ilantimod (BAY 2416964) / Bayer, German Cancer Research Center - LARVOL DELTA

Baseline AHR expression shapes immune response to pharmacological modulation in PBMCs from pancreatic cancer patients. (PubMed, Front Immunol) - "Peripheral blood mononuclear cells (PBMCs) from patients with PDAC and healthy donors were isolated and treated ex vivo with two AHR agonists (Carbidopa and Tapinarof) and one antagonist (BAY 2416964). Baseline AHR expression critically shapes the immune response to pharmacological modulation in PBMCs from PDAC patients. These findings suggest that AHR profiling may serve as a clinically relevant biomarker for stratifying patients and guiding personalized immunotherapy approaches for PDAC."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AHR • IL10 • PD-1 • PD-L1

Inhibition of AhR improves cortical bone and skeletal muscle function via preservation of neuromuscular junctions. (PubMed, JCI Insight) - "Transcriptomic and proteomic data from BAY2416964-treated mice supported a positive impact of BAY2416964 on molecular targets that affect neuromuscular junction function. Taken together, these data support AhR as a therapeutic target for improving musculoskeletal health during aging."

Journal • Musculoskeletal Diseases • Osteoporosis • Rheumatology

The Microbiome and Its Metabolites Promote Cardiac Remodeling in Chronic Kidney Disease via the AhR-IL17A Axis (ERA 2025) - " Experimental CKD was induced in 129/Sv mice by subtotal nephrectomy (STNx), followed by either microbiome depletion using oral antibiotics (Abx) or pharmacological AhR-inhibition (AhRi) with a small molecule AhR inhibitor (BAY 2416964)... Our findings demonstrate that both the Abx-induced reduction of microbial metabolite production in the intestine as well as inhibition of the AhR significantly protect against STNx- induced immune activation, inflammation, and cardiac fibrosis. The reduced IL17A-signature in both Abx and AhRi-treated groups indicates a potential mechanistic link between microbiota- driven AhR activation, TH17 cells, and adverse cardiac remodeling in CKD."

Cardiovascular • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • CRP • IL17A

Expression of the aryl hydrocarbon receptor in Osterix-lineage cells regulates adult skeletal homeostasis in a compartment-specific manner. (PubMed, JBMR Plus) - "Kynurenine's harmful effects were most pronounced in the middle of an osteoblastic differentiation time course, and these effects could be rescued via the AhR antagonist BAY2416964...These results underscore the complexity of AhR signaling in skeletal biology that must be considered while exploring AhR as a therapeutic target for conditions like osteoporosis and musculoskeletal frailty. Future studies will be needed to test the effects of osteoblastic AhR deletion at advanced ages, when the endogenous AhR ligand KYN is elevated in the circulation and skeletal niche."

Journal • Musculoskeletal Diseases • Osteoporosis • Rheumatology • AHR

A Study to Learn How Safe the Study Drug BAY 2416964 (AhR Inhibitor) in Combination With the Treatment Pembrolizumab is, How This Combination Affects the Body, the Maximum Amount That Can be Given, How it Moves Into, Through and Out of the Body and Its Action Against Advanced Solid Cancers in Adults (clinicaltrials.gov) - P1 | N=47 | Terminated | Sponsor: Bayer | Trial completion date: Dec 2025 ➔ Jan 2025 | Active, not recruiting ➔ Terminated; Last patient ongoing on treatment ended the study on 20th January 2025. Hence, the end of study was reached as defined in the protocol.

Trial completion date • Trial termination • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

A Study to Learn How Safe the Study Drug BAY 2416964 (AhR Inhibitor) in Combination With the Treatment Pembrolizumab is, How This Combination Affects the Body, the Maximum Amount That Can be Given, How it Moves Into, Through and Out of the Body and Its Action Against Advanced Solid Cancers in Adults (clinicaltrials.gov) - P1 | N=47 | Active, not recruiting | Sponsor: Bayer | Trial completion date: Mar 2025 ➔ Dec 2025 | Trial primary completion date: Mar 2025 ➔ Jun 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

Long-term exposure to BAY2416964 reduces proliferation, migration and recapitulates transcriptional changes induced by AHR loss in PyMT-induced mammary tumor cells. (PubMed, Front Oncol) - "No differentially expressed genes (DEGs) were identified in wildtype cells exposed to 1 μM BAY2416964 for 24 h; however, 46.4% of DEGs overlapped between AhrKO and LT-BAY cells including gene regulated cell proliferation. Our data reveal long-term pharmacological inhibition of AHR by BAY2416964 closely resembles AHR loss in a mouse model of breast cancer."

Journal • Tumor cell • Breast Cancer • Oncology • Solid Tumor • CYP1A1 • CYP1B1

Combination screen in multi-cell type tumor spheroids reveals interaction between aryl hydrocarbon receptor antagonists and E1 ubiquitin-activating enzyme inhibitor: Aryl-hydrocarbon receptor antagonist drug combinations. (PubMed, SLAS Discov) - "This has led to the discovery and development of selective AhR modulators, including BAY 2416964 which is currently in clinical trials...All three AhR antagonists sensitized tumor spheroids to TAK-243, an E1 ubiquitin-activating enzyme inhibitor...The AhR antagonists also potentiated pevonedistat, a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit, in several tumor spheroid models. In contrast, the AhR antagonists did not enhance the cytotoxicity of the proteasome inhibitor bortezomib."

Journal • Colon Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation

Long-term exposure to BAY2416964 reduces proliferation, migration and recapitulates transcriptional changes induced by AHR loss in PyMT-induced mammary tumor cells (Front Oncol) - "CRISPR/Cas9generated PyMT Ahr KO cells exhibited reduced cell proliferation compared with controls, but treatment with 1 µM BAY2416964 for 96 h had no effect on the proliferation of wildtype cells....No differentially expressed genes (DEGs) were identified in wildtype cells exposed to 1 µM BAY2416964 for 24 h; however, 46.4% of DEGs overlapped between Ahr KO and LT-BAY cells including gene regulated cell proliferation."

Preclinical • Breast Cancer

A Study to Learn How Safe the Study Drug BAY 2416964 (AhR Inhibitor) in Combination With the Treatment Pembrolizumab is, How This Combination Affects the Body, the Maximum Amount That Can be Given, How it Moves Into, Through and Out of the Body and Its Action Against Advanced Solid Cancers in Adults (clinicaltrials.gov) - P1 | N=47 | Active, not recruiting | Sponsor: Bayer | Trial completion date: Dec 2025 ➔ Mar 2025 | Trial primary completion date: Dec 2025 ➔ Mar 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=78 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Metastases • Trial completion • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

A Study to Learn How Safe the Study Drug BAY 2416964 (AhR Inhibitor) in Combination With the Treatment Pembrolizumab is, How This Combination Affects the Body, the Maximum Amount That Can be Given, How it Moves Into, Through and Out of the Body and Its Action Against Advanced Solid Cancers in Adults (clinicaltrials.gov) - P1 | N=47 | Active, not recruiting | Sponsor: Bayer | Recruiting ➔ Active, not recruiting | N=164 ➔ 47

Combination therapy • Enrollment change • Enrollment closed • Metastases • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=78 | Active, not recruiting | Sponsor: Bayer | Trial completion date: Apr 2025 ➔ Jan 2024

Metastases • Trial completion date • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy. (PubMed, J Immunother Cancer) - "These findings identify AhR inhibition as a novel therapeutic approach to overcome immune resistance in various types of cancers."

IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • AHR • TDO2

Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy (J Immunother Cancer) - "AhR expression was observed in tumor cells and tumor-infiltrating immune cells in HNSCC, NSCLC and CRC. BAY 2416964 potently and selectively inhibited AhR activation induced by either exogenous or endogenous AhR ligands. In vitro, BAY 2416964 restored immune cell function in human and mouse cells, and furthermore enhanced antigen-specific cytotoxic T cell responses and killing of tumor spheroids."

Preclinical • Colorectal Cancer • Non Small Cell Lung Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A Study to Learn How Safe the Study Drug BAY 2416964 (AhR Inhibitor) in Combination With the Treatment Pembrolizumab is, How This Combination Affects the Body, the Maximum Amount That Can be Given, How it Moves Into, Through and Out of the Body and Its Action Against Advanced Solid Cancers in Adults (clinicaltrials.gov) - P1 | N=164 | Recruiting | Sponsor: Bayer | Phase classification: P1b ➔ P1

Combination therapy • Metastases • Phase classification • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=78 | Active, not recruiting | Sponsor: Bayer | Recruiting ➔ Active, not recruiting | N=143 ➔ 78 | Trial primary completion date: Apr 2025 ➔ Jan 2024

Enrollment change • Enrollment closed • Metastases • Trial primary completion date • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • IL6

A Study to Learn How Safe the Study Drug BAY 2416964 (AhR Inhibitor) in Combination With the Treatment Pembrolizumab is, How This Combination Affects the Body, the Maximum Amount That Can be Given, How it Moves Into, Through and Out of the Body and Its Action Against Advanced Solid Cancers in Adults (clinicaltrials.gov) - P1b | N=164 | Recruiting | Sponsor: Bayer | N=78 ➔ 164 | Trial primary completion date: Jun 2025 ➔ Nov 2025

Combination therapy • Enrollment change • Metastases • Trial primary completion date • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Initial results from a first-in-human, phase I study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 in patients with advanced solid tumors. (ASCO 2023) - P1 | "BAY2416964 was well tolerated across all dose levels and regimens tested. Initial evaluation of biomarkers shows BAY2416964 inhibits AhR and modulates immune functions. Encouraging preliminary anti-tumor activity was observed in heavily pretreated patients."

Clinical • Immunomodulating • IO biomarker • Metastases • P1 data • Breast Cancer • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Head and Neck Cancer • Hepatology • Immune Modulation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Thymoma • Thymus Cancer

Bayer presents new data across oncology portfolio at the 2023 ASCO Annual Meeting (Bayer Press Release) - "Bayer presents new data from across its oncology research and development programs at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting taking place between June 2-6, 2023....Additional data featuring Bayer’s oncology pipeline will include an oral presentation on the initial results from a first-in-human, Phase I study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 in patients with advanced solid tumors. The six-year safety and efficacy results from CHRONOS-1 study analyzing copanlisib in patients with relapsed or refractory follicular lymphoma (FL) will also be presented."

P1 data • P2 data • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Aryl-hydrocarbon receptor inhibitors in combination with anticancer agents, especially proteasome pathway inhibitors, in a complex spheroid screen using patient-derived cell lines can result in greater-than additive cytotoxicity (AACR 2023) - "Three aryl-hydrocarbon receptor (AhR) selective inhibitors, BAY-2416964, GNF351 and CH-223191, were assayed alone and in combination with 25 approved or investigational anticancer agents in complex spheroids including tumor cells, endothelial cells, and mesenchymal stem cells...Combinations of AhR inhibitors with anticancer agents including doxorubicin, cisplatin, SN38, venetoclax, selinexor, and etoposide (https://dtp.cancer.gov/organization/dscb/obtaining/default.htm) produced primarily additive cytotoxicity in complex spheroids after a 7-day exposure...Bortezomib, a direct inhibitor of the chymotrypsin-like protease of the 26S proteasome, and pevonedistat, a NEDD8-activating enzyme inhibitor, produced additive or greater-than-additive cytotoxicity in some complex spheroids. However, the combination of BAY-2416964 with TAK-243, a ubiquitin activating enzyme inhibitor, produced profound greater-than-additive cytotoxicity in more than half of the 28 PDMR cell lines..."

Combination therapy • Preclinical • Bladder Cancer • Brain Cancer • CNS Tumor • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Glioblastoma • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor • Urothelial Cancer • HIF1A • HSP90AA1

A novel AhR inhibitor ‘DA-4505’ improved the anti-cancer efficacy of surgical and chemotherapy via synergistic anti-tumor effects of aPD-1 (AACR 2023) - "Here, we propose that a best-in-class AhR inhibitor, DA-4505, improves anti-tumor efficacy via modulation of tumor immune surveillance compared to BAY2416964, an AHR antagonist drug candidate being studied in the clinical phase. To evaluate anti-tumor effects of DA-4505 and BAY2416964, the two AhR inhibitors were dosed at 10 mg/kg once daily alone or in combination with aPD-1 (10 mg/kg) in surgical and chemotherapy models, and a PDX model (YHIM2004)...A tumor reduction was shown by treating DA-4505 alone or in combination with pembrolizumab compared to vehicle group (P<0.05)... The AhR inhibitor DA-4505 demonstrated an improvement in anti-tumor efficacy. In addition, it has shown a synergistic effect when combined with aPD-1. Discoveries from this study provide a preclinical rationale for future clinical implications in solid tumor."

Clinical • Oncology • Solid Tumor • CCL7 • CCL8 • CD8

Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first in human phase 1 study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 (AACR 2023) - "This modeling-based PK analysis along with target engagement in peripheral blood informed the posology to be tested in the dose-expansion part of the ongoing clinical trial."

Biomarker • Immunomodulating • IO biomarker • P1 data • PK/PD data • Oncology • Solid Tumor • CYP1A1 • CYP1B1 • IDO1 • TDO2

Bayer to present latest research across its advancing oncology portfolio at AACR 2023 Annual Meeting (Bayer Press Release) - "Bayer will present latest research across its oncology portfolio at the American Association for Cancer Research (AACR) 2023 Annual Meeting, taking place from April 14-19 in Orlando (FL), USA....Bayer will present the first clinical Phase 1 results on aryl hydrocarbon receptor (AhR) inhibitor BAY 2416964, the company’s most advanced Immuno-Oncology program. A focus of the presentation will be on the target engagement results and pharmacokinetics from its ongoing monotherapy dose-escalation study to explore a potential optimal dose and schedule to effectively inhibit AhR. These results, along with a mathematical model-informed approach have supported the currently ongoing dose expansion for BAY 2416964."

P1 data • PK/PD data • Oncology • Solid Tumor

Tubular aryl hydratocarbon receptor upregulates EZH2 to promote cellular senescence in cisplatin-induced acute kidney injury. (PubMed, Cell Death Dis) - "The AhR inhibition by BAY2416964 and tubular conditional deletion both alleviated cisplatin-induced kidney dysfunction and tubular injury. The present study implicated that AhR and EZH2 have mutual regulation, which further accelerated tubular senescence in cisplatin-induced AKI. Notably, the crucial role of AhR is potential to become a promising target for AKI."

Journal • Acute Kidney Injury • Nephrology • Renal Disease • AHR • CDKN1A • EZH2 • IL1B • IL6 • TNFA