization of patients, highlighting the complexity of mutations and their implications for treatment [33][40] 3. **Patient Engagement**: There is a noted increase in CALR mutant patients seeking treatment, indicating a growing awareness and interest in targeted therapies [70] 4. **Long-term Goals**: Incyte aims to develop targeted therapies for all patients with MPNs by the end of the decade, indicating a commitment to addressing unmet medical needs [5][57] This summary encapsulates the key points from the Incyte update, focusing on the company's advancements in treating myeloproliferative neoplasms, particularly through the development of INCA033989.

Core Viewpoint - Incyte's monoclonal antibody, INCA033989, has received Breakthrough Therapy Designation from the U.S. FDA, indicating its potential to significantly improve treatment for patients with certain conditions [1] Group 1: Product Development - INCA033989 is a first-in-class mutCALR-targeted monoclonal antibody, highlighting its innovative approach in targeting specific mutations [1] - The Breakthrough Therapy Designation is a recognition by the FDA that suggests the drug may offer substantial benefits over existing therapies [1] Group 2: Regulatory Impact - The designation may expedite the development and review process for INCA033989, potentially leading to faster market access for patients [1] - This regulatory milestone reflects the company's commitment to advancing treatment options in the oncology space [1]

Core Insights - Incyte announced new clinical data from two Phase 1 studies on INCA033989, a first-in-class monoclonal antibody targeting mutant calreticulin (mutCALR) for patients with myeloproliferative neoplasms (MPNs) [1][2] - The studies evaluated INCA033989 as a monotherapy and in combination with ruxolitinib for patients with myelofibrosis (MF) who are resistant or intolerant to JAK inhibitors [1][2] - Preliminary results showed promising efficacy and safety profiles, with plans for a registrational program in 2026 [2][8] Study Results - In the monotherapy arm, 41.7% of evaluable MF patients achieved a spleen volume reduction of 25% (SVR25) and 33.3% achieved a 35% reduction (SVR35) at Week 24 [5] - Among patients not previously treated with JAK inhibitors, 71.4% achieved SVR25 and 57.1% achieved SVR35 [5] - In the combination therapy arm, 81.3% of patients experienced symptom improvement, with 33.3% achieving a 50% reduction in total symptom score (TSS50) [5] Safety and Tolerability - INCA033989 was well-tolerated, with no dose-limiting toxicities reported in both monotherapy and combination therapy arms [4][6] - The most common treatment-emergent adverse events (TEAEs) were anemia, fatigue, and thrombocytopenia, primarily Grade 1 [13] - Only two patients discontinued treatment due to TEAEs, indicating a favorable safety profile [13] Future Plans - Incyte plans to initiate a registrational program for INCA033989 in MF in 2026, building on the positive results observed [2][8] - The drug is also being evaluated for essential thrombocythemia (ET), with Breakthrough Therapy designation granted by the FDA for patients with Type 1 CALR mutations [8][11] Industry Context - Myelofibrosis (MF) is considered one of the most aggressive types of MPNs, characterized by bone marrow fibrosis and debilitating symptoms [7] - The development of targeted therapies like INCA033989 represents a significant advancement in the treatment landscape for MPNs, particularly for patients who are resistant or intolerant to existing therapies [10][11]

Core Insights - Incyte Corporation is recognized as one of the best performing biotech stocks in 2025, focusing on oncology and autoimmune therapies through regulatory approvals and pipeline innovation [1][2]. Regulatory Approvals and Pipeline Developments - Incyte secured FDA approvals for Zynyz in squamous cell anal carcinoma and Monjuvi in follicular lymphoma, enhancing its hematology-oncology franchise [2]. - Positive Phase 1 results for INCA033989 in essential thrombocythemia have strengthened its position in myeloproliferative neoplasms, with upcoming presentations at ESMO Congress 2025 expected to showcase early data for two promising assets [2]. KRAS Cancer Program - The KRAS program is gaining significant attention, particularly with the experimental oral inhibitor INCB161734 targeting G12D-mutated KRAS, a challenging cancer mutation [3]. - Phase 1 results for this program are anticipated at ESMO, which could provide the first clinical proof of concept, positioning Incyte as a pioneer in cancer drug development [3].

INCA033989 Clinical Trial Results and Safety - INCA033989 demonstrated a favorable safety profile in ET patients, with only 1 out of 49 patients discontinuing therapy due to treatment-emergent adverse events [101, 135] - INCA033989 led to rapid and sustained normalization of platelet counts in previously treated ET patients [105, 135] - Hematologic responses were achieved early and sustained, with 86% of patients receiving ≥400 mg achieving a response [113, 115] - A reduction in peripheral blood mutCALR VAF was observed in 89% (34/38) of evaluable patients, correlating with hematologic responses [119, 120, 135] - Biomarker analysis supports a reduction in mutCALR stem/progenitor cells and megakaryocytes in patients achieving a hematologic response [121, 127, 135] INCA033989 Mechanism and Preclinical Data - INCA033989 is a high-affinity mutant CALR selective monoclonal antibody that selectively inhibits constitutive JAK/STAT signaling induced by mutCALR [94] - INCA033989 directly inhibits mutCALR+ CD34+ HSPCs and megakaryocytes, without affecting non-mutated, healthy cells [94] - In a mutCALR conditional knock-in mouse model of established MPN, INCA033989 treatment led to platelet normalization, reversal of anemia, and elimination of megakaryocyte hyperplasia in the bone marrow [90, 94] Essential Thrombocythemia (ET) and Unmet Needs - CALR mutations account for 25% of Essential Thrombocythemia cases [19] - Current ET treatments aim to reduce disease-associated risks but do not impact the natural history [26] - There is an unmet need for disease-modifying therapies in ET [25, 43] Future Development Plans - A registrational trial in ET is planned to be initiated by early 2026 [137]

Core Insights - Incyte (INCY) shares increased by 5.1% following a global partnership with QIAGEN N.V. to develop a diagnostic panel for myeloproliferative neoplasms (MPNs), which account for approximately 40% of hematological malignancies [1][4] Partnership Details - The collaboration focuses on INCA033989, Incyte's investigational monoclonal antibody targeting mutant calreticulin (mutCALR), currently in early-stage development for myelofibrosis (MF) and essential thrombocythemia (ET) [2] - QIAGEN will create a multimodal panel using next-generation sequencing (NGS) technology to identify key gene alterations in MPNs, initially concentrating on mutCALR, the second most common driver of MPNs [2][5] - The panel will be validated on the Illumina NextSeq 550Dx platform for whole blood samples, with QIAGEN assisting in regulatory submissions and market access in the U.S., EU, and certain Asia-Pacific regions [3][6] Benefits of the Collaboration - The partnership enhances Incyte's precision medicine efforts by facilitating the identification of genetic mutations like CALR, which is crucial for treatment decisions in rare blood cancers [5] - It allows for widespread CALR testing, improving patient selection for Incyte's therapies and increasing the likelihood of better treatment outcomes [6] - The collaboration strengthens Incyte's position in personalized medicine and accelerates regulatory and market access for its mutCALR-targeted treatment [6][7] Clinical Data and Future Prospects - Incyte reported positive data from two Phase I studies of INCA033989, showing rapid and lasting platelet normalization in ET patients, with 86% achieving a complete/partial hematologic response at doses above 400 mg [11][12] - The candidate demonstrated selective targeting of mutCALR cells while sparing healthy cells, indicating potential for disease modification [12] - Incyte plans to advance INCA033989 into late-stage development for MPN indications in 2026 after discussions with regulatory authorities [13]