Nuvisertib (TP-3654), an oral and selective PIM1 kinase inhibitor, is being developed by Sumitomo Pharma America for the treatment of patients with intermediate- or high-risk myelofibrosis, particularly those who are relapsed, refractory, or intolerant to JAK inhibitors. The agent is being studied in an ongoing Phase I/II, multicenter, open-label, dose-escalation trial (NCT04176198) evaluating its safety and efficacy as monotherapy, in combination with ruxolitinib and momelotinib. In light of its potential to offer an alternative therapeutic strategy targeting inflammation and disease progression beyond JAK inhibition, the FDA granted fast-track designation to nuvisertib. The study is enrolling adult patients with primary or secondary myelofibrosis who have failed prior JAK inhibitor therapy, and key endpoints include incidence of dose-limiting toxicities (DLTs), safety, spleen volume reduction of ≥35%, as well as symptom and hematologic improvements.

At the 2025 EHA Congress, updated results from the trial demonstrated that nuvisertib was well tolerated, with no DLTs reported during the dose-escalation phase. In terms of clinical activity, 22.2% of patients achieved a spleen volume reduction of at least 25% (SVR25), and 44.4% achieved a ≥50% reduction in total symptom score (TSS50), indicating meaningful symptom relief. Bone marrow fibrosis improvement was seen in 42.9% of patients, while hemoglobin and platelet count improvements were observed in 24% and 26.7% of patients, respectively. Importantly, nuvisertib was associated with significant modulation of pro- and anti-inflammatory cytokines, with a notable increase in anti-inflammatory cytokines that strongly correlated with spleen and symptom responses (p < 0.001). 

These results suggest that nuvisertib not only has a favorable safety profile but also exerts disease-modifying activity, supporting further evaluation both as a monotherapy and in combination with JAK inhibitors for patients with myelofibrosis.

KOL insights

“The data observed to date demonstrate promising clinical activity for nuvisertib and the strong potential for selective PIM1 inhibition to slow the progression of myelofibrosis.”– Expert Opinion

“Patients with myelofibrosis are in need of new therapeutic approaches, including combination treatment options that can provide increased and durable response rates with limited hematologic adverse events. The FDA Fast Track Designation reinforces the potential of nuvisertib to provide clinical benefits for patients with myelofibrosis, an unmet medical need." – Expert Opinion

Conclusion

The myelofibrosis treatment landscape offers opportunities for innovation, including the development of safe and impactful therapies for lower-risk patients, allowing for earlier intervention when success rates are higher, and advancing first-line therapies through novel or combination strategies for patients with intermediate to higher risks. In addition, there's potential for development of approved medications for managing cytopenia, addressing a critical unmet need in patient care. 

Emerging therapies like pelabresib (BET), navitoclax (BCL-2), nuvisertib (PIM1), and bomedemstat (LSD1) aim to enhance or replace JAKi efficacy through complementary mechanisms. With combination strategies gaining traction, competition is intensifying around differentiation via disease modification, symptom control, and hematologic recovery. For TP-3654 to carve out a niche, it will need to demonstrate sustained efficacy and a favorable safety profile in later-stage trials, particularly in combination with JAK inhibitors. The company’s preparation for a fiscal 2027 launch in the US and Japan suggests confidence in its clinical development, but regulatory and commercial hurdles remain. Market uptake will depend on its ability to provide meaningful differentiation in efficacy and safety, especially in an increasingly crowded myelofibrosis pipeline where novel agents are pushing the boundaries of disease modification.