RS5614 / Renascience - LARVOL DELTA

Study To antagOnize Plasminogen Activator Inhibitor-1 in Severe COVID-19 (clinicaltrials.gov) - P1/2 | N=9 | Terminated | Sponsor: Northwestern University | Suspended ➔ Terminated; Enrollment challenges due to decline in COVID

Trial termination • Infectious Disease • Novel Coronavirus Disease

PAI-1 as a Prognostic Biomarker and Mediator of Chemotherapy Resistance in Extensive-Stage Small Cell Lung Cancer (IASLC-WCLC 2026) - "In vitro experiments demonstrated that exposure to cisplatin, topotecan, and etoposide significantly upregulated PAI-1 expression in SBC-3 and SBC-5 cells (p<0.001)...Furthermore, the combination of cisplatin and TM5614 exerted greater inhibitory effects on cell proliferation than cisplatin alone (p<0.01)...In addition,PAI-1 may contribute to chemotherapy resistance. These findings suggest that PAI-1 represents a potential biomarker and therapeutic target in SCLC."

Biomarker • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Trial in Progress: Phase II Study of TM5614 With Chemoradiotherapy and Durvalumab in Unresectable LA-NSCLC (IASLC-WCLC 2026) - "Patients receive concurrent CRT consisting of weekly carboplatin and paclitaxel with thoracic radiotherapy (60 Gy), together with TM5614, followed by durvalumab consolidation for up to 12 months with continued TM5614. Conclusions : This study investigates a novel therapeutic strategy targeting PAI-1 to simultaneously enhance antitumor efficacy and mitigate lung toxicity. If successful, this approach may improve both treatment outcomes and tolerability in patients with unresectable locally advanced-NSCLC."

P2 data • Fibrosis • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Pneumonia • Respiratory Diseases • Solid Tumor • EGFR

PAI-1 Promotes Survival of Chemotherapy-Induced Drug-Tolerant Persister Cells and Predicts Poor Prognosis in NSCLC (IASLC-WCLC 2026) - "In vitro, A549 human NSCLC cells surviving 6 days after treatment with pemetrexed (PEM) or paclitaxel (PTX) were defined as DTPs...Furthermore, the antiproliferative effect of TM5614 in combination with PEM or PTX was evaluated in treatment-naïve A549 cells...In addition, PAI-1 promotes survival of DTPs in vitro, suggesting its role in chemotherapy resistance. Targeting PAI-1 may represent a promising therapeutic strategy to overcome treatment resistance in NSCLC."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EGFR

Targeting PAI-1 as a Novel Strategy to Enhance Radiotherapy Efficacy in Non-Small Cell Lung Cancer (IASLC-WCLC 2026) - "Conclusions : PAI-1 contributes to cancer cell radiation-tolerance, at least in part through regulation of apoptosis, and represents a potential therapeutic target to enhance the efficacy of radiotherapy. PAI-1 inhibitors, TM5614, may therefore provide a novel strategy to improve the antitumor efficacy of radiotherapy in NSCLC."

Clinical • IO biomarker • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Plasminogen Activator Inhibitor-1 as a Therapeutic Target for Healthy Longevity, Immunosenescence, and Age-Related Disease: Translational Development of the Small-Molecule Inhibitor TM5614. (PubMed, Cells) - "Preclinical studies support anti-thrombotic, anti-fibrotic, anti-inflammatory, anti-senescent, and tumor-microenvironment-modulating effects of PAI-1 inhibition, while early clinical studies have evaluated TM5614 in chronic myeloid leukemia, immune-checkpoint-refractory malignant melanoma, non-small-cell lung cancer, and COVID-19-associated pneumonia. This review summarizes the biology of PAI-1, expands the discussion of immunoaging, reviews representative preclinical and clinical data, compares available PAI-1 inhibitors, and discusses the translational opportunities and safety considerations for TM5614 and related compounds."

Journal • Review • Chronic Myeloid Leukemia • Fibrosis • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Lung Cancer • Melanoma • Metabolic Disorders • Non Small Cell Lung Cancer • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • Solid Tumor • SERPINE1

Announcement of the initiation of a phase II trial for locally advanced non-small cell lung cancer (Renascience Press Release) - "This phase II investigator-initiated clinical trial will be conducted at 12 medical institutions in Japan, including Hiroshima University Hospital, the lead research institution, to investigate the efficacy and safety of combination therapy with a PAI-1 inhibitor (RS5614) in addition to the initial standard treatment of chemoradiotherapy and consolidation therapy3) with the immune checkpoint inhibitor durvalumab."

Trial status • Non Small Cell Lung Cancer

Inflammatory macrophage-derived plasminogen activator inhibitor-1 exacerbates inflammation through efferocytosis inhibition. (PubMed, Cell Death Discov) - "Importantly, administration of a PAI-1 inhibitor, TM5614, restored efferocytosis and significantly improved tissue regeneration. These findings therefore reveal that PAI-1 produced by infiltrating inflammatory macrophages contributes to sustained inflammation by blocking efferocytosis, and that PAI-1 is a promising therapeutic target for the treatment of inflammatory diseases.Dead cells expose an "eat-me" signal molecule CRT, which is recognized by the LRP-1 receptor on macrophages, leading to their phagocytosis through a process known as efferocytosis. However, PAI-1, secreted by infiltrating CCR2+Ly6c+ macrophages, impairs tissue regeneration after injury by inhibiting efferocytosis through competitive binding to LRP-1, thereby prolonging inflammation."

Journal • Dyslipidemia • Inflammation • CALR • CCR2

Phase III Study Investigating the Safety and Efficacy of TM5614 in Combination With Nivolumab for the Treatment of Unresectable Malignant Melanoma: Protocol. (PubMed, Exp Dermatol) - "TRIAL REGISTRATION: jRCT2021240049 (https://jrct.niph.go.jp/en-latest-detail/jRCT2021240049). Protocol version: Ver.1.2 (3rd February, 2025)."

Clinical protocol • Journal • P3 data • Melanoma • Oncology • Solid Tumor

Plasminogen Activator Inhibitor-1 Mediates Tolerance to Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer. (PubMed, Mol Cancer Ther) - "We have previously reported that plasminogen activator inhibitor-1 (PAI-1) is involved in tolerance acquisition to osimertinib in epidermal growth factor receptor-mutated NSCLC. In conclusion, this study underscores the involvement of PAI-1 in the survival of aPD-1-TPs via epithelial-mesenchymal transition and alteration of the tumor microenvironment. Combination treatment with an aPD-1 antibody and TM5614 can be a new therapeutic strategy for NSCLC."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Plasminogen Activator Inhibitor-1 in Skin Malignancies: Therapeutic Implications of Its Inhibition. (PubMed, Biomolecules) - "We also discuss recent preclinical and clinical studies targeting PAI-1, including TM5614, a novel oral PAI-1 inhibitor currently under investigation in phase II /III trials. By summarizing the multifaceted roles of PAI-1 and its impact on the immune and stromal landscape of skin malignancies, this review provides a rationale for PAI-1 as a promising therapeutic target and calls for further clinical validation of PAI-1-directed therapies."

Journal • Review • Angiosarcoma • Cutaneous T-cell Lymphoma • Genetic Disorders • Hematological Malignancies • Lymphoma • Melanoma • Non-melanoma Skin Cancer • Oncology • Sarcoma • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • T Cell Non-Hodgkin Lymphoma

PAI-1 in Skin Malignancies: a Central Regulator of Tumor Progression and Therapeutic Resistance. (PubMed, Curr Treat Options Oncol) - "The PAI-1 inhibitor TM5614 has demonstrated promising activity in early clinical studies, particularly in anti-PD-1-refractory melanoma, and is currently under evaluation in multiple Phase II and III trials. Future strategies should focus on patient stratification using biomarkers such as SASP factors and PAI-1 levels, as well as rational combination therapies targeting interconnected pathways like IL-17/IL-23, AhR, and senescence signaling. Overall, PAI-1 inhibition offers a novel and mechanistically grounded approach to improve outcomes in skin cancers characterized by therapy resistance and an immunosuppressive microenvironment."

IO biomarker • Journal • Review • Angiosarcoma • Cutaneous Melanoma • Cutaneous T-cell Lymphoma • Dermatology • Genetic Disorders • Melanoma • Mycosis Fungoides • Non-melanoma Skin Cancer • Oncology • Sarcoma • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • CAFs • IL17A • IL23A • PD-L1

Efficacy of Nivolumab and TM5614 Combination in Anti-PD-1 Antibody-Resistant Melanoma Verification of the protocol and its safety (JSCS 2025) - No abstract available

Clinical • Melanoma • Solid Tumor

Significance of PAI-1 on the development of skin cancer: optimal targets for cancer therapies. (PubMed, Biomed J) - "Additionally, clinical trials evaluating PAI-1 inhibitors, such as TM5614, highlight its potential as an adjunctive therapy for melanoma and cutaneous angiosarcoma. This review comprehensively explores PAI-1's role in skin cancer progression, its influence on tumor-stromal interactions, and its potential as a therapeutic target."

IO biomarker • Journal • Angiosarcoma • Genetic Disorders • Immunology • Melanoma • Non-melanoma Skin Cancer • Oncology • Sarcoma • Skin Cancer • Solid Tumor • CAFs • PD-L1

Rena's stock price rises due to achievement of target case enrollment in Phase 2 investigator-initiated clinical trial of RS5614 [Google translation] (Yahoo Finance) - "...the company announced that it had achieved the target number of cases enrolled in a Phase 2 investigator-initiated clinical trial of the PAI-1 inhibitor 'RS5614' for interstitial lung disease associated with systemic sclerosis."

New P2 trial • Systemic Sclerosis

An Investigator-Initiated Phase II Study of Combination Treatment of Nivolumab and TM5614, A PAI-1 Inhibitor for Previously Treated NSCLC (IASLC-WCLC 2024) - "The study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment."

P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Association Between Plasminogen Activator Inhibitor-1 & Tolerance Against Anti-PD-1 Antibody in Non-Small Cell Lung Cancer (IASLC-WCLC 2024) - "Our previous research has shown the involvement of plasminogen activator inhibitor-1 (PAI-1) in the tolerance of EGFR-mutated NSCLC cells to osimertinib...In contrast, a combination of anti-PD-1 antibody and a PAI-1 inhibitor, TM5614, resulted in decreased expression of EMT-related genes, PD-L1 expression of cancer cells, and M2 macrophages, alongside increased CD8-positive lymphocytes in tumors...Conclusions : This study underscores the involvement of PAI-1 in tolerance of NSCLC to ICI via its association with EMT of cancer cells and alteration of tumor immune-microenvironment. Additionally, PAI-1 may be a potential therapeutic target to overcome tolerance to ICI in NSCLC."

IO biomarker • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CD8 • EGFR

Decreased serum levels of IL-4 correlate with the efficacy of the PAI-1 inhibitor TM5614 in patients with malignant melanoma refractory to anti-PD-1 antibodies: post hoc study of TM5614-MM trial. (PubMed, Br J Dermatol) - No abstract available

Journal • Retrospective data • Melanoma • Oncology • Solid Tumor • IL4

Multicenter phase II trial of plasminogen activator inhibitor-1 inhibitor (TM5614) plus nivolumab in japanese advanced melanoma patients: Immune resistance remains one of the major efforts in melanoma research. (PubMed, Br J Dermatol) - No abstract available

Journal • Metastases • P2 data • Melanoma • Oncology • Solid Tumor

Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer. (PubMed, J Thorac Dis) - "Results will be published in a peer-reviewed publication. This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023)."

Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Phase II, multicenter study of plasminogen activator inhibitor-1 inhibitor (TM5614) plus nivolumab for treating anti-PD-1 antibody-refractory malignant melanoma: TM5614-MM trial. (PubMed, Br J Dermatol) - "TM5614 in combination with nivolumab is well-tolerated and effective in anti-PD-1 Abs-refractory, unresectable melanoma."

Clinical • Journal • P2 data • Melanoma • Oncology • Solid Tumor

Cutaneous angiosarcoma: Investigation of the safety and efficacy of paclitaxel and TM5614 combination therapy: Phase II study (JSCS 2024) - No abstract available

Clinical • Combination therapy • P2 data • Angiosarcoma • Non-melanoma Skin Cancer • Oncology • Sarcoma • Solid Tumor

Pharmacotherapeutic advances for chronic myelogenous leukemia: beyond tyrosine kinase inhibitors. (PubMed, Expert Opin Pharmacother) - "Other compounds were able to mobilize Ph+ LSCs from the bone marrow niche (DPP-IV inhibitor vildagliptin or PAI-1 inhibitor TM5614) increasing the LSC clearance or target the CD26, a Ph+ specific surface receptor. It is noteworthy that the majority of these alternative strategies still incorporate TKIs. In conclusion, novel therapeutic perspectives are emerging for CML, holding the potential for substantial advancements in disease treatment."

Journal • Review • Chronic Myeloid Leukemia • Gene Therapies • Hematological Malignancies • Leukemia • Oncology • DPP4 • IFNA1