A Phase 3 Study of INCA033989 Versus Best Available Therapy in Participants With Essential Thrombocythemia

• INCA033989 (Drug): Administered intravenous (IV) in accordance with the protocol-defined requirements.
• Best Available Treatment (Drug), also known as BAT could include:, • HU, • ANA, • PEG interferon alfa-2a, • Ropeginterferon alfa-2b: Best Available Therapy (BAT) will be selected by the investigator.

Primary outcomes

• Durable clinicohematologic response (DCR) [Week 24]: Normalization of platelet and white blood cell (WBC) counts and absence of disease progression as defined in the protocol.

Secondary outcomes

• Reduction from baseline in calreticulin exon 9 frameshift mutation(s) (mutCLAR) variant allele frequency (VAF) [Week 24]: Reduction in mutCALR VAF as defined in the protocol.
• Durable clinicohematologic response (DCR) [Week 48]: Normalization of platelet and white blood cell (WBC) counts and absence of disease progression as defined in the protocol.
• Durable partial clinicohematologic response (DPR) [Week 24]: Improvement of platelet and white blood cell (WBC) counts and absence of disease progression as defined in the protocol.
• Durable partial clinicohematologic response (DPR) [Week 48]: Improvement of platelet and white blood cell (WBC) counts and absence of disease progression as defined in the protocol.
• Longest duration of complete hematologic response (CHR) [Up to Week 48]: Longest time from documented CHR until the loss of CHR as defined in the protocol.
• Number of Participants with Treatment Emergent Adverse Events (TEAE) [Up to Week 48 and 60 days after last dose]: Defined as any adverse event occurring after the first dose of study drug until up to 60 days after the last dose of study drug.
• TEAEs leading to dose interruptions, dose reductions or discontinuation of study treatment [Up to Week 48 and 60 days after last dose]: TEAEs leading to dose interruptions, dose reductions or discontinuation of study treatment.
• Number of participants with a reduction in mutCALR VAF [Week 24 and Week 48]: Number of participants with a reduction in mutCALR VAF as defined in the protocol.
• Molecular response [Week 24 and Week 48]: Overall reduction in mutCALR VAF as defined in the protocol.
• Change from baseline in Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total symptom score (TSS) [Up to Week 48]: Defined as the proportion of participants who achieve a protocol defined reduction in TSS.
• Change from baseline in Brief Fatigue Inventory (BFI) fatigue score [Up to Week 48]: The BFI is a 9 item scored from 0 (no fatigue) -10 (as bad as you can imagine), items are averaged with total score from 0-10, with higher score indicating more fatigue.
• Patient Global Impression of Change (PGIC) score [Up to Week 48]: The PGIC is based on a 7-point scale and the participant will rate each question from the start of treatment as 1-very much improved, 2-much improved, 3-minimally improved, 4-no change, 5-minimally worse, 6-much worse, and 7-very much worse.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Confirmed diagnosis of high-risk ET.
* Presence of mutCALR.
* Prior treatment with at least 1 cytoreductive therapy.

Exclusion Criteria:

* Presence of any hematologic malignancy other than ET.
* Major bleeding or thrombosis within the last 3 months prior to study enrollment.
* Any prior allogenic or autologous stem-cell transplantation.
* Unresolved toxicity ≥ Grade 2 from previous therapy except for stable chronic toxicities (Grade 2) not expected to resolve, such as stable Grade 2 peripheral neuropathy.
* Prior nonhematologic malignancy except for the following: Malignancy treated with curative intent and with no evidence of active disease for more than 2 years before screening. Adequately treated carcinoma in situ without current evidence of disease.

Other protocol-defined Inclusion/Exclusion Criteria apply.

78 more sites not listed.

• Incyte Medical Monitor, Study director, Incyte Corporation