BET inhibitors target bromodomain and extra-terminal proteins, which are critical regulators of gene expression driving the development and progression of myelofibrosis. By disrupting these epigenetic mechanisms, BET inhibitors represent a novel approach to modulating disease biology. Although none are FDA-approved for myelofibrosis yet, several are under clinical investigation with encouraging early results. Currently, treatment is dominated by JAK inhibitors like ruxolitinib, fedratinib, and momelotinib. Notably, combining BET and JAK inhibitors has demonstrated synergistic benefits, including deeper spleen responses, improved symptom control, and enhanced disease modification over single-agent therapy.

Novartis recently announced that the Phase III MANIFEST-2 study (NCT04603495), evaluating the efficacy and safety of pelabresib in combination with ruxolitinib in patients with myelofibrosis, successfully met its primary endpoint.

As of August 2024, 67.8%of patients in the pelabresib + ruxolitinib arm and 72.7% of patients in the placebo + ruxolitinib arm remained in the study, with a median follow-up of 92 weeks. Improvements in spleen volume reduction (SVR35), absolute change in total symptom score (TSS), and bone marrow fibrosis (BMF) of ≥1 Grade were observed in favor of the pelabresib + ruxolitinib combination.

At Week 72, the combination of pelabresib and ruxolitinib demonstrated a higher SVR35 response rate (46.3%) compared to the placebo group (29.2%). Moreover, 82.2% of patients in the pelabresib arm achieved SVR35 at any point during the study, significantly more than the 61.1% in the placebo arm. The durability of spleen response was also better in the pelabresib group, with fewer patients experiencing loss of SVR35 response under both the main and alternative definitions. In terms of symptom control, the pelabresib arm showed a greater reduction in total symptom score (TSS), with an average change of −15.42 versus −13.19 in the placebo group which was not statistically significant. Similarly, TSS50 response at Week 72 was higher in the pelabresib group (42.1% vs. 35.2%), though the difference was modest and confidence intervals crossed zero. Notably, the proportion of patients achieving both SVR35 and TSS50 (dual responders) was significantly higher with pelabresib (31.3%) compared to placebo (17.6%), indicating a more comprehensive therapeutic benefit. The pelabresib group also showed a statistically significant improvement in BMF, with 17.8% achieving ≥ 1-grade improvement versus 9.3% in the placebo arm. However, a slightly higher proportion of patients in the pelabresib group progressed to accelerated or blast phase disease (6.1% vs. 4.2%), with the majority of this driven by blast phase progression (5.1% vs. 2.8%). Despite this, the overall findings suggest that pelabresib in combination with ruxolitinib provides superior clinical benefit across multiple endpoints compared to ruxolitinib alone.

In patients with anemia (Hb BL <10 g/dL), Hb response was observed in 20.9% (14/67) vs. 16.9% (12/71) of patients in the pelabresib + ruxolitinib arm vs. the placebo + ruxolitinib arm. Of 426 patients evaluable for safety, Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 65.1% vs. 65.4%, and Grade ≥3 anemia and thrombocytopenia in 27.4% vs. 41.1% and 17.0% vs 7.0% in the pelabresib + ruxolitinib arm vs. the placebo + ruxolitinib arm, respectively. Accelerated- and blast-phase progression, adjudicated independently by external experts, was reported in 6.1% (13/214) of patients in the pelabresib + ruxolitinib arm and 4.2% (9/214) of patients in the placebo + ruxolitinib arm. Comparing pelabresib + ruxolitinib vs. placebo + ruxolitinib, the PFS hazard ratio (HR) was 0.874 (95% CI: 0.49–1.56), OS HR 0.932, and LFS HR 0.994.

KOL insights

“Reduced transfusions associated with anemia improvements are likely to have a direct benefit on the clinical and economic burden of myelofibrosis. The clinically and biologically meaningful benefits of the pelabresib/ruxolitinib combination represent valuable short-term outcomes for patients, which may translate into more profound, longer-term treatment effects than ruxolitinib monotherapy.” – Expert Opinion

Conclusion

With the prevalence of myelofibrosis rising there is a growing need for alternative and more diverse treatment options. Currently, JAK inhibitors remain the only approved therapies and continue to dominate the treatment landscape which includes JAKAFI (ruxolitinib), OJJAARA (momelotinib), VONJO (pacritinib), and INREBIC (fedratinib). However, the potential approval of pelabresib could shift this dynamic, offering a new mechanism of action and potentially reshaping the therapeutic outlook for myelofibrosis.

JAKAFI, developed by Incyte in collaboration with Novartis, currently dominates the first-line treatment landscape for myelofibrosis. However, with key patents set to begin expiring after 2028, Novartis is proactively expanding its portfolio by advancing pelabresib. The goal is to strengthen its position in the myelofibrosis market by offering enhanced clinical outcomes and sustained treatment value.

In support of this strategy, Novartis recently reported promising topline results from the combination of pelabresib and ruxolitinib in JAK inhibitors–naïve myelofibrosis patients. Pelabresib’s potential success could significantly expand the myelofibrosis treatment landscape, reinforcing the franchise value for both Novartis and JAKAFI’s originator, Incyte. However, it may also pose a strategic hurdle for Incyte, whose own BET inhibitor candidate, INCB057643, now faces a well-positioned competitor with strong clinical traction. Still, as the first BET inhibitor showing promising late-stage results, pelabresib may hold a pivotal position and potentially shift the market paradigm in myelofibrosis treatment.