E7766 / Eisai - LARVOL DELTA

CHARACTERIZING THE ROLES OF T-CELLS IN THE CONTEXT OF TUMOR CLEARANCE AND MEMORY IN THE KP MODEL OF SARCOMA FOLLOWING STING THERAPY (CTOS 2025) - "Following treatment with the translational STING agonist E7766, STS tumor clearance is primarily dependent on CD8+ T-cells. However, the adaptive immune protection conferred following STING therapy following re-challenge appears to be largely CD4+ T-cell dependent. Further characterization of the immunologic landscapes of relapsed tumors following re-challenge are ongoing."

Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD8 • STING

The human STING agonist E7766 induces immunogenic tumor clearance, independent of tumor-intrinsic STING expression in the KRASG12D/+ Trp53-/- murine model of sarcoma. (PubMed, Oncoimmunology) - "Using STING deficient mice, and CRISPR/Cas9 gene editing, we demonstrated that STS clearance following STING therapy was dependent on host STING and not tumor-intrinsic STING pathway functionality. E7766 represents a promising candidate able to remodel the TME of murine STS tumors toward an inflamed phenotype independent of tumor-intrinsic STING functionality, and should be considered for potential translation in STS treatment."

IO biomarker • Journal • Preclinical • Immune Modulation • Immunology • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD8 • KRAS • STING • TP53

Phase I dose-escalation and pharmacodynamic study of STING agonist E7766 in advanced solid tumors. (PubMed, J Immunother Cancer) - "In total, E7766 generated on-target pharmacodynamic effects in patients with solid tumors. Further exploration in a homogeneous patient population is necessary to assess efficacy."

Journal • P1 data • PK/PD data • Fatigue • Oncology • Solid Tumor • CD8 • IFNA1 • IFNB1 • IFNG • IL6 • PD-L1 • STING • TNFA

Phase I dose-escalation and pharmacodynamic study of STING agonist E7766 in advanced solid tumors (J Immunother Cancer) - P1 | N=24 | INSTAL-101 (NCT04144140) | Sponsor: Eisai Inc. | "Eight patients (33.3%) achieved stable disease as their best response per modified Response Evaluation Criteria In Solid Tumors version 1.1 with variability between injected and non-injected lesions. Plasma levels of IFN-α, IFN-β, IFN-γ, TNF-α, IL-6, IP-10, MCP1, and MIP1b transiently increased in all evaluable patients within 10 hours postinjection, then dropped to baseline levels. Levels of blood and tumor gene expression increased in most interferon-related and STING genes tested. Further increases in programmed death ligand 1 and cluster of differentiation 8 expression at both the RNA and protein levels were also observed in some patients across dose levels. In total, E7766 generated on-target pharmacodynamic effects in patients with solid tumors."

P1 data • Solid Tumor

INTERFERON STIMULATED GENE SCORES ARE ELEVATED IN THE MYELOID COMPARTMENT OF MURINE KP UNDIFFERENTIATED PLEOMORPHIC TUMORS TREATED WITH TRANSLATIONAL STING AGONISTS (CTOS 2024) - "The objectives of the present study are; 1) To evaluate the anti-tumor potential of two clinically relevant STING agonists; ADU-S100 (CDN) and E7766, 2) To examine the importance of UPS cell STING expression for stimulating anti-tumor responses, and 3) To identify which populations in the UPS TME engage in STING signaling following therapy. To evaluate survival frequencies with translational STING agonists, immune competent C57Bl/6 mice were engrafted with 100,000 UPS cells and treated intratumorally with escalating doses of CDN or E7766 and followed over time using tumor volume measurements and bioluminescence imaging. We are thrilled to report that E7766 is a translational STING agonist capable of stimulating tumor clearance in the KP model of UPS. Additionally, we have established that tumor clearance phenotypes in this model are independent of UPS cell STING expression status. Moreover, neutrophils and myeloid cells in general appear to be important populations in..."

IO biomarker • Preclinical • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma • STING

PSMA-E7766 ADC: harnessing targeted delivery of STING agonists for anti-tumor activity in prostate cancer (SITC 2024) - "The results indicate it is a promising novel agent for prostate cancer. Ethics Approval Animal studies were conducted under Institutional Animal Care and Use Committee (IACUC)-approved protocol 2000-008-1205."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CXCL10 • IFNB1 • IL6 • TNFA

Study of Intratumorally Administered Stimulator of Interferon Genes (STING) Agonist E7766 in Participants With Advanced Solid Tumors or Lymphomas - INSTAL-101 (clinicaltrials.gov) - P1 | N=24 | Terminated | Sponsor: Eisai Inc. | Completed ➔ Terminated; The study was terminated earlier due to a business decision; which was unrelated to safety. In addition, there was no clinical activity data that informed the decision.

Metastases • Trial termination • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

STING THERAPY INDUCES IMMUNOGENIC ANTI-TUMOR RESPONSES THAT ARE INDEPENDENT OF TUMOR STING EXPRESSION IN THE KP MODEL OF SOFT TISSUE SARCOMA (CTOS 2023) - "We have shown that E7766 mediated STING activation is a promising immunotherapeutic strategy for UPS in our murine model. E7766 therapy can induce tumor clearance and adaptive immune protection against UPS re-challenge. Excitingly, E7766 STING therapy can also sensitize our model to anti-PD1 ICB therapy."

IO biomarker • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma • CXCL9 • PD-L1 • STING

[VIRTUAL] Demonstration of E7766, a novel STING agonist, as a potent immunotherapy in BCG-insensitive non-muscle invasive bladder cancer models via intravesical administration (AACR-II 2020) - P1 | "These preclinical studies demonstrated a potent anti-tumor activity and induction of tumor-specific memory response by intravesically administered STING agonist E7766 in orthotopic murine models for BCG- and anti-PD1-insensitive NMIBC. A clinical study for intravesical E7766 in NMIBC patients has been initiated (NCT04109092) in North America."

IO Biomarker • Preclinical • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer • CXCL10 • STING

The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models. (PubMed, Cancers (Basel)) - "Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin's ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies."

IO biomarker • Journal • Preclinical • Breast Cancer • Immunology • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD4 • IFNB1

Use of small molecule STING agonist immunotherapy for canine soft tissue sarcoma: a cross-species analysis (SITC 2022) - "In addition, ADU-S100, MSA-2, and E7766 stimulated the canine and human interferon-dependent STING pathways. Conclusions Overall, our findings suggest that STING agonists – in particular, ADU-S100 – possess potential as a novel and effective therapeutic approach for canine STS. As sarcomas are highly metastatic and commonly fatal in dogs, further evaluating STING agonist therapy in canines may provide therapeutic insights into similar challenges for treating human disease using a comparative biology approach."

Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CXCL10 • IFNB1 • STING

STING Activation in Sarcoma: Assessing Translational Therapeutic Strategies (SITC 2022) - "We have demonstrated that the human and murine compatible STING agonist, E7766, can be used to elicit immune mediated UPS clearance and adaptive immune protection against UPS re-challenge. Ultimately, this study demonstrates the potential opportunity for clinical translation of STING as an immunotherapy for UPS which could significantly improve outcomes for this patient demographic."

Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma • STING

E7766 (AACR-NCI-EORTC 2022) - No abstract available

Oncology

Study of Intratumorally Administered Stimulator of Interferon Genes (STING) Agonist E7766 in Participants With Advanced Solid Tumors or Lymphomas - INSTAL-101 (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Eisai Inc. | Recruiting ➔ Completed | N=120 ➔ 24 | Trial completion date: Dec 2022 ➔ Aug 2022 | Trial primary completion date: Dec 2022 ➔ Aug 2022

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

H3 Biomedicine Presents Update on Intratumoral E7766 Clinical Program for Advanced Solid Tumors or Lymphomas at AACR-NCI-EORTC Conference (Businesswire) - "H3 Biomedicine...announced it will be providing an update on its intratumoral E7766 clinical program for advanced solid tumors or lymphomas in a poster presentation at the 2021 American Association for Cancer Research, the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC) Virtual International Conference on Molecular Targets and Cancer Therapeutics being held on October 7-10, 2021...'We continue to be encouraged by our ongoing clinical results with E7766 and we look forward to further advancing its Phase 1 dose escalation study.'"

Clinical data • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

"E7766, a macrocycle-bridged stimulator of interferon genes (STING) agonist with potent pan-genotypic activity (Kim @EisaiUS) https://t.co/6NItdiWBnH" (@ChemMedChem)

STING

E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity. (PubMed, ChemMedChem) - "E7766 is shown to have potent anti-tumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described."

Journal • Oncology • STING

Prediction of transporter-mediated drug-drug interactions and phenotyping of hepatobiliary transporters involved in the clearance of E7766, a novel macrocycle-bridged dinucleotide. (PubMed, Drug Metab Dispos) - "Studies in OATP1B1/1B3 humanized mice showed that plasma exposure of E7766 increased 4.5-fold when coadministered with Rifampicin. A physiologically based pharmacokinetic model that incorporated parameters from mechanistic in vitro and in vivo experiments was used to predict pharmacokinetics and drug interactions of E7766, a novel dinucleotide drug. The findings highlighted here may shed a light on the pharmacokinetic profile and transporter-mediated drug interaction propensity of other dinucleotide drugs."

IO biomarker • Journal • Cholangiocarcinoma • Hepatology • Oncology • Solid Tumor

A Study of Stimulator of Interferon Genes (STING) Agonist E7766 in Non-muscle Invasive Bladder Cancer (NMIBC) Including Participants Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy, INPUT-102 (clinicaltrials.gov) - P1; N=0; Withdrawn; Sponsor: Eisai Inc.; N=110 ➔ 0; Recruiting ➔ Withdrawn

Clinical • Enrollment change • Trial withdrawal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

A Study of Stimulator of Interferon Genes (STING) Agonist E7766 in Non-muscle Invasive Bladder Cancer (NMIBC) Including Participants Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy, INPUT-102 (clinicaltrials.gov) - P1; N=120; Recruiting; Sponsor: Eisai Inc.; Not yet recruiting ➔ Recruiting; Initiation date: Oct 2019 ➔ Feb 2020

Clinical • Enrollment open • Trial initiation date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

Study of Intratumorally Administered Stimulator of Interferon Genes (STING) Agonist E7766 in Participants With Advanced Solid Tumors or Lymphomas - INSTAL-101 (clinicaltrials.gov) - P1; N=120; Recruiting; Sponsor: Eisai Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Study of Intratumorally Administered Stimulator of Interferon Genes (STING) Agonist E7766 in Participants With Advanced Solid Tumors or Lymphomas - INSTAL-101 (clinicaltrials.gov) - P1; N=120; Not yet recruiting; Sponsor: Eisai Inc.; Initiation date: Nov 2019 ➔ Feb 2020

Clinical • Trial initiation date

Study of Intratumorally Administered Stimulator of Interferon Genes (STING) Agonist E7766 in Participants With Advanced Solid Tumors or Lymphomas - INSTAL-101 (clinicaltrials.gov) - P1; N=120; Not yet recruiting; Sponsor: Eisai Inc.

Clinical • New P1 trial

A Study of Stimulator of Interferon Genes (STING) Agonist E7766 in Non-muscle Invasive Bladder Cancer (NMIBC) Including Participants Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy, INPUT-102 (clinicaltrials.gov) - P1; N=120; Not yet recruiting; Sponsor: Eisai Inc.

Clinical • New P1 trial

Discovery of E7766: A representative of a novel class of macrocycle-bridged STING agonists (MBSAs) with superior potency and pan-genotypic activity (AACR 2019) - "More biological characterization of E7766 can be found in abstract #.ConclusionEisai successfully discovered E7766, a representative of a novel class of macrocycle-bridged STING agonist topologically distinct from conventional STING agonists. E7766 demonstrated pan-genotypic STING activation, potent anti-cancer activities and excellent chemical and metabolic stability for further development."