Bromodomain and extra-terminal (BET) proteins are epigenetic readers that control the expression of key oncoproteins implicated in hematologic malignancies, including myelofibrosis. INCB057643 is an oral small-molecule BET inhibitor that has shown promising tolerability and positive clinical outcomes when used alone or in combination with the JAK inhibitor ruxolitinib in patients with advanced disease in a prior phase I/II basket trial. JAKAFI (ruxolitinib) was the first drug to be approved by the US FDA for the treatment of adults with intermediate or high-risk myelofibrosis in November 2011. Thanks to its unmatched product profile, JAKAFI continues to maintain its leadership in myelofibrosis and holds a significant market share.

The presentation at the EHA 2024 Congress showcased result from the Phase I study of INCB057643 as monotherapy in patients with relapsed/refractory myelofibrosis and in combination with ruxolitinib in patients with advanced myelofibrosis. 

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Key outcomes from the study are summarized below: 

Efficacy

• By Week 24, 3 out of 7 patients on INCB057643 monotherapy ≥10 mg achieved ≥35% reduction in spleen volume (SVR35). Overall, 8 out of 19 patients across all doses achieved ≥25% reduction.

• In the combination therapy group, 3 out of 12 patients achieved SVR35 at Week 24, with improvements seen in 13 out of 16 patients, including 5 achieving ≥25% reduction.

• Regarding MPN-SAF Total Symptom Score (TSS50), 5 out of 14 monotherapy patients and 5 out of 7 patients receiving ≥10 mg achieved ≥50% reduction. Overall, 12 out of 19 patients at any dose achieved TSS50.

• In the combination therapy group, 6 out of 11 patients achieved TSS50 at Week 24, with 10 out of 15 achieving TSS50.

Hemoglobin Levels

• Among non-transfusion-dependent patients in Part 1, 3 achieved >1.5 g/dL increases in hemoglobin for ≥12 weeks.

• In Part 2, 3 non-transfusion-dependent patients had >1.5 g/dL hemoglobin increases.

• Among transfusion-dependent patients, 2 achieved transfusion independence, both in Part 1.

Safety

• Grade 3 treatment-emergent adverse events (TEAEs) occurred in 61.4% of patients, with serious TEAEs in 25.0%.

• Six patients discontinued treatment due to TEAEs.

• Thrombocytopenia was the most common TEAE (26 patients), leading to discontinuation in 5 cases.

• There were 2 dose-limiting toxicities (DLTs) with monotherapy and 1 DLT with combination therapy.

KOL insights

“Treatment with INCB057643 demonstrated a broad therapeutic window, making it a potentially more flexible treatment option compared to some other BET inhibitors.” – MD, United States.

Conclusion 

The prevalence rates of myelofibrosis have increased than previously reported owing to improved diagnostics, increased offerings for preventive checkups, and the classification change of prefibrotic myelofibrosis by the WHO in 2016. The market growth of Myelofibrosis is expected to be hampered by patent expiries of key marketed therapies. JAKAFI is expected to go off patent in 2027 for Novartis and in 2028 for Incyte, creating an opportunity to grab.  Incyte is looking at combination trials using novel drugs to prolong the lifespan of JAKAFI, one of which includes evaluating INCB057643 in combination with Ruxolitinib for treating myelofibrosis.

The myelofibrosis market is attractive, driving substantial investments and acquisitions. The future of myelofibrosis treatment lies in these innovative approaches, aiming to overcome the limitations of existing JAK inhibitors and enhance patient quality of life.