linrodostat (BMS-986205) / BMS, Ono Pharma - LARVOL DELTA

Adverse pro-tumorigenic effects of IDO1 catalytic inhibitors mediated by the non-enzymatic function of IDO1 in tumor cells. (PubMed, Front Immunol) - "By studying the turnover of IDO1 protein in human tumor cells exposed to various IDO1 catalytic inhibitors, such as epacadostat, linrodostat, and navoximod, we show here that these molecules stabilize a non-enzymatic protein conformation of IDO1, independently of their mechanism of inhibition. In the thyroid carcinoma cell line FTC-133, the stabilized and non-enzymatic IDO1 protein promotes the proliferation and migration of the tumor, resulting in an adverse pro-tumorigenic effect. These results uncover an unexpected adverse effect of IDO1 inhibitors in the tumor microenvironment that overcomes the enzymatic inhibition of IDO1, and suggest protein degradation, rather than enzymatic inhibition, as a more effective approach to target IDO1 in the tumor microenvironment."

Journal • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Carcinoma • IDO1

A novel IDO1 PROTAC decreases immunosuppressive extracellular IDO1 levels (SNO 2025) - "We developed a novel protein degrader/PROTAC (NU227326) with a 4.7 nM DC50 for human IDO1 and compared its effects on extracellular IDO1 with a potent IDO1 enzyme inhibitor (BMS-986205; IC50=1.7nM) in cultured human GBM cells and in mice with human GBM...A novel IDO1 protein degrader decreases both intracellular and extracellular IDO1 protein levels. Ongoing studies aim to understand IDO1 PROTAC effects on the anti-GBM immune response in humanized mice with intracranial human GBM PDX and with a human immune system."

IO biomarker • Brain Cancer • Glioblastoma • Solid Tumor • Targeted Protein Degradation • IDO1 • IFNG

A novel IDO1 PROTAC decreases immunosuppressive extracellular IDO1 levels (WFNOS 2025) - "We developed a novel protein degrader/PROTAC (NU227326) with a 4.7 nM DC50 for human IDO1 and compared its effects on extracellular IDO1 with a potent IDO1 enzyme inhibitor (BMS-986205; IC50=1.7nM) in cultured human GBM cells and in mice with human GBM...A novel IDO1 protein degrader decreases both intracellular and extracellular IDO1 protein levels. Ongoing studies aim to understand IDO1 PROTAC effects on the anti-GBM immune response in humanized mice with intracranial human GBM PDX and with a human immune system."

IO biomarker • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Solid Tumor • Targeted Protein Degradation • IDO1 • IFNG

The Unique BCR Inhibiting Properties of BMS-986205 in Chronic Lymphocytic Cells (ASH 2023) - "Efforts are underway to identify the proteome-wide direct target of BMS in CLL cells. In conclusion, our limited and preliminary data suggest that BMS could be considered as a potential therapeutic strategy to target CLL cells with a double hit: by blocking the pro-survival effect of BCR signaling, one of the driving forces for CLL cell survival and proliferation, and by inhibiting IDO1/kynurenine action to restore sensitivity to key leukemia treatments."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Targeted Protein Degradation • BLNK • CD79A • PTPN22 • SYK

Cilia-Dependent Cyst Growth Linked to Tryptophan Metabolism in PKD (KIDNEY WEEK 2025) - "The IDO inhibitor linrodostat significantly decreased oxygen consumption rate in WT 9-12 cells. Conclusion Tryptophan catabolism via the kynurenine pathway is a critical link between primary cilia and metabolism leading to cilia-dependent cyst growth, and IDO1/IDO2 inhibitors, therefore, could be novel therapeutic agents for the treatment of PKD."

IO biomarker • Autosomal Dominant Polycystic Kidney Disease • Polycystic Kidney Disease • PKD1 • PRKD1

CA017-056: Study of BMS-986205 and Nivolumab in Endometrial Cancer or Endometrial Carcinosarcoma That Has Not Responded to Treatment (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2025 ➔ Sep 2026 | Trial primary completion date: Sep 2025 ➔ Sep 2026

Trial completion date • Trial primary completion date • Carcinosarcoma • Endometrial Adenocarcinoma • Endometrial Cancer • Endometrial Carcinosarcoma • Oncology • Sarcoma • Solid Tumor

Three-Year Survival Outcomes of Neoadjuvant Nivolumab-IDO Inhibition in Head and Neck Squamous Cell Carcinoma Patients (AAO-HNSF 2025) - P2 | "This study presents updated 3-year outcomes, including overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS). A single-institutional, randomized, two-arm neoadjuvant trial (NCT03854032) enrolled 37 patients with untreated HNSCC, stratified by HPV status, to receive either nivolumab alone (Arm A) or nivolumab plus BMS986205-IDOi (Arm B). Neoadjuvant nivolumab, with or without an IDOi, achieved favorable 3-year survival outcomes in HNSCC, with OS at 85.3%, RFS at 82.3%, and DFS at 82.2%. While the addition of IDO inhibitor did not significantly enhance survival outcomes at three years, responders achieved markedly higher DFS (89.7% vs. 72.9% in non-responders), suggesting that response to neoadjuvant ICI may portent a favorable oncologic outcome."

Clinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Three-Year Survival Outcomes of Neoadjuvant Nivolumab-IDO Inhibition in Head and Neck Squamous Cell Carcinoma Patients (AAO-HNSF 2025) - P2 | "This study presents updated 3-year outcomes, including overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS). A single-institutional, randomized, two-arm neoadjuvant trial (NCT03854032) enrolled 37 patients with untreated HNSCC, stratified by HPV status, to receive either nivolumab alone (Arm A) or nivolumab plus BMS986205-IDOi (Arm B). Neoadjuvant nivolumab, with or without an IDOi, achieved favorable 3-year survival outcomes in HNSCC, with OS at 85.3%, RFS at 82.3%, and DFS at 82.2%. While the addition of IDO inhibitor did not significantly enhance survival outcomes at three years, responders achieved markedly higher DFS (89.7% vs. 72.9% in non-responders), suggesting that response to neoadjuvant ICI may portent a favorable oncologic outcome."

Clinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Newly diagnosed glioblastoma IDHwt patients treated with radiation, nivolumab, and BMS-986205. (PubMed, Res Sq) - "Cohort A received RT + nivolumab with escalating BMS-986205 doses in MGMT unmethylated GBM patients. Cohort B received the highest dose of BMS-986205 with nivolumab and standard RT/temozolomide (TMZ)"

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • IDO1 • MGMT

Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner. (PubMed, Commun Chem) - "A few IDO1 inhibitors have reached the clinical stage, including navoximod, epacadostat and linrodostat. Using second harmonic generation analysis (SHG) and molecular dynamics simulations, here we show that these clinical inhibitors can induce distinct allosteric motions in the enzyme that affect the stability of the transient signaling complex between IDO1 and Src tyrosine kinase. Next generation sequencing demonstrates that, despite sharing a similar ability to inhibit the enzyme's catalytic function, all three catalytic inhibitors modulate the IDO1's signaling function in different ways, regulating distinct transcriptomes in SKOV3 cells."

IO biomarker • Journal • Oncology • IDO1

Expression of indoleamine-2,3-dioxygenase 1 in sebaceous glands and related tumors of the eyelid: a potential diagnostic target. (PubMed, Orbit) - "Prior to these findings, clinical management centered around surgical excision. The use of molecular compounds such as indoximob, epacadostat, BMS-986205 and navoximod, that directly target IDO1 opens new possibilities for targeting these tumors, improving clinical outcomes, and minimizing the morbidities often associated with surgery."

IO biomarker • Journal • Eye Cancer • Oncology • IDO1

Nivolumab, BMS-986205, and Radiation Therapy With or Without Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P1 | N=18 | Active, not recruiting | Sponsor: Northwestern University | Trial primary completion date: Feb 2025 ➔ Feb 2027

Checkpoint inhibition • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MGMT

Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes. (PubMed, Cell Death Differ) - "Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells...The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention."

Journal • Colorectal Cancer • Oncology • Ovarian Cancer • Solid Tumor • IDO1

ENERGIZE: A Study to Compare Chemotherapy Alone Versus Chemotherapy Plus Nivolumab or Nivolumab and BMS-986205, Followed by Continued Therapy After Surgery With Nivolumab or Nivolumab and BMS-986205 in Participants With Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P3 | N=855 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Trial primary completion date: Apr 2025 ➔ Nov 2025

Trial primary completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

Rationale and feasibility of a rapid integral biomarker program that informs immune-oncology clinical trials: the ADVISE trial. (PubMed, J Immunother Cancer) - P1 | "Actualization of a patient-specific I-O combination treatment selection strategy is feasible, however, determination of de novo integral biomarker thresholds of novel I-O targets to facilitate effective treatment of PD-1-refractory cancer remains fraught. These data emphasize the difficulty of integral biomarker development for I-O in translating from immunotherapy treatment-naïve biospecimens to the selection of patients in the PD-1-refractory state."

Biomarker • IO biomarker • Journal • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • CD8 • CSF1R • FOXP3 • IDO1 • LAG3 • PD-L1 • TNFA

RELATIVITY-048: An Investigational Study of Immunotherapy Combinations in Participants With Solid Cancers That Are Advanced or Have Spread (clinicaltrials.gov) - P1/2 | N=229 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | Trial completion date: Nov 2026 ➔ Feb 2025 | Trial primary completion date: Nov 2026 ➔ Feb 2025

Trial completion • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

IDO Believe in Immunotherapy. (PubMed, Clin Cancer Res) - "A recent phase I/II study tested the IDO1 inhibitor linrodostat with nivolumab +/- ipilimumab in patients with advanced solid tumors. While efficacy was not augmented, correlative analyses identified TDO2 as a resistance mechanism; dual targeting may be necessary to realize improved response to PD-1 inhibition."

Journal • Oncology • Solid Tumor • TDO2

Nivolumab and BMS986205 in Treating Patients With Stage II-IV Squamous Cell Cancer of the Head and Neck (clinicaltrials.gov) - P2 | N=45 | Active, not recruiting | Sponsor: Thomas Jefferson University | Terminated ➔ Active, not recruiting | Trial completion date: Jun 2024 ➔ Dec 2025 | Trial primary completion date: Jun 2024 ➔ Dec 2025

Enrollment closed • Trial completion date • Trial primary completion date • Head and Neck Cancer • Laryngeal Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Nivolumab combination therapies in patients with advanced gastric and gastroesophageal junction cancer: the phase II FRACTION gastric cancer study. (PubMed, ESMO Open) - "While ORR did not meet prespecified expansion criteria in any treatment arm, the safety profile of the combinations was manageable. FRACTION-GC represents a novel adaptive protocol for testing multiple combination immunotherapies."

Journal • P2 data • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • IDO1 • LAG3

Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined with Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies (Clin Cancer Res) - P1/2a | N=627 | NCT02658890 | Sponsor: Bristol-Myers Squibb | "A total of 55, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1% to 63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune-related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naïve patients. Kynurenine decreased with linrodostat + nivolumab regardless of response."

P1/2 data • Melanoma • Non Small Cell Lung Cancer

Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined With Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies. (PubMed, Clin Cancer Res) - "Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported IDO1 pathway inhibition but did not correlate with response. A composite biomarker of low TDO2 expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab."

IO biomarker • Journal • Metastases • P1/2 data • Hematological Disorders • Hematological Malignancies • Non-melanoma Skin Cancer • Solid Tumor • IDO1 • IFNG • TDO2

Response-Adaptive Surgical Timing in neoadjuvant immunotherapy demonstrates enhanced pathologic treatment response in Head and Neck Squamous Cell Carcinoma. (PubMed, Clin Cancer Res) - P2 | "Response-adaptive surgical timing enhanced treatment response. IDO-inhibitor BMS986205 augmented pTR in patients with high IDO1-expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV-status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • IFNG • PD-L1

RELATIVITY-048: An Investigational Study of Immunotherapy Combinations in Participants With Solid Cancers That Are Advanced or Have Spread (clinicaltrials.gov) - P1/2 | N=255 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Trial primary completion date: Apr 2024 ➔ Nov 2026

Combination therapy • Metastases • Trial primary completion date • Oncology • Solid Tumor

Nivolumab, BMS-986205, and Radiation Therapy With or Without Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P1 | N=18 | Active, not recruiting | Sponsor: Northwestern University | Trial completion date: Jun 2025 ➔ Jun 2027 | Trial primary completion date: Feb 2024 ➔ Feb 2025

Checkpoint inhibition • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • MGMT

Evolution of ALIS hit to potent and selective benzimidazole series as heme-displacing IDO1 inhibitors for cancer immunotherapy (ACS-Fall 2024) - "One type is heme-binding inhibitors, such as Epacadostat, which bind to Trp binding site of the enzyme and coordinate with the heme iron. Another type is heme-displacing inhibitors, exemplified by Linrodostat (BMS-986205), where the inhibitor displaces the heme cofactor and binds to the apo-IDO1...Following systematic optimization of this modular lead, guided by property- and structure-based drug design and leveraging strategies to promote active conformational bias, a series of benzimidazole inhibitors were identified displaying exquisite potency and selectivity for IDO1 and good metabolic stability. The leading compounds from this series are predicted to require very low human dosing regimens and display minimized off-target liabilities."

IO biomarker • Oncology