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

PRELIMINARY DATA FROM PHASE I/II STUDY OF NUVISERTIB, AN ORAL INVESTIGATIONAL SELECTIVE PIM1 INHIBITOR, SHOWED CLINICAL RESPONSE CORRELATING WITH CYTOKINE MODULATION IN PATIENTS WITH MYELOFIBROSIS (EHA 2025) - P1/2 | "Nuvisertib monotherapy appeared well tolerated with no DLTs. Preliminary data showed clinical activity including SVR25, symptom improvement correlating with cytokines modulation, BM fibrosis reduction, and Hgb and PLT responses in relapsed/refractory (R/R) MF pts. Emerging data support clinical development of nuvisertib in combination with JAK inhibitors ruxolitinib and momelotinib (NCT04176198, Arms 2 and 3, respectively)."

Clinical • P1/2 data • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Myelofibrosis • Oncology • Thrombocytopenia • PIM1

Sumitomo Pharma America Announces that Nuvisertib (TP-3654) Has Received FDA Fast Track Designation for the Treatment of Myelofibrosis (PRNewswire) - P1/2 | N=240 | NCT04176198 | Sponsor: Sumitomo Pharma America, Inc. | "Sumitomo Pharma America...announced that the U.S. Food and Drug Administration (FDA) granted Fast Track Designation to nuvisertib (TP-3654) for the treatment of patients with intermediate or high-risk myelofibrosis (MF).....Updated data from the ongoing Phase 1/2 study of nuvisertib in patients with relapsed/refractory MF were presented at the EHA Congress on June 12, 2025. Preliminary data showed that nuvisertib monotherapy appears to be well tolerated with no dose-limiting toxicities (DLTs). Evaluable patients showed clinical activity including a ≥25% spleen volume reduction (SVR25) in 22.2% of patients and a ≥50% reduction in total symptom score (TSS50) of 44.4% of patients, as well as improvement of bone marrow fibrosis (42.9% patients), hemoglobin (24% patients) and platelet count (26.7% patients)."

Fast track • P1/2 data • Myelofibrosis

AUM-302, A NOVEL TRIPLE PIM/PI3K/MTOR INHIBITOR, SYNERGIZES WITH KRAS INHIBITION AND IMPEDES THE GROWTH OF PANCREATIC DUCTAL ADENOCARCINOMA SPHEROIDS AND ORGANOIDS (DDW 2025) - "Single- and dual kinase inhibitors TP-3654, GDC-0941, and BEZ-235, and DMSO were used as controls...Finally, combinatorial assays revealed synergy between AUM-302 and the KRAS inhibitor RMC-6236 in reducing the growth of hT1 and hM1A organoids. By blocking kinase activity, AUM-302 demonstrates potent inhibitory activity in PDAC cell lines and organoids in two different 3D culture formats. Treatment with this novel triple PIM/PI3K/mTOR inhibitor may also sensitize PDAC to other therapies, such as KRAS inhibitors."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Nuvisertib: Presentation of efficacy and safety data from P1/2 trial (NCT04176198) for myelofibrosis at EHA (Jun 12-15, 2025) (Sumitomo Dainippon) - FY2024 Results

P1/2 data • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Nuvisertib: Regulatory submission for myelofibrosis in FY 2027 (Sumitomo Dainippon) - FY2024 Results: Launch in US/Japan for myelofibrosis in FY 2028

Filing • Launch Japan • Launch US • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

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

REDD1 is a determinant of the sensitivity of renal cell carcinoma cells to autophagy inhibition that can be therapeutically exploited by targeting PIM activity. (PubMed, Cancer Lett) - "Repurposing FDA approved drugs with off-target autophagy inhibition such as chloroquine/hydroxychloroquine (CQ, HCQ) has produced modest anticancer activity in clinical trials, due in part, to a failure to define predictive biomarkers that enable the selection of patients that best respond to this treatment strategy. Inhibition of autophagy with CQ synergistically enhanced the in vitro and in vivo anticancer activity of TP-3654. Our findings identify REDD1 as a novel determinant of the sensitivity of RCC cells to autophagy inhibition and support further investigation of PIM kinase inhibition as a precision strategy to drive sensitivity to autophagy-targeted therapies through REDD1 upregulation."

Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • AMPK • DDIT4

Nuvisertib: Launch in US/Japan for myelofibrosis in FY 2027 (Sumitomo Dainippon) - Q3 FY2024 Results

Launch Japan • Launch US • Hematological Malignancies • Myelofibrosis • Oncology

Nuvisertib: “Improvements in important efficacy measures were observed even in patients who did not respond to JAK inhibitor and in those with poor prognostic factors such as low hemoglobin and platelet counts”; Myelofibrosis (Sumitomo Dainippon) - Q3 FY2024 Results

P1/2 data • Hematological Malignancies • Myelofibrosis • Oncology

Cytokine Modulation Correlates Strongly with Symptom Improvement in Patients with Myelofibrosis Treated with Nuvisertib (TP-3654), an Investigational Selective PIM1 Kinase Inhibitor (ASH 2024) - P1/2 | "In preclinical murine MF models, TP-3654 alone and in combination with ruxolitinib, showed reduced spleen size, bone marrow (BM) fibrosis and, importantly, cytokine response genes. ENRAGE and adiponectin levels were significant predictors of SVR, TSS50 responses and specific symptom improvement for fatigue, itching and satiety. Translational studies are ongoing to further explore potential disease modification activity of TP-3654."

Clinical • Anemia • Fatigue • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Pruritus • Thrombocytopenia • CD40LG • EGFR • IL18 • IL1R1 • PIM1 • TIMP1 • TNFRSF1A

A Phase 1/2 Study of Nuvisertib (TP-3654), an Investigational Selective PIM1 Kinase Inhibitor, in Combination with JAK Inhibitors Ruxolitinib or Momelotinib in Patients with Myelofibrosis (ASH 2024) - P1/2 | "Recent Phase 3 combination studies of RUX with Pelabresib (Rampal R, 2023) or Navitoclax (Pemmaraju N, 2023) in treatment naïve MF pts with platelet (PLT) count ≥100 x 109/L showed significant increase only in spleen responses; however, did not improve symptoms response, also were limited by overlapping toxicities of thrombocytopenia. For TP-3654 in combination with MMB (Arm 3), pts that have been previously treated with an approved JAK inhibitor (except MMB) for ≥12 weeks, or ≥4 weeks if JAK inhibitor therapy was complicated by a transfusion requirement of ≥4 units of RBC in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma. Combination arms are currently recruiting pts."

Clinical • Combination therapy • P1/2 data • Anemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Myelofibrosis • Oncology • Thrombocytopenia • PIM1

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

Sumitomo Pharma America Presents New Data on Nuvisertib…at the 2024 American Society of Hematology Annual Meeting (PRNewswire) - P1/2 | N=240 | NCT04176198 | Sponsor: Sumitomo Pharma America, Inc. | "Preliminary data in evaluable patients showed clinical activity including spleen volume reduction (SVR25 of 22.2%), symptom reduction (TSS50 of 44.4%), and bone marrow fibrosis (47.8% patients) and hemoglobin (25% patients) and platelet count (27.6% patients) improvement. Additional data presented show nuvisertib treatment led to significant cytokine modulation (e.g. EN-RAGE, IL-18, MIP-1β, and adiponectin) over time correlating with spleen and symptom responses...Also presented were clinical activity results from the dose optimization cohorts....In 23 patients with KMT2Ar, the Objective Response Rate (ORR) using ELN 2017 criteria was 65.2% (15/23) and the proportion to achieve CR+CRh was 30.4% (7/23). In the subset of patients with KMT2Ar to receive 300 mg BID (n = 15), the ORR was 73.3% (11/15) and CR+CR was 40% (6/15)."

P1/2 data • Hematological Malignancies • Myelofibrosis • Oncology

Clinical Data for Investigational Cancer Agents Nuvisertib (TP-3654) and Enzomenib (DSP-5336) to be Presented at ASH 2024 [Google translation] (Dainippon Sumitomo Press Release) - "Results from a Phase 1/2 study of nuvisertib in patients with relapsed or refractory myelofibrosis showed that nuvisertib was well tolerated as a single agent with no dose-limiting toxicities (DLTs) and demonstrated promising early clinical activity...Results from a Phase 1/2 study of enzomenib in patients with relapsed or refractory acute leukemia showed that the drug was well tolerated across a range of doses, with no DLTs or discontinuations due to enzomenib-related adverse events, and demonstrated promising early clinical activity."

P1/2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Myelofibrosis

BBI-TP-3654-102: A Study of Oral TP-3654 in Patients With Myelofibrosis (clinicaltrials.gov) - P1/2 | N=240 | Recruiting | Sponsor: Sumitomo Pharma America, Inc. | N=80 ➔ 240 | Trial completion date: Feb 2025 ➔ Apr 2030 | Trial primary completion date: Dec 2024 ➔ Apr 2027

Enrollment change • Trial completion date • Trial primary completion date • Myelofibrosis

Assessment of Relative Bioavailability and Effect of Food on Capsule and Tablet Formulations of TP-3654 (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: Sumitomo Pharma America, Inc.

New P1 trial

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

TP-3654: Launch in Japan for myelofibrosis in FY 2027 (Sumitomo Dainippon) - Q3 FY2023 Results

Launch Japan • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

TP-3654: “4/20 cases had spleen volume reduced by 35% or more”; Myelofibrosis (Sumitomo Dainippon) - Q3 FY2023 Results: “11/20 (55%) improved total symptom score by 50% or more”

P1/2 data • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Pim kinase inhibitors increase gilteritinib cytotoxicity in FLT3-ITD acute myeloid leukemia through GSK-3β activation and c-Myc and Mcl-1 proteasomal degradation. (PubMed, Cancer Res Commun) - "Cytotoxicity, apoptosis and protein expression and turnover were measured in FLT3-ITD-expressing cell lines and AML patient blasts treated with the FLT3 inhibitor gilteritinib and/or the Pim inhibitors AZD1208 or TP-3654. The data are consistent with c-Myc T58 and Mcl-1 S159 phosphorylation by activated GSK-3β as the mechanism of action of gilteritinib and Pim inhibitor combination treatment, further supporting GSK-3β activation as a therapeutic strategy in FLT3-ITD AML.  ."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • MCL1 • MYC • PIM1 • STAT5

BBI-TP-3654-102: A Study of Oral TP-3654 in Patients With Myelofibrosis (clinicaltrials.gov) - P1/2 | N=80 | Recruiting | Sponsor: Sumitomo Pharma America, Inc.

Trial completion date • Trial primary completion date • Myelofibrosis

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 • Hematological Disorders • Hematological Malignancies • Immunology • Myelofibrosis • Oncology • CD40 • CXCL8 • IL18 • PIM1 • TGFB1

TP-3654 Monotherapy Appears Safe, Effective in Relapsed or Refractory Myelofibrosis (DocWire) - P1/2 | N=80 | NCT04176198 | Sponsor: Sumitomo Pharma America, Inc. | "Patients with relapsed or refractory myelofibrosis (MF) treated with TP-3654 monotherapy showed promising early signs in spleen volume reduction (SVR), total symptom score (TSS) improvement, and cytokine reductions, according to a study that will be presented at the 65th ASH Annual Meeting & Exposition, which is taking place December 9-12 in San Diego, California....Over the 24-week treatment period, the investigators observed that hemoglobin and platelet counts remained stable. SVR was observed in 77% of evaluable patients treated for ≥12 weeks, and 3 patients showed ≥35% SVR. TSS was observed in most (92%) of the evaluable patients, and 7 patients showed ≥50% TSS response, while 5 had durable response for ≥12 weeks."

P1/2 data • Hematological Malignancies • Myelofibrosis • Oncology

Preliminary results from the ongoing phase 1/2 study of TP-3654, an investigational selective PIM1 kinase inhibitor, showed clinical responses and cytokine reduction in relapsed/refractory myelofibrosis (IMPN 2023) - No abstract available

Clinical • P1/2 data • Myelofibrosis • PIM1