nuvisertib (TP-3654) / Sumitomo Pharma - LARVOL DELTA

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 (ASH 2025) - P1/2 | "Nuvisertib (NUVI, TP-3654), an oralinvestigational 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 MPLW515LMF mouse models. NUVI + MMB combo appeared to be well tolerated. Preliminary data showed early clinicalactivity 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 supportsfurther development of NUVI + MMB combo for pts with MF."

Clinical • Combination therapy • P1/2 data • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Thrombocytopenia • ACVR1 • PIM1

Preliminary Data From Ongoing Global Phase 1/2 Study of Investigational PIM1 Inhibitor Nuvisertib in Combination With Momelotinib Show Promising Clinical Activity in Patients With Myelofibrosis and Anemia (SOHO 2026) - P1/2 | "According to preliminary data from this ongoing phase 1 dose-escalation study in patients with R/R myelofibrosis and anemia, NUVI+ MMB (fed) appeared to be well tolerated and showed promising clinical activity, including symptom and spleen responses, anemia improvement, and cytokine modulation. Emerging data support further development of the NUVI+ MMB combination (fed) for myelofibrosis. DIPSS: Dynamic International Prognostic Scoring System, JAK, Janus kinase, PIM1: proto-oncogene serine/threonine-protein kinase Pim-1, SVR: spleen volume reduction, TSS: total symptom score."

Clinical • Combination therapy • P1/2 data • Myelofibrosis • Oncology • ACVR1 • IL18

Preliminary Data from the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients with Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy (ASH 2022) - P1/2 | "TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation. The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors."

Clinical • P1/2 data • Hematological Disorders • Immunology • Myelofibrosis • CALR • IL18 • MMP9 • PIM1 • TIMP1

Phase 1/2 Study of TP-3654, a Selective PIM1 Kinase Inhibitor: Preliminary Data Showed Clinical Activity and Cytokine Reductions in Relapsed/Refractory Myelofibrosis Patients (ASH 2023) - P1/2 | "In preclinical studies, TP-3654 alone and in combination with ruxolitinib showed spleen size and bone marrow (BM) fibrosis reduction in murine MF models. This preliminary data of TP-3654 in relapsed/refractory MF pts showed early signs of clinical activity including spleen volume reduction, TSS improvement, and correlating cytokine reductions. TP-3654 is well tolerated with limited myelosuppressive adverse events. Enrollment is ongoing as monotherapy and current data support the development of TP-3654 in combination with JAK inhibitors given the preliminary clinical activity and minimal cytopenia."

Clinical • IO biomarker • P1/2 data • Fibrosis • Hematological Malignancies • Immunology • Myelofibrosis • Oncology • CD40 • CXCL8 • IL18 • PIM1 • TGFB1

Closing the disease modification gap: Emerging therapies in myelofibrosis beyond JAK inhibition. (PubMed, Semin Hematol) - "We discuss BET inhibitors (pelabresib), PIM kinase inhibitors (TP-3654), telomerase inhibition (imetelstat), nuclear export inhibition (selinexor), LSD1 inhibition (bomedemstat), MDM2 antagonism (navtemadlin), mutant CALR-directed immunotherapies, and activin receptor ligand traps (elritercept). Strategies such as high-molecular-risk mutation profiling and variant allele frequency monitoring to assess disease progression and clonal burden will also be discussed. As the focus of MPN management shifts towards curative nontransplant options, a combination of improved access to clinical trials and accounting for patient-reported outcomes will be vital if we are to realize the promise of these next-generation therapies."

IO biomarker • Journal • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Transplantation • CALR

Nuvisertib (TP-3654), an Investigational Selective PIM1 Kinase Inhibitor, Showed Durable Clinical Response and Sustained Hematological Improvement in Relapsed/Refractory Myelofibrosis Patients (ASH 2024) - P1/2 | "Preliminary data of TP-3654 in relapsed/refractory MF pts showed clinical activity including SVR25, symptom improvement correlating with cytokines reduction, BM fibrosis reduction, and Hgb and PLT responses. Current monotherapy and preclinical data support the development of TP-3654 in combination with JAK inhibitors ruxolitinib and momelotinib (NCT04176198, Arms 2 and 3, respectively); enrollment ongoing in all 3 arms."

Clinical • Anemia • Fatigue • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Musculoskeletal Pain • Myelofibrosis • Oncology • Pain • PIM1

INVESTIGATIONAL PIM1 INHIBITOR NUVISERTIB IN COMBINATION WITH MOMELOTINIB SHOWED PROMISING CLINICAL ACTIVITY IN PATIENTS WITH MYELOFIBROSIS AND ANEMIA: DATA FROM AN ONGOING GLOBAL PHASE 1/2 STUDY (EHA 2026) - P1/2 | "Summary/Conclusion Preliminary data from the ongoing Phase 1 dose escalation study in pts with R/R MF and anemia, nuvi + MMB (fed) appeared well tolerated and showed promising clinical activity including symptom and spleen responses, anemia improvement and cytokine modulation. Emerging data supports further development of nuvi + MMB combination (fed) for pts with MF."

Clinical • Combination therapy • P1/2 data • Anemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytopenia • ACVR1 • IL18

PRECLINICAL EVIDENCE OF TARGETING ACVR1/HEPCIDIN BY NUVISERTIB, AN ORAL INVESTIGATIONAL PIM1 KINASE INHIBITOR, SUGGESTS POTENTIAL MECHANISTIC BASIS FOR HEMOGLOBIN BENEFIT IN MYELOFIBROSIS (EHA 2026) - P1/2 | "In a preclinical in vitro study, nuvi treatment resulted in a dose-dependent reduction in Hamp mRNA (EC50= 380 nM), comparable to the ACVR1/JAK inhibitor momelotinib (MMB) (EC50= 470 nM). Plasma hepcidin levels are inversely correlated with Hgb. For each patient, multiple time points were included as available, with each dot representing a single time-point measurement."

Preclinical • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Thrombocytopenia • ACVR1 • BMP6 • CD34 • HAMP • IL6 • PIM1

Promising clinical response with nuvisertib and momelotinib in myelofibrosis (Businesswire) - "As of December 6, 2025, a total of 26 patients with relapsed/refractory (R/R) MF and anemia were enrolled across four dose levels of nuvisertib (240, 360, 480, and 720 mg twice daily under fed condition) in combination with the approved dose of momelotinib in MF (200 mg once daily)...Spleen volume reduction of at least 25% (SVR25) was achieved by 73% of patients at Week 12 and reached 100% at Week 24 (n=5). Similarly, 53% of patients achieved a total symptom score reduction of at least 50% percent (TSS50) at Week 12 that further improved to 60% of patients at Week 24 (n=5). Anemia response by IWG ELN2024 criteria was observed in 50% of patients at any time. Most significantly, 60% of patients achieved a triple response at the Week 24 mark, meeting concurrent criteria for symptom reduction, spleen volume reduction, and anemia improvement."

P1/2 data • Myelofibrosis

New Nuvisertib translational research presented in MF (Businesswire) - "In addition to its primary activity as a PIM1 inhibitor, in vitro and biochemical data demonstrated that nuvisertib also binds to and inhibits ACVR1, resulting in reduced hepcidin mRNA expression, a central regulator of iron homeostasis. Consistent with these findings, preliminary clinical data from a Phase 1/2 study of nuvisertib monotherapy showed reduced hepcidin levels in patients with R/R MF, providing a potential mechanistic explanation for the hemoglobin stability and improvement observed in patients with MF treated with nuvisertib."

P1/2 data • Preclinical • Myelofibrosis

The Path Forward in MF: Small Molecules in the Limelight. (PubMed, Cancers (Basel)) - "However, a substantial percentage of patients fail to achieve sustained benefit, are intolerant, or become refractory; real-world and clinical trial data indicate that approximately half of treated patients discontinue ruxolitinib treatment within 3 years and up to approximately 75% within 5 years, with poor outcomes after discontinuation (median survival in several series is approximately 12-14 months)...These include agents targeting telomerase (imetelstat), epigenetic regulation via BET inhibition (pelabresib/CPI-0610), the MDM2-p53 axis (navtemadlin/KRT-232), erythroid maturation and the bone marrow microenvironment (luspatercept), PI3K signaling (parsaclisib), and PIM inhibitors (nuvisertib). Early clinical data show promising results for symptom and splenic control in specific settings and, importantly, suggest potential disease-modifying activity (improvements in marrow fibrosis and molecular responses) for some compounds. This review summarizes the biological..."

Journal • Review • Chronic Eosinophilic Leukemia • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Nuvisertib (TP-3654) and Dordaviprone (ONC201) synergize to reduce renal cell carcinoma cell viability (AACR 2026) - "Our findings highlight actionable novel candidate targets and strategies for therapeutic intervention in RCC. Ongoing studies are aimed to uncover mechanistic insights of these treatments in RCC and guide the development of optimal treatment strategies."

Genito-urinary Cancer • Myelofibrosis • Oncology • Renal Cell Carcinoma • Solid Tumor • PIM1 • TNFRSF10B

Development of the pyridopyrimidine derivative KC12 as a selective dual Pim/Mnk inhibitor to inhibit leukemia cell growth (AACR 2026) - "KC12 exhibits increased aqueous solubility and superior anti-proliferative activity compared to 21o, as well as to the Pim inhibitor TP-3654 and the Mnk inhibitor eFT508. Moreover, KC12 demonstrated a more favorable pharmacokinetic profile than 21o and exhibited enhanced antitumor efficacy in MOLM-13 xenograft models. These findings suggest that KC12 acts as a novel, potent, and selective dual Pim/Mnk inhibitor and is worthy of further development as a therapeutic agent."

Hematological Malignancies • Leukemia • Oncology • EIF4E • EIF4EBP1 • MCL1 • MYC • PIM1

MEN1703/SEL24 exhibits promising antitumoral activity in preclinical models of myelofibrosis both as single agent and combined with ruxolitinib (AACR 2024) - "MEN1703/SEL24 (MEN) is an oral, first-in-class, dual PIM/FLT3 kinase inhibitor in development for hematologic malignancies.This study aims to investigate the efficacy of MEN alone and in combination with the JAKi ruxolitinib (RUX) in preclinical MF models and to elucidate the underlying signaling pathways.MF cell lines (JAK2V617F and JAK2 wild type) were used in MTS assays to assess the in vitro cytotoxicity of MEN alone and in combination with RUX, compared with the PIM inhibitor TP-3654 (Dutta 2022). Importantly, MEN combined with the standard of care RUX was synergistic, and molecular analyses confirmed the role of PIM downstream target inhibition. Our results support the therapeutic potential and relevance of MEN in MF treatment strategies."

Preclinical • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • FLT3 • MCL1 • PIM1

PIM inhibition increases membrane expression of TNFRSF10B(DR5) and combination with recombinant human TRAIL synergizes to reduce renal cell carcinoma cell viability (AACR 2025) - "To investigate synergism between PIM inhibitors and recombinant human TRAIL (rhTRAIL), RCC cell lines were treated with increasing concentrations of SGI-1776 or TP-3654 and rhTRAIL (TLY012) for 24 hours and assessed for viability via Cell Titer Glo assay. These results reveal novel therapeutic strategies for the treatment of RCC, highlighting PIM kinases as targets to potentiate TRAIL induced apoptosis. Current studies are ongoing to understand the mechanism of PIM kinase involvement in DR5 regulation and sensitivity to TRAIL in RCC."

Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioblastoma • Oncology • Renal Cell Carcinoma • Solid Tumor • PIM1 • TNFRSF10B

PIM1 contributes to tumor progression, immune evasion and metastasis of triple-negative breast cancer (AACR 2025) - "Gene Set Enrichment Analysis (GSEA) revealed significant downregulation of genes related to cell proliferation, translation, EMT and metastasis in PIM1-deleted or TP-3654-treated TNBC cells compared to control TNBC cells. Collectively, our results suggest that PIM1 plays an important role in tumor progression, immune evasion and metastasis of TNBC, and inhibition of PIM1 with TP-3654 might be potentially useful for treatment of TNBC."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • MET • PIM1 • SNAI2 • VIM

Nuvisertib (TP-3654) and Dordaviprone (ONC201) synergize to reduce renal cell carcinoma cell viability (AACR-Kidney 2026) - "Our findings highlight actionable novel candidate targets and strategies for therapeutic intervention in RCC. Ongoing studies are aimed to uncover mechanistic insights of these treatments in RCC and guide the development of optimal treatment strategies."

Genito-urinary Cancer • Myelofibrosis • Oncology • Renal Cell Carcinoma • Solid Tumor • PIM1 • TNFRSF10B

TP-3654 Food Effect Study (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Sumitomo Pharma America, Inc.

New P1 trial

Nuvisertib: “Nuvisertib has demonstrated tolerability and efficacy both as monotherapy and in combination with momelotinib”; Myelofibrosis (Sumitomo Pharma) - R&D Meeting 2026: “Shown clinical activity even in patients previously treated with JAK inhibitors”

P1/2 data • Hematological Malignancies • Myelofibrosis • Oncology

AUM-302, a novel triple PIM/PI3K/mTOR inhibitor, synergizes with RAS inhibition and impedes the growth of pancreatic ductal adenocarcinoma spheroids and organoids. (PubMed, Front Pharmacol) - "Single- and dual-kinase inhibitors TP-3654, GDC-0941, BEZ-235, respectively, and DMSO were used as controls. The synergy studies were performed using AUM-302 and the RAS inhibitor RMC-6236...By blocking kinase activity, AUM-302 demonstrates potent inhibition in PDAC cell lines and organoids across two 3D culture formats. Treatment with this novel triple PIM/PI3K/mTOR inhibitor may also chemosensitize PDAC to other cancer therapies, such as RAS inhibitors."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Nuvisertib: Launch in US/Japan for myelofibrosis in FY 2028 (Sumitomo Pharma) - Q3 FY2025 Results

Launch Japan • Launch US • Myelofibrosis • Oncology

Nuvisertib, an oral investigational selective PIM1 kinase inhibitor, showed clinical responses strongly correlating with cytokine modulation in patients with relapsed/refractory myelofibrosis in the ongoing global phase I/II study (ASH 2025) - P1/2 | "Nuvisertib monotherapy appeared well tolerated with no DLTs. Preliminary data in pts withR/R MF showed that nuvisertib treatment leads to significant modulation of cytokine profiles,demonstrating a strong correlation with clinical responses, including SVR25 and TSS50 responses, andimprovements in Hgb, PLT and BM fibrosis, suggesting that selective PIM1 inhibition may offer disease-modification with limited hematologic toxicity. Emerging data supports ongoing clinical development ofnuvisertib in combination with ruxolitinib and momelotinib (NCT04176198, Arms 2 and 3, respectively)."

Clinical • P1/2 data • Fibrosis • Hematological Malignancies • Immunology • Myelofibrosis • Thrombocytopenia • IL1R1 • PIM1 • TNFRSF1A • VCAM1

For the first time, clinical data were presented from the ongoing global Phase 1/2 study evaluating the safety and efficacy of nuvisertib in combination with momelotinib (MMB) in 18 patients with R/R MF with anemia. (PRNewswire) - "Preliminary data showed that the treatment with nuvisertib and MMB combination appeared well tolerated, with early clinical activity observed, including ³50% total symptom score reduction (TSS50 response) in 58% of patients with an absolute reduction in all individual symptoms, a spleen volume reduction 25% (SVR25 response) in 50% of patients, anemia improvement, and cytokine modulation in patients with relapsed or refractory MF with anemia. These preliminary data, collected as of October 15, 2025, support further development of nuvisertib in combination with MMB as a potential treatment option for patients with MF."

P1/2 data • Anemia • Myelofibrosis

Additionally, data presented from the ongoing global Phase 1/2 study of nuvisertib in patients with relapsed or refractory MF (N=77) showed that nuvisertib monotherapy continued to be well tolerated with no DLTs and limited myelosuppression. (PRNewswire) - "The results showed that treatment with nuvisertib monotherapy led to SVR25 response in 20% of patients, TSS50 response in 45% of patients with absolute reduction in all individual symptoms. Data also showed that treatment with nuvisertib resulted in significant cytokine modulation over time, correlating with spleen and symptom responses and one-year overall survival rate of 81%."

P1/2 data • Myelofibrosis

Highlights of JTCC Research to be presented at ASH 2025: Myeloproliferative Neoplasms (PRNewswire) - "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 25-3882); Safety and efficacy results from A phase 1b study of R289, a dual irak 1/4 inhibitor, in patients with Relapsed/Refractory (R/R) lower risk myelodysplastic syndrome (LR-MDS) (ABSTRACT 25-13480); Nuvisertib, an oral investigational selective PIM1 kinase inhibitor, showed clinical responses strongly correlating with cytokine modulation in patients with relapsed/refractory myelofibrosis in the ongoing global phase I/II study (ABSTRACT 25-2614)."

Clinical data • Myelodysplastic Syndrome • Myelofibrosis