Selective BET Inhibition With ABBV-744 Shows Early Clinical Activity in Myelofibrosis

Myelofibrosis (MF) remains a challenging myeloproliferative neoplasm characterized by bone marrow fibrosis, cytopenias, and symptomatic splenomegaly. Although Janus kinase (JAK) inhibitors such as ruxolitinib (Jakafi; Incyte Corporation) have improved symptom burden and spleen size, many patients experience suboptimal responses or treatment-related cytopenias, underscoring the need for novel therapeutic approaches.¹

BET proteins regulate gene transcription involved in inflammation, fibrosis, and oncogenic signaling, making them an attractive target in MF.²

ABBV-744 is an orally bioavailable, selective inhibitor of the BD2 domain of BET proteins, including BRD2, BRD3, and BRD4. By preferentially targeting BD2, ABBV-744 aims to preserve antitumor activity while minimizing toxicities historically associated with pan-BET inhibition, such as thrombocytopenia and gastrointestinal effects.^2,3 Preclinical studies have demonstrated that ABBV-744 disrupts chromatin-mediated transcription and reduces expression of proinflammatory and profibrotic genes, supporting its development in hematologic malignancies.³

Phase 1b Study Design and Patient Population

An open-label phase 1b study evaluated ABBV-744 as monotherapy and in combination regimens in patients with intermediate- or high-risk MF, including those previously treated with JAK inhibitors.¹ The study consisted of multiple segments designed to assess safety, pharmacokinetics, and preliminary efficacy across dosing schedules. In the monotherapy cohort, ABBV-744 was administered orally to determine the recommended phase 2 dose and characterize tolerability.¹

Patients enrolled in the trial had symptomatic disease with measurable splenomegaly and were not candidates for allogeneic stem cell transplantation. The study also included expansion cohorts evaluating ABBV-744 in combination with ruxolitinib or navitoclax (AbbVie), reflecting a strategy to enhance therapeutic response through complementary mechanisms.^1,4

Safety and Tolerability Profile

Consistent with the study’s primary objective, safety and tolerability were key end points. ABBV-744 demonstrated a manageable safety profile, with hematologic adverse events (AEs) such as anemia and thrombocytopenia among the most commonly observed toxicities.¹ These findings align with the known class effects of BET inhibition but suggest that BD2 selectivity may mitigate severity compared with earlier pan-BET inhibitors.^2,3

Nonhematologic AEs were generally low grade, and dose-limiting toxicities were infrequent, allowing for continued dose optimization. Importantly, the safety profile supported further evaluation of ABBV-744 both as monotherapy and in combination regimens.¹

Preliminary Signals of Clinical Activity

Although not powered for efficacy, the phase 1b study reported encouraging signals of clinical activity. Reductions in spleen volume and improvements in symptom burden were observed in a subset of patients receiving ABBV-744 monotherapy.¹ These findings are particularly notable given the heavily pretreated population and the limitations of existing therapies.

The rationale for combining BET inhibition with JAK inhibitors is supported by preclinical and clinical evidence suggesting synergistic suppression of inflammatory cytokine signaling and malignant hematopoiesis.⁴ Early data from combination cohorts indicate the potential for enhanced responses compared with monotherapy, although further investigation is needed to confirm durability and clinical benefit.¹

Implications for Future Treatment Strategies

The development of ABBV-744 highlights a broader shift toward epigenetic therapies in MF. By selectively targeting BD2, ABBV-744 represents an evolution in BET inhibition aimed at improving therapeutic index while maintaining efficacy. These early-phase data support continued clinical development and suggest that BET inhibitors may play a complementary role alongside JAK inhibitors in the MF treatment paradigm.

Ongoing studies will further define the optimal dosing strategy, combination partners, and patient populations most likely to benefit. If confirmed in later-phase trials, ABBV-744 could offer a novel mechanism-driven option for patients with MF who have limited therapeutic alternatives.

REFERENCES

1. Mascarenhas JO, Fogliatto LM, Green SD, et al. Phase 1b study of ABBV-744, a novel, selective BET inhibitor, as monotherapy in patients with myelofibrosis. Blood Adv. Published online March 17, 2026. doi:10.1182/bloodadvances.2025018695

2. Shorstova T, Foulkes WD, Witcher M. Achieving clinical success with BET inhibitors as anti-cancer agents. Br J Cancer. 2021;124(9):1478-1490. doi:10.1038/s41416-021-01321-0

3. Xie Y, Pan Y, Chen Q, et al. Selective BD2 inhibitor exerts anti-fibrotic effects via BRD4/FoxM1/Plk1 axis in orbital fibroblasts from patients with thyroid eye disease. Invest Ophthalmol Vis Sci. 2023;64(7):9. doi:10.1167/iovs.64.7.9

4. Mascarenhas J, He L, Saab R, et al. PB2224: ABBV-744 alone or in combination with ruxolitinib or navitoclax in patients with myelofibrosis: a phase 1B study. Hemasphere. 2023;7(suppl ):e8258903. doi:10.1097/01.HS9.0000975640.82589.03