Janus kinase inhibitors (JAKi) are standard of care for patients with myelofibrosis (MF) but can be associated with treatment-limiting cytopenias and do not modify underlying disease. Novel treatments targeting other clinically relevant pathways are needed. Inhibitors of bromodomain (BD) and extra-terminal domain (BET) proteins are a promising class of drugs that have demonstrated the ability to modulate key pathways involved in inflammation, fibrosis, and apoptosis. ABBV-744 is a novel small molecule that targets the BDII domain of BET proteins and has previously been shown to be well tolerated when administered daily at doses of 120 mg and 180 mg to patients with acute myeloid leukemia. We report the outcomes of a multicenter, open-label phase 1b study of ABBV-744 in patients with MF who received 1 or more prior lines of therapy, including a JAKi. The primary objective was safety, including dose-limiting toxicities (DLTs). Secondary endpoints included a reduction in spleen volume of ‚â•35% (SVR35), ‚â•50% reduction in total symptom score (TSS50), objective response rate, and pharmacokinetics. All 21 patients experienced at least 1 treatment-emergent adverse event, and 11 patients experienced a DLT. The most common events leading to DLTs were thrombocytopenia (33%) and anemia (24%). SVR35 was attained in 24% of patients at Week 12 and 33% at Week 24. TSS50 was reported for 29% of patients at 12 weeks and 19% at Week 24. These outcomes are noteworthy in this heavily pretreated population considering the advanced disease state and limited treatment options for this patient population. (NCT04454658).