AZD8701 / AstraZeneca, Ionis - LARVOL DELTA

Strong antitumor effect elicited by inhibition of AKT or FOXP3 in combination with anti-PD-L1 in Pten mutant lung squamous cell carcinoma (AACR 2024) - "Based on these findings, we have investigated whether blockade of AKT signaling with capivasertib (AZD5363) and/or inhibition of Treg-associated FOXP3 transcription factor, using the FOXP3 targeting antisense oligonucleotide (ASO) AZD8701 (FOXP3i), would cause tumor growth inhibition in the PTEN mutant context. Combination of capivasertib+FOXP3i at the same doses did not cause further tumor growth inhibition, but combination of capivasertib+anti-PD-L1 or FOXP3i+anti-PD-L1 increased antitumor benefit compared to monotherapy treatment, and further increased survival. In summary, we demonstrate that immunotherapy resistant tumors with hyperactivation of AKT due to Pten mutation are highly sensitive to AKT or FOXP3 inhibition and that combinatorial strategies using these targets and anti-PD-L1 can be appropriate strategies to treat these tumors."

Combination therapy • IO biomarker • Late-breaking abstract • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • CCND1 • FOXP3 • PTEN

Targeting macrophages and regulatory T cells improves response to chemotherapy in high-grade serous ovarian cancer (AACR 2024) - "Bulk RNAseq of tumors treated with anti-stab1 ab were enriched with CXCL9 positive macrophages, while Foxp3-ASO treatment showed significant increase in T helper cell infiltration and activation. Potentially cured long-term survivors (300 days+) were resistant to tumor rechallenge.In a third HGSOC mouse model (60577), in which tumors relapsed after a good initial response to chemotherapy, combinations of chemotherapy with anti-stab1 ab and/or Foxp3-ASO significantly increased the post relapse survival compared to chemotherapy alone.We believe that modulating Tregs and STAB1 could improve response to chemotherapy and can have translational potential as each AZD8701 and a humanized anti-stab1 ab are in phase I clinical trials."

IO biomarker • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • CD4 • CXCL9 • FOXP3 • ITGAX

First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2023 ➔ Jan 2025 | Trial primary completion date: Dec 2023 ➔ Jan 2025

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Cervical Cancer • Clear Cell Renal Cell Carcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: May 2023 ➔ Dec 2023 | Trial primary completion date: May 2023 ➔ Dec 2023

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Cervical Cancer • Clear Cell Renal Cell Carcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • FOXP3

Immunotherapies that repolarize macrophages and CD4 T cells enhance the effect of chemotherapy in high-grade serous ovarian cancer (AACR 2023) - "Combinations of chemotherapy with anti-stabilin1 antibody and/or FOXP3 inhibitor (AZD8701), FOXP3i, significantly increased median survival of mice with established peritoneal disease...There was significant reduction in FOXP3 positive cells and significant increase of Tbet positive cells in FOXP3i treated murine tumors suggesting repolarization of naive T cells in the tumor microenvironment towards a more anti-tumor T helper phenotype. As there are early phase clinical trials of FOXP3 inhibitor and anti-stabilin1 (Clever-1) antibody in patients with advanced cancer, these results suggest ways of improving response to chemotherapy not only in HGSOC but in other cancers that are treated by NACT."

Late-breaking abstract • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • CD4 • FOXP3

First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours (clinicaltrials.gov) - P1 | N=61 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | N=153 ➔ 61 | Trial completion date: Jan 2024 ➔ May 2023 | Trial primary completion date: Jan 2024 ➔ May 2023

Combination therapy • Enrollment change • Enrollment closed • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Cervical Cancer • Clear Cell Renal Cell Carcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • FOXP3

Rationale and design of phase 1 FTIH study of FOXP3 antisense oligonucleotide AZD8701 in patients with selected advanced solid tumors. (ASCO 2022) - P1 | " This is a Phase I multicenter study of AZD8701 alone or in combination with durvalumab in participants with selected advanced solid tumors. Secondary endpoints include, disease control rate, duration of response, progression free survival and overall survival, pharmacokinetics and pharmacodynamics (including changes in Foxp3 mRNA in paired tumor samples). The trial is currently recruiting."

Clinical • IO biomarker • P1 data • Breast Cancer • Cervical Cancer • Clear Cell Renal Cell Carcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Immunology • Lung Cancer • Melanoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD8 • FOXP3

"@AstraZeneca #Oncology #EarlyClinicalDevelepment The most anticipated drugs🤔 ➡️#AZD0466: #Dendrimer(@Starpharma_ASX)-conjugated dual #Bcl2/#BclxL inhibitor ➡️#AZD8701: #FOXP3 #ASO, #Tregs depletion💘 ➡️#AZD8205: #B7H4 #TOP1i #ADC, Synergy with #PARP1 selective inhibitor👌" (@gasingiltv)

Oncology • BCL2 • BCL2L1 • FOXP3 • VTCN1

Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer. (PubMed, J Immunother Cancer) - P1 | "Antisense inhibitors of FOXP3 offer a promising novel cancer immunotherapy approach. AZD8701 is being developed clinically as a first-in-class FOXP3 inhibitor for the treatment of cancer currently in Ph1a/b clinical trial (NCT04504669)."

IO biomarker • Journal • Immune Modulation • Inflammation • Oncology • CD8 • CTLA4 • FOXP3 • ICOS • IL2RA

First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours (clinicaltrials.gov) - P1 | N=153 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Sep 2023 ➔ Jan 2024 | Trial primary completion date: Sep 2023 ➔ Jan 2024

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Cervical Cancer • Clear Cell Renal Cell Carcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • FOXP3

"$AZN projects newly into phase 1. AZD8701 is a FoxP3-targeting oligo (via $IONS) to relieve Treg suppression" (@JacobPlieth)

New P1 trial • P1 data • FOXP3

First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours (clinicaltrials.gov) - P1; N=110; Recruiting; Sponsor: AstraZeneca; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Monotherapy • Breast Cancer • Cervical Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • FOXP3

First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours (clinicaltrials.gov) - P1; N=123; Not yet recruiting; Sponsor: AstraZeneca

Clinical • Combination therapy • Monotherapy • New P1 trial • Breast Cancer • Cervical Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

Directly targeting FOXP3 with AZD8701, a first-in-class high affinity antisense oligonucleotide to relieve immunosuppression in cancer. (SITC 2019) - "In summary, AZD8701 represents a first-in-class clinical candidate to target Tregs in cancer in a highly selective manner, and may provide therapeutic benefit to patients either as a monotherapy or in combination with immune checkpoint blockade."

IO Biomarker

"Development and Characterization of AZD8701, a High Affinity Antisense Oligonucleotide Targeting FOXP3 to Relieve Immunosuppression in Cancer A. Robert MacLeod, PhD, Ionis Pharmaceuticals @ionispharma @AstraZeneca #otsmunich" (@OTSociety)

Discovery and characterization of AZD8701, a high affinity antisense oligonucleotide targeting FOXP3 to relieve immunosuppression in cancer (AACR 2019) - "Collectively, FOXP3 ASOs represent a first-in-class strategy to target Tregs in cancer in a highly selective manner. The clinical application of AZD8701 may provide therapeutic benefit to patients either as a monotherapy or in combination with immune checkpoint blocking agents."

IO Biomarker

Newly added product (AACR 2019) - Preclinical, Oncology

Pipeline update