Preliminary data from the Phase I/II study of nuvisertib, an oral investigational selective PIM1 inhibitor, in combination with momelotinib showed clinical responses in patients with relapsed/refractory myelofibrosis

Abstract

Abstract Background: Janus Kinase (JAK) inhibitors are the current standard of care for patients (pts) with myelofibrosis (MF). However, many pts may not achieve spleen volume reduction (SVR) or total symptom score (TSS) response after frontline treatment, and most pts with relapsed/refractory (R/R) MF lack adequate responses. Momelotinib (MMB), a recently approved JAK/ACVR1 inhibitor for MF pts with anemia, showed symptom and spleen responses in about 25% pts in R/R setting. Combination strategies of JAK inhibitor and agent with unique mechanism of action and minimal overlapping toxicities (e.g. cytopenias) are needed to improve response rates in MF. PIM1 expression is upregulated in MF CD34 cells. In preclinical models, PIM1 knockout (KO) was shown to prevent MF progression without affecting PLT counts, whereas pan-PIM KO caused thrombocytopenia (TCP). Nuvisertib (NUVI, TP-3654), an oral investigational highly selective PIM1 kinase inhibitor, alone and in combination with ruxolitinib (RUX) showed spleen size reduction and bone marrow (BM) fibrosis improvement in JAK2V617F and MPLW515L MF mouse models. Preliminary data from the ongoing Phase 1/2 study in R/R MF pts with PLT count ≥25 x 109/L showed that NUVI monotherapy was well tolerated with limited myelosuppression, and clinical activity including SVR and TSS responses strongly correlating with cytokines modulation, and hemoglobin (Hgb), PLT, and BM improvement. Preclinical and monotherapy clinical data support the development of NUVI + MMB combo in MF. Methods: The global Phase 1/2 study evaluates the safety and efficacy of NUVI + MMB combo in pts with MF (NCT04176198, Arm 3). Key eligibility criteria include primary or secondary MF, previously treated with JAK inhibitor, DIPSS intermediate or high-risk MF, Hgb <10 g/dL, PLT ≥50 x 109/L, splenomegaly (≥450 cm3 by imaging), and ≥2 measurable symptoms with each score ≥3 or a total average score of ≥10 per MFSAF v4. The study aims to identify the RP2D of NUVI when given with MMB, and to assess the safety, clinical activity (SVR, TSS improvement), and PK and PD markers (cytokine, BM fibrosis etc.). Results: Here we present the first ever combination data of MMB in MF. As of 29 May 2025, total 18 pts enrolled in 4 dose levels of NUVI BID at 240 mg (n=4), 360 mg (n=8), 480 mg (n=5) and 720 mg (N=1) + MMB 200 mg QD using the BLRM dose escalation. At baseline, median age 75 years (range 51, 82); TSS 29 (9, 37); spleen volume 1370 cm3 (614, 4250); Hgb 9.1 g/dL (7.9, 10.1; 50% pts required transfusion); and PLT 196 x 109/L (81, 601). All pts received prior JAK inhibitor, and 53% pts had high molecular risk mutation. Median treatment duration of NUVI + MMB combo was 21 weeks (1, 30), and 13 of 18 (72%) pts were on treatment. One DLT of Grade 4 TCP without any bleeding occurred in NUVI 360 mg BID + MMB 200 mg QD dose. Treatment-related adverse events (TRAEs) occurring in ≥20% of pts were diarrhea, nausea, and TCP. Grade ≥3 TRAE occurring in ≥2 pts included TCP (n=2; 1 pt had baseline TCP). Mean Hgb and PLT remained stable throughout the 24-week treatment. Emerging NUVI + MMB combo safety data was generally consistent with NUVI monotherapy data. 5 pts in the NUVI 360 mg BID + MMB 200 mg QD dose completed ≥24 weeks of treatment and were considered efficacy evaluable. TSS improvement at WK24 was observed in all 5 patients (median change -65%, range -38% to -72%); 3 of 5 (60%) pts showed ≥50% TSS reduction. In addition, absolute reduction was observed in all 7 symptom parameters, including >50% reduction in mean fatigue score at WK24. 2 of 5 (40%) pts showed ≥25% SVR at WK24. Decreased EN-RAGE and increased adiponectin were observed in all 5 pts, consistent with NUVI monotherapy findings where modulation of these cytokines strongly correlated with TSS50, individual symptoms and SVR25 responses. Anemia improvement was observed in 2 of 5 (40%) pts during 24 weeks of treatment: 1 pt showed Hgb response (defined as mean ≥1.0 g/dL increase for ≥12 weeks without transfusion), and 1 pt achieved a >50% reduction in transfusions. Dose escalation is ongoing, and updated data will be presented.Conclusions: NUVI + MMB combo appeared to be well tolerated. Preliminary data showed early clinical activity including 60% TSS50 response and absolute symptom improvement, 40% SVR25 response, cytokine modulation and anemia improvement in R/R MF pts with anemia. Preliminary data supports further development of NUVI + MMB combo for pts with MF.