Announcement of Publication of a Paper Demonstrating the Role of PAI-1 (SERPINE1) in Regulating Tumor Immune Evasion in Pancreatic Cancer— Findings Suggesting the Scientific Rationale for the Investigator-Initiated Clinical Trial of the PAI-1 Inhibitor RS5614 in Pancreatic Cancer —

Renascience Inc. announces the publication in the international scientific journal Nature of a paper entitled “A serpin–myeloid axis in pancreatic cancer heterogeneity and immune evasion” by a research group at the Icahn School of Medicine at Mount Sinai in the United States (doi: 10.1038/s41586-026-11002-8).

Although this paper does not report research conducted by Renascience, the findings from this independent external research group provide scientific support for the rationale underlying the Company’s selection of pancreatic cancer as a target indication for the development of the PAI-1 inhibitor RS5614.

Overview of the Paper
Pancreatic ductal adenocarcinoma (PDAC) is a highly refractory malignancy, with a reported five-year survival rate of approximately 13%. One of the major challenges in treating PDAC is its poor responsiveness to immune checkpoint blockade (ICB).

Using their proprietary spatial functional genomics platform, Perturb-map, the researchers conducted a comprehensive analysis of mouse models of pancreatic cancer to identify genes involved in regulating the tumor microenvironment and immune evasion.

The study identified SERPINE1, which encodes PAI-1 (plasminogen activator inhibitor-1), and SERPINB2, which encodes PAI-2, as key regulators of the tumor microenvironment and immune evasion.

The major findings are summarized below
● SERPINE1 and SERPINB2 stabilize fibrin-rich extracellular matrix niches, retaining macrophages locally and inducing an immunosuppressive phenotype, while excluding cytotoxic T cells and thereby contributing to tumor immune evasion.

● In mouse models, genetic deletion of either Serpine1 or Serpinb2 in combination with an anti-PD-1 antibody approximately doubled median survival compared with the control group treated with anti-PD-1 monotherapy, extending median survival from 24 days to 47 days.

● Pharmacological inhibition using the small-molecule PAI-1 inhibitor PAI-039 (tiplaxtinin), in combination with an anti-PD-1 antibody, also significantly prolonged survival in mouse models, whereas anti-PD-1 monotherapy showed no therapeutic effect. PAI-039 itself was discontinued during Phase I clinical development in humans due to concerns including bleeding risk and is not a PAI-1 inhibitor with established clinical use in humans.

● Spatial analysis of human pancreatic cancer tissue also demonstrated the formation of immunosuppressive niches surrounding a small subpopulation of tumor cells expressing SERPINB2 and SERPINE1, characterized primarily by SPP1-positive and MARCO-positive macrophages.

● A meta-analysis of multiple patient cohorts showed that high expression of either SERPINE1 or SERPINB2 was associated with shorter survival across several cancer types, including pancreatic cancer.

Relevance to the Company’s Pipeline
Renascience is currently conducting an investigator-initiated clinical trial of the PAI-1 inhibitor RS5614 in patients with metastatic, unresectable, or recurrent pancreatic cancer. The trial evaluates RS5614 as an add-on treatment to gemcitabine plus nab-paclitaxel (GnP) therapy and is being led by Professor Michiaki Unno of the Department of Surgery, Tohoku University Hospital.

The paper published in Nature does not evaluate RS5614 itself. Rather, it reports basic and preclinical research using genetically deficient mouse models and the known small-molecule PAI-1 inhibitor PAI-039. Therefore, the findings do not directly demonstrate the efficacy of RS5614 in humans.

Nevertheless, the Company believes that the independent demonstration that PAI-1 (SERPINE1) plays a central role in the formation of the pancreatic cancer tumor microenvironment and in tumor immune evasion provides support for the scientific rationale underlying the Company’s selection of PAI-1 as a therapeutic target in pancreatic cancer.

In addition, the study’s findings suggesting a synergistic effect between PAI-1 inhibition and anti-PD-1 antibody therapy may provide useful scientific insights when considering potential combination therapies in the future clinical development of RS5614.

At the same time, PAI-039, which was used for pharmacological validation in the study, is a compound whose development was discontinued during clinical development in humans, as described above.

In contrast, RS5614 has already been administered to humans and has advanced to the stage of an investigator-initiated clinical trial in pancreatic cancer. The Company therefore considers RS5614 to be one of the limited number of PAI-1 inhibitors currently positioned to enable clinical evaluation in humans of the therapeutic significance of targeting PAI-1 suggested by this paper.

Important Notes

● This announcement is intended to provide information regarding the publication of an academic paper by an independent third-party research group and does not contain any definitive fact that directly affects the Company’s financial performance.

● The findings reported in the paper are primarily based on exploratory analyses using mouse models and human tissue samples and do not establish the efficacy or safety of the Company’s RS5614 in humans.

● The findings do not guarantee the outcome of the ongoing investigator-initiated clinical trial.

Reference
Falcomatà, C. et al. A serpin–myeloid axis in pancreatic cancer heterogeneity and immune evasion. Nature (2026). doi: 10.1038/s41586-026-11002-8