entolimod (STAT-600) / Statera BioPharma, Coeptis - LARVOL DELTA

Tivic Health Extends its Worldwide License of TLR5 Agonist Entolimod to Include the Treatment of Neutropenia (Businesswire) - "Tivic Health Systems, Inc...today announced that, on March 28, 2025, it exercised its licensing option for the exclusive, worldwide rights to advance Entolimod for a second indication, Neutropenia. This expansion of commercial rights is part of the license agreement with Statera Biopharma for its late-stage Toll-like Receptor 5 (TLR5) immunotherapy program Entolimod....Under the terms of the company’s previously announced agreement with Statera Biopharma, Inc., Tivic secured a worldwide exclusive license for Entolimod as a potential treatment for acute radiation syndrome, or ARS."

Licensing / partnership • Neutropenia

Novel strategy to improve response of high risk HPV+ HNSCC to radiation therapy (EORTC-NCI-AACR 2024) - "To activate NF-κB, we used two clinically applicable drugs with different mechanisms of action: Toll-like receptor 5 (TLR5) agonist entolimod and mitochondria-derived activator of caspases (SMAC) mimetic birinapant. Because of the average relatively favorable prognosis of HPV+ HNSCC, urgent need for improved therapy for patients with aggressive high risk tumors is greatly undervalued. Here, we begin to explore pharmacological activation of NF-κB as a strategy to sensitize HPV+ HNSCC to radiation therapy. Entolimod is well known for the remarkable normal tissue protective effects against radiation and other damaging conditions; the dual effect of entolimod – sensitization of HPV+ HNSCC to radiation, while simultaneously protecting normal tissues from severe side effects - may be useful for patients with high-risk HPV+ head and neck cancer in combination with radiotherapy."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Toll-like Receptor Agonist CBLB502 Protects Against Radiation-induced Intestinal Injury in Mice. (PubMed, In Vivo) - "This study preliminarily describes the regulatory mechanism of IR-induced intestinal injury and the potential molecular protective mechanism of CBLB502, providing a basis for identifying the functional genes and molecular mechanisms that mediate protection against IR-induced injury."

IO biomarker • Journal • Preclinical

LYMPHOCYTE, NK CELL AND MITOCHONDRIAL GENE DYSREGULATION PATTERNS SEPARATE PATIENTS WITH NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS INTO DISTINCT SUBGROUPS WITH DIFFERENTIAL ANTICIPATED RESPONSE TO TARGETED THERAPIES (EULAR 2024) - "Drugs annotated to the cytotoxic/NK cell network included pegaptanib, a selective vascular endothelial growth factor (VEGF) antagonist, while many anticonvulsants such as zonisamide, lamotrigine, and oxcarbazepine showed potential for counteracting the transcriptomic signature associated with the B cell module. Druggability analysis for the mitochondrial cluster module revealed potential for the centrally acting angiotensin-converting enzyme inhibitor captopril, the mammalian target of rapamycin (mTOR) inhibitor everolimus, the proteasome inhibitor bortezomib, the toll-like receptor 5 (TLR5) agonist entolimod, and the spleen tyrosine kinase (SYK) inhibitor fostamatinib. In silico prediction algorithms demonstrated a greater anticipated response to anifrolumab and calcineurin inhibitors for the active CNS subgroup with B cell, T cell, cytotoxic/NK cell, and mitochondrial gene downregulation compared with the patient subgroup of mixed dysregulation patterns. In this..."

Clinical • IO biomarker • Immunology • Inflammatory Arthritis • Lupus • Metabolic Disorders • Psychiatry • Systemic Lupus Erythematosus • SYK

Entolimod, a clinical stage flagellin derivative, improves clinically relevant chemo-immunotherapy responses in pre-clinical triple negative breast cancer (IMMUNOLOGY 2024) - "Here, we used Paclitaxel+anti-PD-1 as a clinically oriented CTx-I platform in pre-clinical metastatic TNBC models. Collectively, the immune enhancing effects of entolimod can be leveraged to boost urgently needed CTx-I outcomes in TNBC. Because entolimod has successfully completed Phase I clinical trials, this preclinical work supports the rationale design of a clinical trial that combines CTx-I with entolimod as an effective immunotherapy platform."

Late-breaking abstract • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PD-L1 • TLR5

Response of Male Reproductive System Against Ionizing Radiation and Available Radio-protective Agents: Cellular and Molecular Insight. (PubMed, Curr Radiopharm) - "Further study is needed to optimize these tactics and fill knowledge gaps. Also, the effective components of herbal, synthetic drugs, etc., should be isolated and tested up to clinical levels, paving the way for successful radioprotection and radiomitigation strategies in the male reproductive system."

IO biomarker • Journal • Oncology • ER • FGF2 • PCNA • TLR4 • TLR5 • TNFA

The role of TRIF protein in regulating the proliferation and antigen presentation ability of myeloid dendritic cells through the ERK1/2 signaling pathway in chronic low-grade inflammation of intestinal mucosa mediated by flagellin-TLR5 complex signal. (PubMed, PeerJ) - "Mouse bone marrow-derived DC line DC2.4 was divided into four groups: control group (BC) was DC2.4 cells cultured normally; flagellin single signal stimulation group (DC2.4+CBLB502) was DC2.4 cells stimulated with flagellin derivative CBLB502 during culture; TLR5-flagellin complex signal stimulation group (ov-TLR5-DC2.4+CBLB502) was flagellin derivative CBLB502 stimulated ov-TLR5-DC2.4 cells with TLR5 gene overexpression; TRIF signal interference group (ov-TLR5-DC2.4+CBLB502+Pepinh-TRIFTFA) was ov-TLR5-DC2.4 cells with TLR5 gene overexpression stimulated with flagellin derivative CBLB502 and intervened with TRIF-specific inhibitor Pepinh-TRIFTFA...After stimulation of flagellin protein-TLR5 complex signal, TRIF protein and p-ERK1/2 protein expression in myeloid dendritic cells were significantly up-regulated, accompanied by increased proliferation activity and maturity of DCs, enhanced antigen presentation function, increased secretion of pro-inflammatory cytokines IL-12..."

Journal • Inflammation • Mucositis • CD80 • IL12A • IL4 • TLR5

Toll-like Receptor Agonist CBLB502 Protects Against Cisplatin-induced Liver and Kidney Damage in Mice. (PubMed, In Vivo) - "Our data provide insights into the protective mechanism of CBLB502 against CDDP-induced tissue damage in the liver and kidney and might provide a basis for future studies on functional genes and regulatory mechanisms that mediate protection against chemoradiotherapy-induced damage."

Journal • Preclinical • Hepatology • Liver Failure • Oncology • Renal Disease • TLR5

The inducible secreting TLR5 agonist, CBLB502, enhances the anti-tumor activity of CAR133-NK92 cells in colorectal cancer. (PubMed, Cancer Biol Med) - "Armed with a CBLB502 TLR5 agonist, CAR133-NK92 cells were shown to be capable of specifically eliminating CD133-positive colon cancer cells in a CAR133-dependent manner and indirectly eradicating CD133-negative colon cancer cells in a CBLB502-specific endogenous immune response manner. This study describes a novel technique for optimizing CAR-T/NK cells for the treatment of antigenically-diverse solid tumors."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD133

TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy. (PubMed, Commun Biol) - "CBLB502-induced enhancement of ICT was also observed in poorly immunogenic B16-F10 melanoma tumors. Combination immune checkpoint therapy plus TLR5 agonists may offer a new therapeutic strategy to treat ICT-refractory solid tumors."

IO biomarker • Journal • Breast Cancer • Immune Modulation • Immunology • Inflammation • Melanoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • CXCL5 • IL15

A Clinical Trial of Entolimod a TLR-5 Adjuvant for Vaccines Using Diphtheria or Tetanus as Carrier Proteins. (PubMed, Vaccines (Basel)) - "Medical safety was excellent, and a TLR5 missense polymorphism reduced anti-DPT AB production, but Ent increased anti-DPT AB titers to levels induced in subjects with genetically "normal" TRL5 functioning. Further clinical testing of TLR5 adjuvants like Ent seems warranted for anti-drug vaccines."

Journal • Infectious Disease • Tetanus • TLR5

Active and Passive Immunization with an Anti-Methamphetamine Vaccine Attenuates the Behavioral and Cardiovascular Effects of Methamphetamine. (PubMed, Vaccines (Basel)) - "We determined the effects of a formulation that included tetanus-toxoid (TT) conjugated to succinyl-methamphetamine (TT-SMA) adsorbed onto aluminum hydroxide (alum) in combination with the novel Toll-Like Receptor-5 agonist, entolimod. Passive immunization also attenuated the ability of MA to reinstate extinguished drug-seeking behavior in male and female rats. Results support further development of this vaccine for relapse prevention for individuals with MUD."

Journal • Cardiovascular • Infectious Disease • Tetanus • TLR5

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Codelivery of SARS-CoV-2 Prefusion-Spike Protein with CBLB502 by a Dual-Chambered Ferritin Nanocarrier Potentiates Systemic and Mucosal Immunity. (PubMed, ACS Appl Bio Mater) - "Moreover, the codelivery nanoparticle showed a Th1-biased cellular immune response as the release of splenic INF-γ was significantly heightened while the level of IL-4 was elevated to a moderate extent. In general, the developed dual-chambered nanoparticle can trigger multifaceted immune responses and shows great potential for mucosal vaccine development."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • IL4

Entolimod on Immunosenescence in Healthy Geriatric Subjects Receiving Influenza Vaccination (clinicaltrials.gov) - P2 | N=61 | Completed | Sponsor: Mayo Clinic | Active, not recruiting ➔ Completed | N=100 ➔ 61 | Trial completion date: Dec 2022 ➔ Mar 2022

Enrollment change • Trial completion • Trial completion date • Infectious Disease • Respiratory Diseases

"#StateraBiopharma and #CoeptisTherapeutics Announce Strategic Agreement for Rights to #Entolimod $STAB https://t.co/QoxIyiIfnc" (@1stOncology)

M&A

Statera Biopharma and Coeptis Therapeutics Announce Strategic Agreement for Rights to Entolimod (GlobeNewswire) - "Statera Biopharma...announced today that the Company has agreed to enter into a strategic agreement with Coeptis Therapeutics...to sell Statera’s rights to Entolimod and other related toll-like receptor 5 (TLR5) agonists....Under the terms of the definitive agreement, Statera will receive a $6 million upfront payment and revenue-based milestone payments from Coeptis in exchange for Statera’s rights to any product containing Entolimod as an active ingredient and all other related TLR5 agonists."

Licensing / partnership • Oncology

Entolimod on Immunosenescence in Healthy Geriatric Subjects Receiving Influenza Vaccination (clinicaltrials.gov) - P2; N=100; Active, not recruiting; Sponsor: Mayo Clinic; Trial completion date: Apr 2022 ➔ Dec 2022

Clinical • Trial completion date • Infectious Disease • Respiratory Diseases

A clinical-stage toll-like receptor 5 agonist, entolimod, boosts chemo-immunotherapy in pre-clinical TNBC by generating durable antitumor immunity (SABCS 2021) - "The FDA has now approved chemo-immunotherapy (CTx-I) regimens (αPD-L1/nab-Paclitaxel, αPD-1/CTx) as standard-of-care for early-stage, locally advanced, and metastatic TNBC. Importantly, systemically administered entolimod was shown to be safe in Phase I clinical trials cumulatively involving nearly 200 subjects in both healthy volunteers and advanced cancer patients. Thus, this work will aid in formulating a more effective CTx-I treatment regimen with potentially important clinical implications for patients with locally advanced or metastatic TNBC."

Preclinical • Breast Cancer • Oncology • Triple Negative Breast Cancer • CD8 • TLR5

Statera Biopharma Announces FDA Lifts Clinical Hold on Entolimod (GlobeNewswire) - "Statera Biopharma...announced today that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold placed on the Company’s Entolimod research and development activity in acute radiation syndrome (ARS). Based on the Company’s response, the FDA acknowledged that the Company satisfactorily addressed historical regulatory matters....In addition, Statera is establishing a development program in Oncology and Hematology based on the potential that toll-like receptor 5 agonists, such as Entolimod, have shown in the treatment of neutropenia and anemia in cancer patients. Discussions are underway with a renowned U.S. academic institution to initiate the first study of Entolimod in this new area of focus in 2022."

FDA event • New trial • Hematological Disorders • Neutropenia • Oncology

Statera Biopharma Provides Third Quarter 2021 Financial and Corporate Update (GlobeNewswire) - "Clinical trials for STAT-401 in pancreatic cancer and STAT-600 (Entolimod) in hematologic indications expected in 2022."

New trial • Gastrointestinal Cancer • Hematological Malignancies • Oncology • Pancreatic Cancer

Signaling through TLR5 mitigates lethal radiation damage by neutrophil-dependent release of MMP-9. (PubMed, Cell Death Discov) - "A TLR5 agonist, entolimod, is among the most powerful experimental radiation countermeasures and shows efficacy in rodents and non-human primates as a prophylactic (radioprotection) and treatment (radiomitigation) modality...Importantly, recombinant MMP-9 by itself has radiomitigative activity and, in the absence of neutrophils, accelerates the recovery of the hematopoietic system. Unveiling this novel TLR5-neutrophil-MMP-9 axis of radiomitigation opens new opportunities for the development of efficacious radiation countermeasures to treat ARS following accidental radiation disasters."

Journal • MMP9 • TLR5

Entolimod on Immunosenescence in Healthy Geriatric Subjects Receiving Influenza Vaccination (clinicaltrials.gov) - P2; N=100; Active, not recruiting; Sponsor: Mayo Clinic; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Infectious Disease • Respiratory Diseases

A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications. (PubMed, Commun Biol) - "Like entolimod, GP532 demonstrated potent prophylactic and therapeutic efficacy in mouse models of radiation-induced death and tissue damage. These results establish GP532 as an optimized TLR5 agonist suitable for multi-dose therapies and for patients with high titers of preexisting flagellin-neutralizing antibodies."

IO biomarker • Journal • Oncology • TLR5

Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury. (PubMed, Cell Death Dis) - "In IL-22 knockout mice, the loss of IL-22 resulted in a decrease of hepatic STAT3 activation, a reduction in the cytoprotective signature, and a loss of hepatoprotection following ischemia-reperfusion-induced liver injury. Taken together, these findings suggest that CBLB502 protects the liver by increasing hepatocyte resistance to acute liver injury through the cooperation of TLR5-NF-κB and IL-22-STAT3 signaling pathways."

Journal • Hepatology • Liver Failure • Reperfusion Injury • IL22