Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm with increased risk of thrombosis, hemorrhage, and transformation to myelofibrosis (MF) or acute myeloid leukemia. About 25% of patients (pts) with ET harbor calreticulin exon 9 mutations (mutCALR). Current cytoreductive treatments (tx) in ET have limited efficacy in reducing mutCALR variant allele frequency (VAF) and fail to achieve disease modification. INCA033989 (‘989‘), a novel, fully human, Fc-silenced, IgG1 monoclonal antibody, selectively inhibits oncogenic signaling and proliferation of cells expressing mutCALR and thrombopoietin receptor. INCA033989-101 (NCT05936359) and -102 (NCT06034002) are phase 1, first-in-human, multicenter, open-label studies evaluating 989 in pts expressing mutCALR with ET or MF. Updated safety and efficacy data from dose escalation in pts with ET are presented.

Methods: Pts had a pathogenic CALR mutation, resistance/intolerance to prior ET tx, platelet (PLT) count >450×109/L, and high-risk disease (age ≥60 y, history of thrombosis, major bleeding, acquired von Willebrand disease or extreme thrombocytosis). Pts received 989 intravenously every 2 weeks; concomitant hydroxyurea (HU) or anagrelide was permitted. The primary endpoint was safety and tolerability. Efficacy was evaluated via hematologic response defined as PLT count ≤400×109/L (complete hematologic response [CHR]) or ≤600×109/L (partial hematologic response [PHR]), together with leukocytes <10×109/L. Best reduction in mutCALR VAF was also assessed.

Results: As of May 8, 2025, 51 pts were enrolled and received 989 at doses ranging from 24 to 2500 mg; median (range) exposure was 27 weeks (0.6, 74). Median (range) age was 60.5 y (23, 82), 61% were female. The median (range) baseline PLT count was 931×109/L (447, 2017), whereas the mean (SD) baseline mutCALR VAF was 32% (7.9; n=45). Thirty pts (59%) were enrolled with concomitant HU or anagrelide, of whom, 20 (67%) discontinued.

Across all dose cohorts (24 to 2500 mg), no dose-limiting toxicities were observed, and a maximum tolerated dose was not reached; 48/51 pts (94%) continued on tx. Three pts discontinued; 1 pt due to pregnancy, 1 pt due to adverse event (AE) (venous thrombosis), and 1 pt withdrew from the study (pt decision). Forty-eight pts (94%) had tx emergent AEs (TEAEs) of any grade, most commonly fatigue (28%) and upper respiratory tract infection (20%). Seventeen pts (33%) had a Gr ≥3 TEAE, most commonly asymptomatic lipase increase (8%); 32 pts (63%) had tx-related AEs, most commonly fatigue (20%). Thrombocytopenia was not observed in any pt, whereas anemia and neutropenia occurred in 9 (18%) and 5 (10%) pts, respectively, most commonly with concomitant HU. Two pts (24 and 400 mg) had serious TEAEs: 1 pt had diverticulitis; 1 pt had visceral venous thrombosis, followed by melena (after anticoagulant initiation) and tx discontinuation. One pt had a dose reduction and no pts had infusion interruptions due to TEAEs.

Rapid and durable normalization of PLT counts was observed across all dose levels. Best hematologic response rate (CHR+PHR) was 80% (41/51), with 37 pts (73%) achieving a CHR. The median (range) time to onset of CHR was 21 days (8-324). Durable hematologic responses (sustained CHR or PHR for ≥12 wks) were observed in 51% of 41 evaluable pts, with 39% achieving a durable CHR. Median (range) time to onset of durable CHR was 15 days (13, 125). A postbaseline mutCALR VAF reduction occurred in 90% (37/41) of pts with ≥1 postbaseline VAF measurement, with 44% (18/41) achieving a best reduction of ≥20% and 20% (8/41) achieving ≥50% reduction. Exploratory immunohistochemistry analysis of bone marrow samples in a subset of pts showed decreased mutCALR-positive megakaryocytes (MK) and increased mutCALR-negative MK by 24 wks, as well as decreased MK density assessed by CD61. In addition, exploratory single cell analysis revealed rapid reductions of mutCALR-positive hematopoietic stem/progenitor cell fractions after 3 cycles of tx.

Conclusions: In pts with ET with resistance/intolerance to prior ET tx, 989 monotherapy was well tolerated with no DLTs and 94% of pts remaining on tx. Rapid and sustained normalization of blood counts was observed with most pts achieving CHR as best hematologic response. Rapid reduction of mutCALR VAF in most pts, improvement of MK hyperplasia, and shift from mutated to normal hematopoiesis supports the disease modification potential of 989 for pts with mutCALR ET.

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2025
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