fresolimumab (GC 1008) / Sanofi - LARVOL DELTA

In vitro analysis of collagen deposition in lung cancer-associated fibroblasts using clinically validated biomarkers (AACR 2025) - "The pseudo-3D in vitro model using lCAFs and lNFs successfully replicates key aspects of the lung tumor microenvironment, particularly the differential collagen deposition patterns. The model demonstrated that lCAFs exhibit distinct collagen formation responses to TGF-β1, especially in type I and VI collagens, compared to lNFs. Additionally, treatment with ALK5i and Fresolimumab effectively reduced collagen formation, underscoring the model's potential for preclinical anti-fibrotic drug screening."

Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAFs • TGFB1 • TGFBR1

Predictive Biomarkers for Response to TGF- β Inhibition in Resensitizing Chemo(radiated) Esophageal Adenocarcinoma. (PubMed, Pharmacol Res) - "TGF-β inhibitors fresolimumab and A83-01 were employed to inhibit EMT, and mesenchymal markers were quantified via flow cytometry to assess efficacy...Our findings reveal a distinct gene expression pattern associated with the response to TGF-β inhibition in chemo(radiated) EAC. The identified DEGs and predictive markers may assist patient selection in clinical studies investigating TGF-β targeting."

Biomarker • Journal • Esophageal Adenocarcinoma • Esophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2 • TGFB1

Current and Developing Pharmacologic Agents for Improving Skeletal Health in Adults with Osteogenesis Imperfecta. (PubMed, Calcif Tissue Int) - "Several therapeutics, including teriparatide, setrusumab, anti-TGF-β antibodies, and allogeneic stem cells, are being studied in clinical trials. Preclinical studies involving Dickkopf-1 antagonists present promising data in non-OI bone disease, and could be useful in OI. Research is ongoing to improve therapeutic options for adults with OI and clinical trials involving gene-editing may be possible in the coming decade."

Journal • Review • Genetic Disorders • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • DKK1 • TGFB1

In-silico prediction of TGF-β1 non-synonymous variants and their impact on binding affinity to Fresolimumab. (PubMed, J Biomol Struct Dyn) - "Among them, the E35D variant significantly destabilized the TGF-β1 protein structure, resulting in rearrangement in the binding site and affecting the interactions with the Fresolimumab. This study identified four variants that can affect the TGF-β1 protein structure and result in functional consequences such as impaired response to Fresolimumab.Communicated by Ramaswamy H. Sarma."

Journal • Fibrosis • Immunology • Oncology • TGFB1

SABR-ATAC: A Trial of TGF-beta Inhibition and Stereotactic Ablative Radiotherapy for Early Stage Non-small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=24 | Completed | Sponsor: Stanford University | Trial completion date: Dec 2021 ➔ Mar 2023 | Trial primary completion date: Dec 2021 ➔ Mar 2023

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

Immune evasion mechanisms in melanoma resistant to targeted- and/or immunotherapy (AACR 2018) - P1,P1b/2; "...Of interest, a study has shown some efficacy of targeting the TGFB pathway by fresolimumab (a human monoclonal antibody against TGFB1-3) in melanoma (Clinical Trial ID: NCT0035646017). Another study currently combines nivolumab (anti-PD-1) with galunisertib (a TGFBR type I/II small molecule inhibitor) in multiple solid tumors (NCT02423343)...This implies that the tumor cell-intrinsic up-expression of IPRES-related genes is regulated at the epigenetic level. In summary, we anticipate that our study will lead to novel insights into the determinants and/or bottlenecks of effective and durable anti-tumor responses by tumor-specific T-cells in order to pave the way to a new combination therapies in human melanoma patients."

IO biomarker • PD(L)-1 Biomarker • Melanoma • Renal Cell Carcinoma

Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses. (PubMed, J Immunother Cancer) - "BA more effectively blocks TGF-β by targeting TGF-β trap to the tumor via PD-L1 binding. Such colocalized targeting elicits distinct and superior antitumor responses relative to single agent combination therapy."

IO biomarker • Journal • Fibrosis • Immunology • Lung Cancer • Oncology • Solid Tumor • TGFB1

Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta (clinicaltrials.gov) - P1 | N=11 | Completed | Sponsor: Baylor College of Medicine | Active, not recruiting ➔ Completed | Trial completion date: Aug 2023 ➔ Jul 2022

Trial completion • Trial completion date • Genetic Disorders • COL1A1 • COL1A2

Variability of Proteinuria in Nephrotic Syndrome: GC1008 PH2 Trial in FSGS (ERA-EDTA 2022) - P2 | "These data suggest that labour intensive, cumbersome timed 24-h urine collections should not be performed in clinical trials of nephrotic syndrome patients. Importantly, these data should allow for more precise power and sample size estimates for future interventional clinical trials of nephrotic syndrome."

Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Nephrology • Renal Disease

Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta (clinicaltrials.gov) - P1 | N=11 | Active, not recruiting | Sponsor: Baylor College of Medicine | Recruiting ➔ Active, not recruiting | N=16 ➔ 11

Enrollment change • Enrollment closed • Genetic Disorders • COL1A1 • COL1A2

Interventions for focal segmental glomerulosclerosis in adults. (PubMed, Cochrane Database Syst Rev) - "Five studies (240 participants) compared cyclosporin with or without prednisone with different comparators (no specific treatment, prednisone, methylprednisolone, mycophenolate mofetil (MMF), dexamethasone). Three small studies compared monoclonal antibodies (adalimumab, fresolimumab) with other agents or placebo. Six single small studies compared rituximab with tacrolimus, cyclosporin plus valsartan with cyclosporin alone, MMF with prednisone, chlorambucil plus methylprednisolone and prednisone with no specific treatment, different regimens of dexamethasone and CCX140-B (an antagonist of the chemokine receptor CCR2) with placebo. The final study (109 participants) compared sparsentan, a dual inhibitor of endothelin Type A receptor and of the angiotensin II Type 1 receptor, with irbesartan...Treatment with cyclosporin for at least six months was more likely to achieve complete remission of proteinuria compared with other treatments but there was considerable imprecision..."

Journal • Review • Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Hypertension • Infectious Disease • Nephrology • Renal Disease • Transplantation

Targeting transforming growth factor- β (TGF-β) for treatment of osteogenesis imperfecta. (PubMed, J Clin Invest) - P1 | "Our data confirm that TGF-β signaling is a driver pathogenic mechanism in OI bone and that anti-TGF-β therapy could be a potential disease-specific therapy with dose-dependent effects on bone mass and turnover."

Journal • Dermatology • Genetic Disorders • Immunology • Musculoskeletal Diseases • Orthopedics • Rare Diseases • Rheumatology • TGFB1

SABR-ATAC: A Trial of TGF-beta Inhibition and Stereotactic Ablative Radiotherapy for Early Stage Non-small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=24 | Completed | Sponsor: Maximilian Diehn | Active, not recruiting ➔ Completed | Trial completion date: Dec 2022 ➔ Dec 2021

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

SABR-ATAC: A Trial of TGF-beta Inhibition and Stereotactic Ablative Radiotherapy for Early Stage Non-small Cell Lung Cancer (clinicaltrials.gov) - P1/2; N=24; Active, not recruiting; Sponsor: Maximilian Diehn; Trial completion date: Dec 2021 ➔ Dec 2022; Trial primary completion date: Dec 2020 ➔ Dec 2021

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

SABR-ATAC: A Trial of TGF-beta Inhibition and Stereotactic Ablative Radiotherapy for Early Stage Non-small Cell Lung Cancer (clinicaltrials.gov) - P1/2; N=24; Active, not recruiting; Sponsor: Maximilian Diehn; Trial primary completion date: Jun 2021 ➔ Dec 2020

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

Discovery of Selective Transforming Growth Factor β Type II Receptor Inhibitors as Antifibrosis Agents. (PubMed, ACS Med Chem Lett) - "Recently, fresolimumab and disitertide, two peptidic TGF-β blockers, demonstrated significant therapeutic effects toward human skin fibrosis. In this report, we disclose selective TGF-β type II receptor (TGF-βRII) inhibitors that exhibited high functional selectivity in cell-based assays. The representative compound 29 attenuated collagen type I alpha 1 chain (COL1A1) expression in a mouse fibrosis model, which suggests that selective inhibition of TGF-βRII-dependent signaling could be a new treatment for fibrotic disorders."

Journal • Dermatology • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • COL1A1 • TGFB1

Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta (clinicaltrials.gov) - P1; N=16; Recruiting; Sponsor: Baylor College of Medicine; Trial completion date: Oct 2022 ➔ Aug 2023

Clinical • Trial completion date • Genetic Disorders • COL1A1 • COL1A2

SABR-ATAC: A Trial of TGF-beta Inhibition and Stereotactic Ablative Radiotherapy for Early Stage Non-small Cell Lung Cancer (clinicaltrials.gov) - P1/2; N=24; Active, not recruiting; Sponsor: Maximilian Diehn; Recruiting ➔ Active, not recruiting; N=60 ➔ 24

Enrollment change • Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

[VIRTUAL] Integration of high dimensional datasets in an immunocompetent mammary mouse model reveals pathways of tolerance and resistance to immune checkpoint blockade (SITC 2020) - "We visualized and quantified TGFβ activity using PET-CT imaging of 89Zr-fresolimumab, a TGFβ neutralizing antibody...Conclusions The immunocompetent mTDT provides a model that bridges the gap between the immune landscape and tumor microenvironment. Integration of these high-dimensional data with further studies of response to immunotherapies will help to identify tumor features that favor response to treatment or the means to convert those that are unresponsive."

Checkpoint inhibition • IO Biomarker • Preclinical • Breast Cancer • Oncology • Solid Tumor • CD8 • IL1B • PD-L1 • TNFA

[VIRTUAL] Integration of high dimensional datasets in an immunocompetent mammary mouse model reveals pathways of tolerance and resistance to immune checkpoint blockade (SITC 2020) - "We visualized and quantified TGFβ activity using PET-CT imaging of 89Zr-fresolimumab, a TGFβ neutralizing antibody...Conclusions The immunocompetent mTDT provides a model that bridges the gap between the immune landscape and tumor microenvironment. Integration of these high-dimensional data with further studies of response to immunotherapies will help to identify tumor features that favor response to treatment or the means to convert those that are unresponsive."

Checkpoint inhibition • IO Biomarker • Preclinical • Breast Cancer • Oncology • Solid Tumor • CD8 • IL1B • PD-L1 • TNFA

Positron Emission Tomography Imaging of Functional TGFβ Activity and Benefit of TGFβ Inhibition in Irradiated Intracranial Tumors. (PubMed, Int J Radiat Oncol Biol Phys) - "This study demonstrates that Zr -fresolimumab PET imaging detects radiation-induced TGFβ activation in tumors. Functional imaging indicated a range of TGFβ activity in intracranial tumors, but TGFβ blockade provided survival benefit only in the context of radiation treatment. These studies are further evidence that radiation-induced TGFβ activity opposes therapeutic response to radiation."

Journal • Breast Cancer • Glioblastoma • Oncology • Solid Tumor

TGFβ-Directed Therapeutics: 2020. (PubMed, Pharmacol Ther) - "Two small molecule kinase inhibitors which block the serine-threonine kinase activity of TGFβRI on TGFβRII, a pan-TGFβ neutralizing antibody, a TGFβ trap, a TGFβ antisense agent, an antibody which stabilizes the latent complex of TGFβ and a fusion protein which neutralizes TGFβ and binds PD-L1 are in clinical development. The challenge is how to most effectively incorporate blocking TGFβ activity alone and in combination with other therapeutics to improve treatment outcome."

Journal • Review • Fibrosis • Oncology • PD-L1

Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients. (PubMed, J Immunother Cancer) - P2 | "Functional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy."

Clinical • IO Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor

SABR-ATAC: A Trial of TGF-beta Inhibition and Stereotactic Ablative Radiotherapy for Early Stage Non-small Cell Lung Cancer (clinicaltrials.gov) - P1/2; N=60; Recruiting; Sponsor: Maximilian Diehn; Trial completion date: Jan 2020 ➔ Dec 2021; Trial primary completion date: Jan 2020 ➔ Jun 2021

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

Role of the PD-1/PDL-1 pathway in resistance of patients with metastatic breast cancer to treatment with radiotherapy and TGFβ neutralization (AACR 2016) - P2, N=22; NCT01401062; "Elevated PD-1 (p=0.054) and OX-40 (p=0.014) expression were identified on CD4+ T cells of pts. Upon TCR modulation, CD4+ and CD8+ T cells from pts showed reduced signaling through p-AKT and, to a lesser extent, p-Erk, compared to HD. Signaling was lower in PD-1+ vs PD-1- CD8+ and CD4+ T cells. Addition of anti-PD-1 pembrolizumab partially restored TCR-mediated signaling through p-AKT and p-Erk in PD-1+ but not PD-1- T cells."

P2 data • Breast Cancer • Oncology