BMS-986299 / BMS - LARVOL DELTA

Correction: Phase I study of BMS-986299, an NLRP3 agonist, as monotherapy and in combination with nivolumab and ipilimumab in patients with advanced solid tumors. (PubMed, J Immunother Cancer) - No abstract available

Journal • Monotherapy • P1 data • Oncology • Solid Tumor • NLRP3

Neutrophil extracellular traps-induced pyroptosis of liver sinusoidal endothelial cells exacerbates intrahepatic coagulation in cholestatic mice (APASL 2025) - "However, NLRP3 inhibition (MCC950) or activation (BMS-986299) did not alter NETs release... NETs-induced LSECs pyroptosis exacerbates intrahepatic coagulation in cholestasis. Targeting NETs and LSECs pyroptosis holds promise for treating chronic liver injury in CLD. Table and Figure:Figure 1."

Preclinical • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • IL1B • NLRP3

CPCGI Alleviates Neural Damage by Modulating Microglial Pyroptosis After Traumatic Brain Injury. (PubMed, CNS Neurosci Ther) - "These findings suggest that CPCGI provides neuroprotection in TBI by targeting NLRP3 inflammasome-mediated microglial pyroptosis, thereby improving the neuroinflammatory microenvironment and promoting neurological recovery. This underscores its potential as a promising candidate for TBI treatment."

Journal • CNS Disorders • Inflammation • Vascular Neurology • NLRP3

Transcranial pulsed current stimulation alleviates neuronal pyroptosis and neurological dysfunction following traumatic brain injury via the orexin-A/NLRP3 pathway. (PubMed, Neuropeptides) - "However, this effect could be reversed by the NLRP3 agonist BMS-986299. Our findings suggest that tPCS promotes the release of OX-A and modulates the OX1R/NLRP3 pathway to mitigate the inflammatory response following TBI, thereby exerting neuroprotective effects."

Journal • CNS Disorders • Cognitive Disorders • Inflammation • Vascular Neurology • NLRP3

Phase I study of BMS-986299, an NLRP3 agonist, as monotherapy and in combination with nivolumab and ipilimumab in patients with advanced solid tumors. (PubMed, J Immunother Cancer) - P1 | "BMS-986299 in combination with immune checkpoint inhibitors demonstrated manageable toxicities, good tolerability, and promising antitumor activity in certain cancer types."

Journal • Monotherapy • P1 data • Breast Cancer • Gastroenterology • Gastrointestinal Disorder • Hepatology • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immunology • Nephrology • Non-melanoma Skin Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • Triple Negative Breast Cancer • CD4 • HER-2 • IL1B • IL6 • NLRP3

Neutrophil extracellular traps-induced pyroptosis of liver sinusoidal endothelial cells exacerbates intrahepatic coagulation in cholestatic mice. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "NETs-induced LSECs pyroptosis exacerbates intrahepatic coagulation in cholestasis. Targeting NETs and LSECs pyroptosis holds promise for treating chronic liver injury in CLD."

Journal • Preclinical • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • IL1B • NLRP3

Phase I study of BMS-986299, an NLRP3 agonist, as monotherapy and in combination with nivolumab and ipilimumab in patients with advanced solid tumors (J Immunother Cancer) - P1 | N=82 | NCT03444753 | Sponsor: Bristol-Myers Squibb | "36 patients were enrolled, with breast (31%), colorectal (17%), and head and neck (14%) being the more commonly enrolled cancers....Intratumoral BMS-986299 monotherapy resulted in dose-dependent increases in systemic exposure with increase in tumor CTLs (67%), CD4+ TILs (63%), along with notable above twofold increases in serum IL-1B, G-CSF and IL-6 at doses above 2000 µg. Systemic BMS-986299 exposure was positively associated with systemic cytokine elevation for G-CSF and IL-6. No antitumor activity was noted in BMS-986299 monotherapy cohort. However, in the combination therapy cohort (BMS-986299+nivolumab+ipilimumab), overall objective response rate was 10%, with confirmed PRs observed in TNBC, hormone receptor-positive, human epidermal growth factor receptor 2 negative breast cancer, and cutaneous squamous cell carcinoma."

P1 data • Colorectal Cancer • Head and Neck Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Squamous Cell Skin Cancer • Triple Negative Breast Cancer

TAOK1-mediated regulation of the YAP/TEAD pathway as a potential therapeutic target in heart failure. (PubMed, PLoS One) - "TAOK1 played a crucial role in regulating IL-17-mediated increase in the pyroptosis and decrease in the proliferation of cardiomyocytes by regulating the activities of the NLRP3 inflammasomes and the YAP/TEAD pathway."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • IL17A • NLRP3

Aminoquinoline synthesis and process development enabled by non-aqueous Suzuki-Miyaura cross-coupling reaction (ACS-Fall 2024) - "This talk will present the strategic bond disconnections of BMS-986299, an aminoquinoline NLRP3 Agonist. The process development of the key convergent sequence of steps will be described featuring a Miyaura borylation followed by a non-aqueous Suzuki-Miyaura cross-coupling and an acid-mediated concurrent cyclization and THP deprotection in a streamlined telescoped process. The aminoquinoline is isolated in high purity from a kinetic analysis driven reactive crystallization."

NLRP3

Structural Insight into the Binding Pattern and Interaction Mechanism of Antagonist MCC950 and Agonist BMS986299 with NLRP3 by Molecular Dynamics Simulation. (PubMed, Curr Comput Aided Drug Des) - "The antagonist may interact with residues mainly in the NBD, HD1, WHD, and HD2 domains, and the agonist may interact in the NBD and WHD domains. Our study provided new insights into the development of NLRP3 regulators."

Journal • Inflammation • Oncology • NLRP3

Overcome the challenge for intratumoral injection of STING agonist for pancreatic cancer by systemic administration (AACR 2024) - "Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment.Design: Using a transplant murine model with spontaneously formed liver metastasis and also the genetically engineered KPC mouse model that spontaneously develops PDAC, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. For the first time, our study supports the clinical development of innate agonists via systemic administration, instead of local administration, for treating PDAC."

IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • NLRP3

The protective effects of ruscogenin against lipopolysaccharide-induced myocardial injury in septic mice. (PubMed, J Cardiovasc Pharmacol) - "Furthermore, the cardioprotective effects of RUS on HL-1 cells under LPS stimulation were abolished by the novel NLRP3 agonist BMS-986299. Taken together, our results suggest that RUS can alleviate myocardial injury during sepsis, at least in part by suppressing NLRP3-mediated inflammation and pyroptosis, highlighting the potential of this molecule as a promising candidate for SIMD therapy."

Journal • Preclinical • Infectious Disease • Inflammation • Septic Shock • NLRP3

TRIM6 Promotes ROS-Mediated Inflammasome Activation and Pyroptosis in Renal Tubular Epithelial Cells via Ubiquitination and Degradation of GPX3 Protein. (PubMed, Front Biosci (Landmark Ed)) - "TRIM6 increases oxidative stress and promotes the pyroptosis of HK2 cells by regulating GPX3 ubiquitination. These findings could contribute to the development of novel drugs for the treatment of RF."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Oncology • Renal Disease • Targeted Protein Degradation • CASP1 • GPX3 • IL18 • IL1B • IL6 • NLRP3 • TNFA • TRIM6

First in human phase Ⅰ study of BMS-986299 as monotherapy and combined with nivolumab and ipilimumab in advanced solid tumors. (ASCO 2023) - P1 | "BMS-986299 in combination with ICI resulted in modest clinical activity in select tumor types and carried a manageable toxicity profile. However, definitive conclusions could not be drawn as the study was not powered for inference testing. Further exploration is warranted to define the role of this novel agent in the ICI refractory population."

Metastases • Monotherapy • P1 data • Breast Cancer • Gastroenterology • Gastrointestinal Disorder • Hepatology • Hormone Receptor Positive Breast Cancer • Immune Modulation • Immunology • Infectious Disease • Melanoma • Metabolic Disorders • Nephrology • Non-melanoma Skin Cancer • Novel Coronavirus Disease • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • Triple Negative Breast Cancer • CTLA4 • NLRP3

Coupling-Condensation Strategy for the Convergent Synthesis of an Imidazole-Fused 2-Aminoquinoline NLRP3 Agonist. (PubMed, J Org Chem) - "The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported...Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis."

Journal • NLRP3

An Investigational Immunotherapy Study of BMS-986299 Alone and in Combination With Nivolumab and Ipilimumab in Participants With Solid Cancers That Have Spread or Cannot be Removed (clinicaltrials.gov) - P1 | N=82 | Terminated | Sponsor: Bristol-Myers Squibb | N=127 ➔ 82 | Trial completion date: Oct 2023 ➔ Feb 2022 | Recruiting ➔ Terminated | Trial primary completion date: Oct 2022 ➔ Feb 2022; business objectives have changed

Combination therapy • Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Oncology • Solid Tumor

An Investigational Immunotherapy Study of BMS-986299 Alone and in Combination With Nivolumab and Ipilimumab in Participants With Solid Cancers That Have Spread or Cannot be Removed (clinicaltrials.gov) - P1; N=127; Recruiting; Sponsor: Bristol-Myers Squibb; Trial completion date: Dec 2021 ➔ Oct 2023; Trial primary completion date: Nov 2021 ➔ Oct 2022

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

Phase 0 Master Protocol for CIVO Intratumoral Microdosing of Anti-Cancer Therapies (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Presage Biosciences; Not yet recruiting ➔ Recruiting; N=12 ➔ 36; Initiation date: Feb 2021 ➔ Jun 2021

Clinical • Enrollment change • Enrollment open • Trial initiation date • Oncology • Solid Tumor • CASP3 • CD163 • CD4 • CD68 • CD8 • CD86 • GZMB • NCAM1 • TNFA

"When BMS-986299 injected into mouse with tumors, saw high antitumor activity, led to localized increase of IL-1β #ACSSpring2021" (@cenmag)

Preclinical • Oncology

"Complete responses with addition of BMS-986299 and anti-PD1, goes up to 73% cures #ACSSpring2021" (@cenmag)

Clinical

[VIRTUAL] Discovery and preclinical characterization of BMS-986299, a first-in-class NLRP3 agonist with potent antitumor activity in combination with checkpoint blockade (ACS-Sp 2021) - "In vivo studies demonstrated that BMS-986299 enhanced the antitumor activity of CPIs and induced durable immunological memory in solid tumor models. BMS-986299 is currently in Phase I clinical trials for the treatment of cancer."

Checkpoint inhibition • Combination therapy • Preclinical • Immunology • Inflammation • Oncology • Solid Tumor • IL18 • IL1B

Phase 0 Master Protocol for CIVO Intratumoral Microdosing of Anti-Cancer Therapies (clinicaltrials.gov) - P1; N=12; Not yet recruiting; Sponsor: Presage Biosciences

Clinical • New P1 trial • Oncology • Solid Tumor

Phase 0 Master Protocol for CIVO Intratumoral Microdosing of Anti-Cancer Therapies (clinicaltrials.gov) - P1; N=12; Not yet recruiting; Sponsor: Presage Biosciences; Trial completion date: Dec 2030 ➔ Dec 2031; Initiation date: Nov 2020 ➔ Feb 2021; Trial primary completion date: Dec 2030 ➔ Dec 2031

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

An Investigational Immunotherapy Study of BMS-986299 Alone and in Combination With Nivolumab and Ipilimumab in Participants With Solid Cancers That Have Spread or Cannot be Removed (clinicaltrials.gov) - P1; N=117; Recruiting; Sponsor: Bristol-Myers Squibb; N=90 ➔ 117

Combination therapy • Enrollment change • Monotherapy