Abstract: Essential thrombocythemia (ET) and myelofibrosis (MF) are classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) characterized by overactive JAK-STAT signaling. While Janus kinase (JAK) inhibitors like ruxolitinib are the standard of care, they primarily provide symptom and spleen burden relief without significantly modifying the underlying disease, reversing bone marrow fibrosis, or preventing disease evolution. Pelabresib (CPI-0610) is a novel, potent bromodomain and extra-terminal domain (BET) inhibitor being developed to address these unmet clinical needs in MPNs, including MF that arises de novo or secondary to ET (post-ET MF). By acting as an epigenetic modulator, pelabresib inhibits BET proteins (such as BRD4), thereby downregulating the NF-κB pathway, suppressing pro-inflammatory cytokine production, and modifying megakaryocyte differentiation. Clinical data from the MANIFEST trials demonstrate that pelabresib, particularly in combination with ruxolitinib, yields meaningful improvements in spleen volume, symptom burden, and bone marrow fibrosis. This review summarizes the pharmacological activity, molecular mechanism, limitations, and future perspectives of pelabresib in the treatment of MPNs.
1. Introduction
Myeloproliferative neoplasms (MPNs) are a group of clonal hematological malignancies that include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). MF can arise de novo (primary MF) or evolve from an antecedent MPN, such as ET (post-ET MF) or PV [1]. These diseases are characterized by the universal activation of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathway, alongside bone marrow fibrosis, extramedullary hematopoiesis, and debilitating constitutional symptoms [1][2].
Currently, JAK inhibitors (such as ruxolitinib) form the cornerstone of therapy for these MPNs. While they are highly successful in reducing splenomegaly and symptom burden, their "disease-modifying" effects—such as the reduction of mutant allele burden and the reversal of bone marrow fibrosis—are notably limited [2]. Furthermore, JAK inhibitors do not reliably prevent disease evolution to advanced MF or acute myeloid leukemia (AML), and many patients eventually become refractory to or intolerant of these therapies, leading to a dismal survival prognosis [1][2]. To overcome these limitations, novel non-JAK inhibitor-based therapies are being explored. Among these, pelabresib (CPI-0610), an epigenetic modifier targeting the bromodomain and extra-terminal (BET) proteins, has emerged as a highly promising therapeutic agent capable of altering the natural history of MPNs [1][5].
2. Pharmacological Activity
The pharmacological efficacy of pelabresib (CPI-0610) has been extensively evaluated in the multi-arm Phase 2 MANIFEST study, which investigated the drug across distinct patient populations, including those with post-ET MF [1].
As a monotherapy in patients who were refractory or intolerant to JAK inhibitors, pelabresib demonstrated clinical activity, particularly in improving anemia. In a cohort of red blood cell transfusion-dependent patients, 21.4% to 23.8% converted to transfusion independence [1][2]. Furthermore, among non-transfusion-dependent patients with baseline hemoglobin <10 g/dL, 57.9% achieved a sustained ≥1.5 g/dL improvement in hemoglobin without requiring transfusions [2].
Pelabresib has shown even greater pharmacological activity when used in combination with ruxolitinib. When utilized as an "add-on" therapy for patients experiencing a suboptimal response to ruxolitinib, 34.4% of transfusion-dependent patients converted to transfusion independence. Additionally, 20.8% to 22.2% of patients achieved a spleen volume reduction of ≥35% (SVR35), and 36.8% to 46.2% achieved a ≥50% reduction in total symptom score (TSS50) at 24 weeks [1].
The most compelling data for pelabresib comes from its use in the upfront (JAK inhibitor-naive) setting in combination with ruxolitinib. In this population, the combination achieved a median SVR of 50%, with 67% to 68% of patients reaching the SVR35 benchmark [1][3]. Symptom responses (TSS50) were observed in 56% to 57% of patients. Crucially, pelabresib demonstrated disease-modifying pharmacological activity: 28% to 33% of patients experienced at least a 1-grade improvement in bone marrow fibrosis, and 29.5% of patients achieved a >25% reduction in the JAK2V617F-mutant allele fraction [1][3].
3. Molecular Mechanism of Action
Pelabresib (CPI-0610) functions as a potent inhibitor of the BET (bromodomain and extra-terminal domain) family of proteins, which includes BRD2, BRD3, BRD4, and BRDt [1]. BET proteins act as epigenetic "readers" that recognize and bind to acetylated lysine residues on histone tails. This binding localizes BET proteins to discrete chromosomal locations, allowing them to recruit regulatory complexes that control RNA polymerase II and influence the transcription of multiple oncoproteins [1][2].
In the context of MPNs such as ET and MF, the inhibition of BRD4 by pelabresib leads to the attenuation of the nuclear factor kappa B (NF-κB) pathway, which plays a pivotal role in driving the pro-inflammatory state characteristic of these diseases [1][2]. By blocking BET proteins, pelabresib significantly dampens the inflammatory response of bone marrow-derived macrophages, suppressing the expression of key inflammatory cytokines including interleukin (IL)-6, IFN-b1, IL-1b, IL-12a, CXCL9, and CCL12 [1]. Additionally, BET inhibition controls the transcription of other critical targets such as c-Myc and B-cell lymphoma-2 (BCL-2) [2]. Biologically, this mechanism is hypothesized to modify aberrant megakaryocyte differentiation and proliferation, which are central to the pathogenesis of bone marrow fibrosis in MPNs [3]. Preclinical models have shown that the combination of JAK and BET inhibition synergistically abrogates NF-κB signaling, reduces inflammatory cytokine production, and diminishes both splenomegaly and bone marrow fibrosis [1][2].
4. Structure-Activity Relationship (SAR)
The provided literature focuses primarily on the clinical efficacy and biological pathways of pelabresib rather than detailing specific chemical structure-activity relationship (SAR) modifications. However, from a structural biology perspective, the activity of pelabresib is strictly dependent on its ability to act as a synthetic mimic that competitively binds to the bromodomain binding pockets. By occupying these pockets, pelabresib prevents BET proteins from recognizing and binding to acetylated lysine residues on chromatin [1]. This structural blockade is what prevents the subsequent recruitment of transcriptional regulatory complexes to discrete chromosomal locations, thereby translating the structural inhibition of the BET domain into the downstream pharmacological downregulation of NF-κB and pro-inflammatory cytokines [1].
5. Current Limitations
Despite its promising efficacy, the clinical application of pelabresib is associated with certain limitations, primarily related to hematological toxicities and variable monotherapy efficacy.
In clinical trials, the most common treatment-emergent adverse events (TEAEs) associated with pelabresib were hematological. In the monotherapy setting, thrombocytopenia occurred in 25.6% of patients (reaching grade 3 in 14% of patients), and anemia occurred in 11.6% of patients (reaching grade 3 in 9.3%) [1]. When used in combination with ruxolitinib in the upfront setting, the incidence of these cytopenias was higher, with anemia and thrombocytopenia occurring in 33% and 32% of patients, respectively (grade 3/4 in 29% and 8%, respectively) [1].
Furthermore, while pelabresib showed utility in improving anemia, its efficacy as a monotherapy for reducing spleen size and symptom burden in certain cohorts was limited. In a cohort of non-transfusion-dependent patients who were refractory or intolerant to JAK inhibitors, pelabresib monotherapy yielded disappointing results, with a 0% rate of ≥35% SVR and only an 8.3% rate of ≥50% TSS reduction at 24 weeks [2].
6. Future Perspectives
Because of the synergistic effects observed when targeting both the JAK-STAT and epigenetic pathways, the primary developmental path forward for pelabresib is as a combination therapy with ruxolitinib in the frontline setting [2]. To this end, the global, randomized, double-blind Phase 3 MANIFEST-2 trial (NCT04603495) is currently evaluating the combination of pelabresib and ruxolitinib versus ruxolitinib plus placebo in JAK inhibitor-naive patients [1][3][4][5].
Interim data from MANIFEST-2 have demonstrated positive clinical outcomes and good tolerability, supporting a potential paradigm shift toward early combination therapy [3]. Sub-group analyses have shown consistent spleen volume reductions across all risk groups. Future research will need to determine the long-term clinical benefits of commencing BET inhibitor treatment at an early stage of the disease (e.g., in intermediate-1 risk patients or those transitioning from ET to MF) to achieve true disease modification, reverse bone marrow fibrosis, and prevent leukemic transformation [3]. The breadth of data expected from these ongoing Phase 3 trials will provide critical insight into the ability of non-JAK inhibitor treatments like pelabresib to fundamentally alter the natural history of MPNs [5].
