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 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]