INCA033989 (novel investigational agent for MPN)

Current understanding

To be populated as evidence accumulates.

Evidence log

• 2026 (rece — Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications: Review (2025, review-level) on mutant CALR mechanism describes the mutant CALR–MPL complex as a tetramer with the mutant CALR C-terminus exposed on the cell surface, providing the structural rationale for neoepitope-targeting antibodies like INCA033989. (novelty: 3)
• May 1, 202 — Mutant calreticulin–directed immunotherapies in myeloproliferative neoplasms: Review (2025) on mutant CALR-directed immunotherapies positions antibody-based agents like INCA033989 as the most clinically advanced modality among CALR-neoepitope strategies, ahead of CAR-T and vaccine approaches still in early testing. (novelty: 3)
• December 7 — Early Data Show Mutant CALR-Specific Monoclonal Antibody Well Tolerated in Myelofibrosis: ASH 2025 (trial-early): INCA033989, a first-in-class mutant CALR-specific monoclonal antibody, was well tolerated in myelofibrosis patients as both monotherapy and in combination with ruxolitinib, supporting continued development of neoantigen-directed selective targeting in MF. (novelty: 4)
• May 1, 202 — Myelofibrosis (MF) in 2026: Matching Therapy to the Dominant Clinical Problem: Narrative review (2026, review-level) positions INCA033989 alongside CALR-directed bispecific antibodies as exemplars of mutation-specific therapy matched to the dominant clinical problem in MF. (novelty: 3)
• June 12-15 — Advancing Frontiers in Myeloproliferative Neoplasms - EHA 2025 Congress Review: EHA 2025 congress review (review-level) groups INCA033989 with INCA035784 as Incyte’s CALR-mutation-directed MPN portfolio, contrasting the anti-mutant-CALR antibody (INCA033989) with the T-cell-redirecting bispecific (INCA035784). (novelty: 3)
• 2026-06-03 — A Phase 3 Study of INCA033989 Versus Best Available Therapy in Participants With Essential Thrombocythemia: Phase 3 trial (trial-late) launched evaluating INCA033989 versus best available therapy in CALR-mutant ET patients previously treated with cytoreductive therapy, advancing this first-in-class mutant-CALR-targeting antibody into pivotal late-phase testing. (novelty: 4)
• 2026-06-02 — Genomic insights transform diagnosis, prognosis, and therapy in BCR::ABL1-negative myeloproliferative neoplasms.: Review (review-level) cites INCA033989 as a prototype mutation-selective, mechanism-aligned therapy (anti-mutant CALR) exemplifying how genomic profiling enables clone-directed treatment in MPN. (novelty: 3)
• May 21, 20 — CALR Mutation–Directed Agents and Targeted Therapies Represent Key Research Avenue in MPN Management: Review-level synthesis (May 2026) groups INCA033989 with JNJ-88549968 as the leading CALR mutation–directed agents, framed as a ‘key emerging research avenue’ in MPN precision therapy alongside JAK-pathway combination trials. (novelty: 3)
• November 1 — New Essential Thrombocythemia Treatment Appears to Address Underlying Disease: Early-phase ET cohort (n=49, trial-early): INCA033989 achieved 66% complete hematologic response (platelet normalization) and reduced mutant CALR variant allele frequency in 89% of evaluable patients, suggesting disease-modifying activity against the CALR-mutant clone. (novelty: 4)
• May 17, 20 — MPN | Tumor | CURE: Regulatory milestone (other): FDA granted Breakthrough Therapy Designation to INCA033989 for essential thrombocythemia, recognizing the mutant-CALR-neoepitope antibody’s early clinical signal. (novelty: 3)
• March 24, — ASH 2025: Myelofibrosis Roundup: ASH 2025 Phase 1 update (trial-early): INCA033989, a first-in-class antibody targeting the mutant CALR neoepitope, showed 87% treatment retention with spleen volume reduction, anemia improvement, and symptom reduction in myelofibrosis patients, including JAKi-resistant/intolerant cases. (novelty: 5)
• May 12, 20 — CALR Mutation–Directed Agents and Targeted Therapies Represent Key Research Avenue in MPN Management: Review-level synthesis frames INCA033989 within the precision-medicine wave of investigational MPN agents being developed alongside CALR mutation–directed therapies and JAK2/MPL-targeted approaches. (novelty: 3)
• 2026-03-24 — A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms: Phase 1 dose-escalation trial (trial-early): INCA033989 being evaluated as monotherapy and in combination with ruxolitinib in MPN patients, with primary endpoints of safety, tolerability, DLT, MTD, and recommended dose for expansion (RDE). (novelty: 4)

Open questions

Related