vactosertib (TEW-7197) / National OncoVenture, Theragen Etex, Ewha Womans University - LARVOL DELTA

Unmet Needs in Multiple Myeloma and Potential Solutions: A Systemic Literature Review (ASH 2024) - "Other unmet needs reported were patient and family experience/supportive care (11%), pathophysiology (4%), diagnosis/response assessment (4%), toxicity management/prevention (3%) and poor prognosis (4%).Unmet needs that were reported starting from 2010 [and their proposed solutions] include treatment of high-risk cytogenetic features (4%) [elotuzumab/isatuximab/melflufen/selinexor/anti-BCMA conjugates], treatment of plasma cell leukemia/extramedullary disease (3%) [utilizing MM drugs (daratumumab/boretezemib/melfufen/frontline ASCT etc.)], prevention/management of toxicities (mucositis, neuropathy, nephropathy and GVHD) (1%) [CR4056/amifostine/cannabidiol], treatment/prevention of thromboembolism (1%) [risk assessment model for thromboembolism/studies on anticoagulation], treatment of frail/elderly (1%) [SEA BCMA/melflufen], immune response in MM (<1%) [immunological studies], and measures to assess response to treatment (<1%) [heavy light chain ratio/DW..."

Review • Geriatric Disorders • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Mucositis • Multiple Myeloma • Oncology • Orthopedics • Plasma Cell Leukemia • Renal Disease • Respiratory Diseases

The TGFβ Type I Receptor Kinase Inhibitor Vactosertib Improves T-Cell Fitness in Relapsed/Refractory Multiple Myeloma: A Phase 1b Trial (ASH 2024) - P1 | "Vactosertib combined with pomalidomide was well-tolerated at all dose levels, displayed a manageable adverse event profile and induced durable responses. Current studies are focused on defining the antimyeloma effects of vactosertib in combination with immune checkpoint inhibitors, autologous and allogeneic chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers. Accumulating evidence suggests that functional blockade of the TGF pathway offers promise to optimize CAR-T-cell therapy for hematologic and solid tumors, albeit with efficacy anticipated restricted to specific populations."

IO biomarker • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • CD8 • TGFB1

Vactosertib, a Novel TGFb Type I Receptor Kinase Inhibitor, Improves T-Cell Fitness:a Single-Arm, Phase 1b Trial in Relapsed/Refractory Multiple Myeloma (ASH 2023) - "To probe the tumor intrinsic anti-myeloma activity of vactosertib, we first determined the relative effect of vactosertib compared to the IMiDs pomalidomide and lenalidomide (Fig. Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, Vactosertib reduced TGFβ in patient bone marrow and suppressed PD-1 expression on CD8+ T-cells and lead to reduction of PD-L1/PD-L2 expression on CD138+ cells and enhanced autologous T-cell cytotoxicity. Taken together, our results support the safety and efficacy of vactosertib to treat RRMM and revealed that vactosertib modulates the T-cell immunophenotype and reinvigorates T-cell fitness."

IO biomarker • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology • BTLA • CD8 • CTLA4 • HAVCR2 • LAG3 • PD-1 • PD-L1 • PD-L2 • SDC1

The company announced interim results from a global Phase 1 clinical trial of its immunotherapy candidate, "vactosertib," targeting osteosarcoma patients at SITC 2025, held in Maryland, USA, from the 7th to the 9th. [Google translation] (HIT News) - "One patient achieved complete remission (CR) and three achieved partial remission (PR). The objective response rate (ORR) was 36.4%. Safety and tolerability were good, and no dose-limiting toxicities (DLTs) were observed."

P1 data • Osteosarcoma

TGF-β1-SMAD2 Axis Regulates Hematopoiesis and β-Globin Gene Expression Via Super-Enhancer Associated Chromatin Reorganization (ASH 2024) - "Taken together, faster erythroid differentiation and reduced cell divisions lead to anemia phenotypes. These can be rescued with a novel, clinically useful ALK5 inhibitor, Vactosertib."

Anemia • Aplastic Anemia • Hematological Disorders • Myelodysplastic Syndrome • MYC • SMAD2 • TGFB1 • TGFBR1

The role of TGF-β1 in chronic multilobar segmental bronchial stenosis and advances in targeted drug research. (PubMed, Front Pharmacol) - "In recent years, groundbreaking progress has been made in research on therapeutics targeting the TGF-β1 signaling pathway, including monoclonal antibodies (e.g., Fresolimumab), small molecule kinase inhibitors (e.g., Galunisertib, TEW-7197), and novel targeted delivery systems. Furthermore, it proposes future research directions focused on CMBS-specific applications, such as validating these therapeutics in preclinical CMBS models, developing inhaled formulations for localized delivery, establishing biomarker-driven patient stratification, and exploring combination therapies with anti-fibrotic agents. This aims to provide a comprehensive theoretical foundation for elucidating the disease's pathology and developing novel, precise diagnostic and therapeutic strategies for CMBS."

Journal • Review • Asthma • Chronic Cough • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Tuberculosis • TGFB1

Combination of THU/ALK-5i exhibits profound anti-MASH activity through suppression of lipogenesis and fibrogenesis. (PubMed, Sci Rep) - "While these findings highlight a synergistic anti-MASH effect of THU and EW-7197, the study is positioned as proof-of-concept. Further validation in metabolically relevant models (e.g., HFD/HFHC) and pharmacokinetic analyses are warranted before clinical translation can be considered."

Journal • Acute Myelogenous Leukemia • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • TGFB1 • TGFBR1

Targeting TGF-β RI Signaling with the Novel Vactosertib: Preliminary Antitumor Activity in a Phase 1 Study in Patients with Recurrent, Refractory, and Progressive Osteosarcoma (SITC 2025) - "These preliminary findings warrant further clinical investigation to validate the potential efficacy of vactosertib in osteosarcoma.Acknowledgements The authors thank the patients, their families, and caregivers for their participation and support.Trial Registration NCT05588648Ethics Approval The study was approved by Ethics Board of National Cancer Center (NCC2023-0182), Korea Institute of Radiological & Medical Sciences (KIRAMS 2023-04-001-001), Washington University of St. Louis and Sarcoma Oncology Research Center (SOC) (20226645).Abstract 1311 Table 1View inline•Open as popupBaseline Characteristics"

Clinical • Late-breaking abstract • P1 data • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • TGFB1

Detachable Microneedle Patch for Local Delivery of TGF-β Inhibitor to Suppress Scar Formation. (PubMed, ACS Biomater Sci Eng) - "This minimally invasive, patient-friendly approach effectively regulates TGF-β signaling to suppress fibrosis during the wound-healing process. Our findings indicate that EW-7197-loaded d-MN patches are a promising therapeutic strategy for improving healing outcomes and reducing fibrotic scar formation."

Journal • Fibrosis • Immunology • TGFB1

Unveiling therapeutic potential: In Silico discovery of prognostic markers and potential inhibitors for TGFßR1 in pancreatic cancer. (PubMed, Comput Biol Chem) - "These hits exhibited lower free energies (ΔG) as compared to the benchmark inhibitors, Galunisertib and Vactosertib. The results offer valuable insights into the binding mechanism of protein TGFßR1 and its role in the disease, suggesting that targeting the TGF-ß signaling pathway may represent a promising therapeutic strategy."

Biomarker • Journal • Oncology • Pancreatic Cancer • Solid Tumor • AHNAK2 • IGFBP3 • LAMC2 • SMAD4 • TSC2

MedPacto begins phase 2 trial of vactosertib in osteosarcoma patients in Korea, US (Korea Biomedical Review) - "The company is conducting studies in both adults and adolescents aged 12 to 17 in Korea and the U.S....Enrollment for the adolescent phase 1 cohort is nearly complete, and a transition to phase 2 is expected soon."

Trial status • Osteosarcoma

Synergistic effects of CC chemokine receptor 2 inhibitor and transforming growth factor-β type I receptor kinase inhibitor combination in metabolic dysfunction-associated steatohepatitis. (PubMed, Metabolism) - "These findings indicate that dual inhibition of CCR2 and TGF-β signaling pathways could serve as an effective therapeutic approach for MASH. By addressing lipid accumulation, inflammation, and fibrosis while promoting metabolic balance, this strategy holds promise for improved clinical applications in treating this complex disease."

Journal • Diabetes • Dyslipidemia • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • CCR2 • TGFB1

Spatio-Temporal Dynamics of M1 and M2 Macrophages in a Multiphase Model of Tumor Growth. (PubMed, Bull Math Biol) - "Furthermore, this is the first multiphase model to incorporate the effects of TGF- -targeting immunotherapy using vactosertib. Our simulations demonstrate that treatment initially enhances the presence of anti-tumor macrophages, followed by a relapse period where tumor dynamics returns to pre-treatment trends. Model parameters are grounded in experimental data and clinically relevant dosage protocols."

Journal • Oncology

Computational Drug Repurposing Screening Targeting Profibrotic Cytokine in Acute Respiratory Distress Syndrome. (PubMed, Cell Biochem Biophys) - "This study demonstrates the possibility of targeting TGFBR1 with Galunisertib, Vactosertib, and other prospective ARDS treatments. The findings lay the groundwork for additional experimental validation and the development of innovative therapeutics aimed at reducing ARDS severity."

Journal • Acute Respiratory Distress Syndrome • Fibrosis • Gastrointestinal Disorder • Pulmonary Disease • Respiratory Diseases • TGFB1 • TGFBR1

A quiescence-like/TGF-β1-specific CRISPRi screen reveals drug uptake transporters as secondary targets of kinase inhibitors in AML. (PubMed, Drug Resist Updat) - "However, pretreatment with vactosertib unexpectedly induced complete resistance to cytarabine. Importantly, we found that this drug interaction is not unique to TGFBR1 inhibitors, but extends to other clinically significant kinase inhibitors, such as the FLT3 inhibitor midostaurin. These findings may have important implications for optimizing combination therapies in AML treatment."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • FLT3 • SLC29A1 • TGFB1 • TGFBR1

Antitumor Activity of Vactosertib in Combination With Pembrolizumab in Acral and Mucosal Melanoma Patients Progressed From Prior Immune Check Point Inhibitor (clinicaltrials.gov) - P2 | N=14 | Terminated | Sponsor: Yonsei University | N=30 ➔ 14 | Trial completion date: Dec 2025 ➔ Mar 2025 | Not yet recruiting ➔ Terminated | Trial primary completion date: Jul 2025 ➔ Mar 2025; According to the protocol criteria, during the Phase 1 analysis, the registered participants' imaging evaluation responses did not meet the criteria, leading to an early termination

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • BRAF

MP-VAC-203: Phase 1b/2a, Open-label Study of Vactosertib in Combination with Durvalumab in Advanced NSCLC (clinicaltrials.gov) - P1/2 | N=60 | Completed | Sponsor: MedPacto, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ May 2024

Trial completion • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • UGT1A1

KEYNOTE 900: Vactosertib in Combination with Pembrolizumab in Metastatic Colorectal or Gastric Cancer (clinicaltrials.gov) - P1/2 | N=120 | Completed | Sponsor: MedPacto, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jan 2025 ➔ May 2024

Trial completion • Trial completion date • Colorectal Cancer • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation. (PubMed, Neurol Res Int) - "Therefore, the present study investigated the neuroprotective effect of TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. The inhibition of the TGF-β signaling pathway in neuronal and microglia cells by TGF-βR1 inhibitors resulted in neuroprotection against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Hence, targeting the TGF-β signaling pathway in both neuronal and microglia cells could provide a promising therapeutic strategy in AD."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • IL1B • TGFB1 • TGFBR1 • TNFA

Preoperative Immunotherapy (Pembrolizumab) for Patients With Colorectal Cancer and Resectable Hepatic Metastases (clinicaltrials.gov) - P2 | N=6 | Active, not recruiting | Sponsor: Chloe Atreya, MD, PhD | Recruiting ➔ Active, not recruiting | N=19 ➔ 6 | Trial completion date: Jan 2027 ➔ Apr 2026 | Trial primary completion date: Jan 2027 ➔ Apr 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MLH1 • MSH2 • MSH6 • PD-L1

MedPacto to launch US phase 2 study for using vactosertib to treat pediatric osteosarcoma (Korea Biomedical Review) - "MedPacto said it will conduct a phase 2 investigator-initiated clinical trial using vactosertib, a TGF-β inhibitor anti-cancer drug, for pediatric osteosarcoma in collaboration with various U.S. medical institutions, including Stanford University and Case Western Reserve University Hospitals...MedPacto highlighted that vactosertib had already demonstrated safety and potential efficacy in inhibiting osteosarcoma cell growth and lung metastasis in preclinical and phase 1 trials, and that the upcoming phase 2 study aims to validate these findings...The trial will be conducted in collaboration with 12 research institutions under the POETIC and is scheduled to begin within the year."

New P2 trial • Osteosarcoma

A phase II double window of opportunity trial evaluating the oral TGF-beta receptor I inhibitor vactosertib in patients undergoing standard of care preoperative therapy for locally advanced esophageal adenocarcinoma. (ASCO-GI 2025) - P2 | "Pre- and post-first window of opportunity treatment biopsies will be obtained for correlative and exploratory analyses. Clinical trial registry number is NCT06044311."

Clinical • Metastases • P2 data • Esophageal Adenocarcinoma • Esophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • TGFB1

Quantification of Vactosertib an Inhibitor of TGFBR1 by LC-MS/MS in Rat Plasma and Its Pharmacokinetic Profiling. (PubMed, Biomed Chromatogr) - "The method demonstrated a sensitivity of 1.0 ng/mL, linearity ranging from 1.0 to 1000.0 ng/mL, an r2 of 0.999, accuracy ranged between 91.60% and 100.70%, and the drug was found to be stable across all freeze-thaw cycles. The results indicated that the method was selective, accurate, and validated for quantification of vactosertib in biological fluids and pharmacokinetic profiling of vactosertib."

Journal • PK/PD data • Preclinical • Oncology • TGFBR1

KEYNOTE 900: Vactosertib in Combination with Pembrolizumab in Metastatic Colorectal or Gastric Cancer (clinicaltrials.gov) - P1/2 | N=120 | Active, not recruiting | Sponsor: MedPacto, Inc. | Trial completion date: Aug 2024 ➔ Jan 2025

Combination therapy • Metastases • Trial completion date • Colorectal Cancer • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Vactosertib with Durvalumab in Urothelial Carcinoma Failing Checkpoint Inhibition (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: MedPacto, Inc. | N=48 ➔ 0 | Not yet recruiting ➔ Withdrawn

Checkpoint inhibition • Enrollment change • Metastases • Trial withdrawal • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer