BMS-986360 / BMS - LARVOL DELTA

A Study of BMS-986360/CC-90001 Alone and in Combination With Chemotherapy or Nivolumab in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=220 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • Colorectal Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

Inhibiting JNK signaling enhances the antitumor efficacy of macrophage-targeting agents in triple-negative breast cancer by inducing an immunoactive tumor microenvironment (SABCS 2024) - P1 | "Indeed, JNK inhibitor (JNKi) BMS-986360 is currently being tested alone and in combination with chemotherapy or nivolumab in advanced solid tumors (NCT05625412)...The antitumor efficacy of JNKi (BMS-986360, a reversible orally active pan-JNKi; or JNK-IN-8, a covalent pan-JNKi) combined with macrophage-targeting agents (pexidartinib or sotuletinib, both of which are orally active CSF-1R inhibitors) was assessed using immunocompetent syngeneic models of E0771 (M1 macrophage-enriched TME, sensitive to immune checkpoint inhibitors [ICI]), PyMT-M (M2-macrophage-enriched TME, partially sensitive to ICI), and 4T1.2 (neutrophil-enriched TME, resistant to ICI)... JNKi can potentiate macrophage-targeting agents in TNBC by inducing an immunoactive TME. This finding highlights the need to conduct further studies of combining JNKi with immunotherapy to capitalize on JNK's immune regulation of the TME and the potency of JNKi in synergistically improving the efficacy of..."

Biomarker • Clinical • IO biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCL2 • CD8 • MAPK8 • TGFB1

Discovery of a selective and potent inhibitor of c-Jun N-terminal kinase 1 with anti-pulmonary fibrosis effect. (PubMed, Bioorg Med Chem Lett) - "Compounds 13, 14 and 19 demonstrated significant inhibitory activity at both the enzyme and cellular level compared to the lead compound 1 and clinical candidate CC-90001. Notably, 14 exhibited strong inhibitory potency against JNK1 with sub-nanomolar efficacy and suppresses TGF-β-induced epithelial-mesenchymal transition, indicating its potential as a promising candidate for further development as an anti-pulmonary fibrosis agent targeting JNK1."

Journal • Immunology • Pulmonary Disease • Respiratory Diseases • MAPK8 • TGFB1

Structure Optimization of c-Jun N-terminal Kinase 1 Inhibitors for Treating Idiopathic Pulmonary Fibrosis. (PubMed, J Med Chem) - "The introduction of a dimethylamine side chain has significantly enhanced the ability of E1 to inhibit c-Jun phosphorylation, surpassing the clinical candidate CC-90001. Furthermore, compound E1 exerted significant antifibrotic effects in a bleomycin-induced IPF mouse model and prevented a TGF-β-induced epithelial-to-mesenchymal transition in vitro. These findings position E1 as a promising lead for further drug development targeting IPF."

Journal • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • MAPK8 • TGFB1

Developing personalized immunotherapy strategies using an ex vivo tumor fragment platform (EACR 2024) - "We cultured PDTFs from four cancer types (kidney, lung, skin, ovary) that were either left untreated or exposed to different agents including anti-PD-1 (nivolumab), anti-LAG3 (relatlimab), anti-ILT4 (BMS-986406), anti-CCR8 (BMS-986340) and/or JNK inhibitor (BMS-986360). Whereas in some tumors single or dual checkpoint blockade could enhance immune activity, most tumors required targeting of additional pathways to overcome immune resistance. Notably, individual tumors showed response to distinct treatment combinations, highlighting the need for developing personalized immunotherapy strategies.Conclusion Translational studies using patient-derived tumor models may help to identify rational immunotherapy combinations overcoming anti-PD-1 resistance and their biomarkers, and to prioritize them for clinical development."

IO biomarker • Preclinical • Oncology • CCR8

Developing personalized immunotherapy strategies using an ex vivo tumor fragment platform (EACR 2024) - "We cultured PDTFs from four cancer types (kidney, lung, skin, ovary) that were either left untreated or exposed to different agents including anti-PD-1 (nivolumab), anti-LAG3 (relatlimab), anti-ILT4 (BMS-986406), anti-CCR8 (BMS-986340) and/or JNK inhibitor (BMS-986360). Whereas in some tumors single or dual checkpoint blockade could enhance immune activity, most tumors required targeting of additional pathways to overcome immune resistance. Notably, individual tumors showed response to distinct treatment combinations, highlighting the need for developing personalized immunotherapy strategies.Conclusion Translational studies using patient-derived tumor models may help to identify rational immunotherapy combinations overcoming anti-PD-1 resistance and their biomarkers, and to prioritize them for clinical development."

IO biomarker • Preclinical • Oncology • CCR8

Phase 2, Double-Blind, Placebo-controlled Trial of a c-Jun N-Terminal Kinase Inhibitor in Idiopathic Pulmonary Fibrosis. (PubMed, Am J Respir Crit Care Med) - P2 | "Background antifibrotic treatment (pirfenidone) was allowed. CC-90001 was generally well tolerated, consistent with previous studies. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT03142191."

Journal • P2 data • Cough • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • MAPK8

Phase 2 Study Results for Agents That Target LPA1 & JNK1 in Pulmonary Fibrosis (IPF Summit 2023) - "Synopsis Comparing BMS-986278 (LPA1 antagonist) and CC-90001 (JNK1 inhibitor) programs in idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF): scientific rationale; study designs Key results from BMS-986278 and CC-90001 phase 2 trials Looking to phase 3 for the LPA1 program"

P2 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • MAPK8

Safety, Pharmacokinetics, and Antifibrotic Activity of CC-90001 (BMS-986360), a c-Jun N-Terminal Kinase Inhibitor, in Pulmonary Fibrosis. (PubMed, Clin Pharmacol Drug Dev) - P1b | "CC-90001 reduced in vitro profibrotic gene expression in both lung epithelial cells and fibroblasts, supporting a potential direct antifibrotic action of c-Jun N-terminal kinase inhibition in either or both cell types. Overall, CC-90001 was generally safe and well tolerated, and treatment was associated with forced vital capacity improvement and reductions in profibrotic biomarkers."

Journal • PK/PD data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pain • Pulmonary Disease • Respiratory Diseases • MAPK8 • TGFB1

A Study to Evaluate the Efficacy and Safety of CC-90001 in Subjects With Idiopathic Pulmonary Fibrosis (clinicaltrials.gov) - P2 | N=138 | Terminated | Sponsor: Celgene | Completed ➔ Terminated; Business objectives have changed.

Trial termination • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Interstitial Lung Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases

Synthesis-accessibility-oriented design of c-Jun N-terminal kinase 1 inhibitor. (PubMed, Eur J Med Chem) - "This strategy led to the discovery of several potent JNK1 inhibitors, such as compound C6 (IC = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC = 24.4 nM)...Our findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1. In addition, the discovery of C6 also demonstrates the feasibility of synthesis-accessibility-oriented strategy in lead discovery."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • MAPK8

A Study of BMS-986360/CC-90001 Alone and in Combination With Chemotherapy or Nivolumab in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=220 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

[VIRTUAL] Pharmacokinetics, safety, and tolerability of CC-90001, a c-Jun N-terminal kinase (JNK) inhibitor, in participants with hepatic impairment (EASL-ILC 2021) - P1 | "Mild to moderate HI had a minimal effect on CC-90001 AUC0−t compared with normal-matched ppts. Severe HI modestly increased CC-90001 AUC0−t but Cmax was unchanged. CC-90001 was generally well tolerated."

Clinical • PK/PD data • Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Non-alcoholic Steatohepatitis • Pulmonary Disease • Respiratory Diseases • MAPK8

[VIRTUAL] Pharmacokinetics, safety, and tolerability of multiple-dose CC-90001, a c-Jun N-terminal kinase (JNK) inhibitor, in healthy Japanese and non-Japanese adults (EASL-ILC 2021) - P1 | "Oral administration of 100–400 mg CC-90001 QD for 7 days was generally well-tolerated; similar PK profiles were observed in JPN and non-JPN ppts after single and multiple doses. Phase 2 studies in patients with NASH and advanced fibrosis and idiopathic pulmonary fibrosis are ongoing."

Clinical • PK/PD data • Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Musculoskeletal Pain • Non-alcoholic Steatohepatitis • Pain • Pulmonary Disease • Respiratory Diseases • MAPK8

A Study of BMS-986360/CC-90001 Alone and in Combination With Chemotherapy or Nivolumab in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=220 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

Combination therapy • New P1 trial • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

Safety, Pharmacokinetics, and Pharmacodynamics of CC-90001 (BMS-986360), a c-Jun N-terminal Kinase Inhibitor, in Phase 1 Studies in Healthy Participants. (PubMed, Clin Pharmacol Drug Dev) - "Overall, single- and multiple-dose CC-90001 were generally safe and well tolerated at the tested doses and demonstrated JNK pathway engagement. These results support further clinical evaluation of CC-90001."

Journal • P1 data • PK/PD data • Fibrosis • Immunology • Pain • MAPK8

A Study to Evaluate the Efficacy and Safety of CC-90001 in Subjects With Idiopathic Pulmonary Fibrosis (clinicaltrials.gov) - P2 | N=138 | Completed | Sponsor: Celgene | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Interstitial Lung Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases

CC-90001, a c-Jun N-terminal kinase (JNK) inhibitor, in patients with pulmonary fibrosis: design of a phase 2, randomised, placebo-controlled trial. (PubMed, BMJ Open Respir Res) - P2 | "Patients with IPF (n=165) will be randomised 1:1:1 to receive 200 mg or 400 mg CC-90001 or placebo administered PO one time per day; up to 25 patients/arm will be permitted concomitant pirfenidone use. Results will be reported in a peer-reviewed publication. NCT03142191."

Journal • P2 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • MAPK8

Molecular pathways and role of epigenetics in the idiopathic pulmonary fibrosis. (PubMed, Life Sci) - "Drug like nintedanib acts through vascular endothelial growth factor receptors (VEGFR), while drug pirfenidone acts through transforming growth factor (TGF), which is useful in IPF. Gefitinib, a tyrosine kinase inhibitor of EGFR, is useful as an anti-fibrosis agent in preclinical models. Newer drugs such as Celgene-CC90001 and Fibrogen FG-3019 are currently under investigations acts through the modulating epigenetic mechanisms...This study provides an elementary analysis of multiple regulators of epigenetics and their roles associated with the pathology of IPF. Further, this review also includes epigenetic drugs under development in preclinical and clinical stages."

Journal • Review • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • EGFR • TERT

Assessment of Drug-Drug Interactions of CC-90001, a Potent and Selective Inhibitor of c-Jun N-terminal Kinase. (PubMed, Xenobiotica) - "A clinical study demonstrated that CC-90001 has no or little impact on the exposure of warfarin (CYP2C9), omeprazole (CYP2C19), midazolam (CYP3A) or metformin (OCT2, MATE1/2k). CC-90001 co-administration increases the AUC and C 176% and 339% for rosuvastatin (BCRP/OATP1B1/3), 116% and 171% for digoxin (P-gp), and 266% and 321% for nintedanib (CYP3A & P-gp), respectively.6. In conclusion, CC-90001 in unlikely to be a victim or perpetrator of clinically relevant interactions involving CYPs or UGTs. Weak to moderate interactions are expected in clinic with substrates of P-gp and OATP1B1 due to CC-90001 inhibition of these transporters."

Journal • CYP1A2 • CYP2C19 • CYP2C8 • CYP2C9 • CYP3A4 • MAPK8 • UGT1A1 • UGT1A9

Discovery of the c-Jun N-Terminal Kinase Inhibitor CC-90001. (PubMed, J Med Chem) - P2 | "As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191)."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • MAPK8 • MAPK9

Study to Evaluate the Efficacy and Safety of CC-90001 in Participants With Non-alcoholic Steatohepatitis (NASH) and Liver Fibrosis (clinicaltrials.gov) - P2; N=56; Terminated; Sponsor: Celgene; Active, not recruiting ➔ Terminated; Business objectives have changed

Clinical • Trial termination • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

A Study to Evaluate the Efficacy and Safety of CC-90001 in Subjects With Idiopathic Pulmonary Fibrosis (clinicaltrials.gov) - P2; N=138; Active, not recruiting; Sponsor: Celgene; Trial completion date: Feb 2024 ➔ Dec 2021; Trial primary completion date: Sep 2022 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Interstitial Lung Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases

Study to Evaluate the Efficacy and Safety of CC-90001 in Participants With Non-alcoholic Steatohepatitis (NASH) and Liver Fibrosis (clinicaltrials.gov) - P2; N=56; Active, not recruiting; Sponsor: Celgene; Recruiting ➔ Active, not recruiting; N=195 ➔ 56; Trial completion date: Oct 2024 ➔ Oct 2021; Trial primary completion date: Jun 2023 ➔ Oct 2021

Clinical • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

"Live at #ACSFall2021 synthesis of selective JNK inhibitor CC-90001 presented. Currently in phase II studies for IPF" (@ClarivateHealth)

P2 data