BMS-986235 / BMS, Kyorin - LARVOL DELTA

Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis. (PubMed, EMBO Mol Med) - "This cellular response lies downstream of FPR1-mediated potentiation of CCL2-dependent monocyte chemotaxis and activation. This finding supports the therapeutic development of selective FPR2 agonists to mitigate two impactful comorbidities associated with inflammatory arthritides."

Journal • Cardiovascular • Immunology • Inflammatory Arthritis • Pulmonary Disease • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • CCL2 • FPR2

Pro-resolving lipid mediators and therapeutic innovations in resolution of inflammation. (PubMed, Pharmacol Ther) - "In addition to SPMs, we highlight the discovery, biosynthesis, biofunctions, and latest research updates on innovative therapeutics (including annexin-A1 peptide-mimetic RTP-026, small molecule FPR2 agonist BM-986235/LAR-1219, biased agonist for FPR1/FPR2 Cmpd17b, lipoxin mimetics AT-01-KG and AT-02-CT, melanocortin receptor agonist AP1189, gold nanoparticles, angiotensin-(1-7), and CD300a) that can promote resolution of inflammation directly or through modulation of SPMs production. Drug development strategies based on the biology of the resolution of inflammation can offer novel therapeutic means and/or add-on therapies for the treatment of chronic diseases."

Journal • Review • Allergy • Cardiovascular • Immunology • Infectious Disease • Inflammation • Rheumatology • ANXA1

Biased receptor signalling and intracellular trafficking profiles of structurally distinct formylpeptide receptor 2 agonists. (PubMed, Br J Pharmacol) - "In vitro characterisation demonstrated that WKYMVm and ACT-389949 differ from BMS-986235 and compound 43 in their signalling and protein coupling profile. This observation may be explained by differences in the ligand-receptor interactions. In vitro characterisation provided significant insights into identifying the desired bias profile for FPR2-based pharmacotherapy."

Journal • Inflammation

Unleashing the power of formyl peptide receptor 2 in cardiovascular disease. (PubMed, Cytokine) - "Several endogenous (AnxA1, LXA) and synthetic compounds (compound 43, BMS-986235) reduced infarct size and promoted the resolution of inflammation via the activation of FPR2 on cardiac macrophages. Further studies should evaluate FPR2 role in other cardiovascular disorders."

Journal • Cardiovascular • Heart Failure • Immune Modulation • Inflammation • Myocardial Infarction • ANXA1 • FPR2 • FPR3

Comparisons of gene expression between peripheral blood mononuclear cells and bone tissue in osteoporosis. (PubMed, Medicine (Baltimore)) - "This study enhanced our understanding of the pathogenesis of OP. PI3K1, GNB5, FPR2, GNG13, and PLCG1 might be the potential targets of OP."

Journal • Osteoporosis • Rheumatology • CREB1 • CREBBP • FPR2 • GLI1 • RUNX1 • STAT3

Eosinophils Protect Against Pulmonary Hypertension through 14-HDHA and 17-HDHA. (PubMed, Eur Respir J) - "In PH development without external inflammatory stimulus, peripheral blood exhibits a low EOS level, in which EOS play a protective role through suppressing perivascular inflammation and maintaining PASMC homeostasis via 14/17-HDHA."

Journal • Cardiovascular • Hypertension • Immunology • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ALOX15 • CCL11 • FPR2 • GATA1 • IL5 • PDGFB

Molecular Mechanisms of Desensitization Underlying the Differential Effects of Formyl Peptide Receptor 2 Agonists on Cardiac Structure-Function Post Myocardial Infarction. (PubMed, ACS Pharmacol Transl Sci) - "By contrast, with long-term dosing, only BMS-986235 preserved the infarct wall thickness and increased left ventricular ejection fraction in a rat model of myocardial infarction. Altogether, the study shows that differences in the desensitization profiles induced by ACT-389949 and BMS-986235 at the molecular level may explain their distinct inflammatory/pro-resolving activities in vivo."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction

"Nick Wurtz @bmsnews will now describe discovery of a clinical candidate FPR2 agonist. #GPCRs22" (@RSC_BMCS)

Clinical

A Study of Experimental Medication BMS-986235 in Healthy Subjects (clinicaltrials.gov) - P1 | N=122 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | Trial completion date: Apr 2021 ➔ Jul 2021 | Trial primary completion date: Apr 2021 ➔ Jul 2021

Trial completion • Trial completion date • Trial primary completion date • Immunology • Inflammation

Study to Evaluate the Effect of Rifampin on the Drug Levels in Blood and Safety of BMS-986235 in Healthy Participants (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Bristol-Myers Squibb | N=16 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal

A Study to Evaluate the Effect of Fluconazole, Bupropion, or Itraconazole on the Drug Levels and Safety of BMS-986235 (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Bristol-Myers Squibb | N=42 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal

Formyl peptide receptor 2 and heart disease. (PubMed, Semin Immunol) - "We summarize key preclinical studies that support use of FPR2 agonists in heart disease. Finally, we briefly discuss the status of FPR2 agonists under evaluation in the clinic."

Journal • Review • Cardiovascular • Congestive Heart Failure • Heart Failure • Immunology • Inflammation • Myocardial Infarction

Selective FPR2 Agonism Promotes a Proresolution Macrophage Phenotype and Improves Cardiac Structure-Function Post Myocardial Infarction. (PubMed, JACC Basic Transl Sci) - "In rats following MI, BMS-986235 preserved viable myocardium, attenuated left ventricular remodeling, and increased ejection fraction relative to control animals. Therefore, FPR2 agonism improves post-MI healing, limits remodeling and preserves function, and may offer an innovative therapeutic option to improve outcomes."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Immunology • Inflammation • Myocardial Infarction • Oncology • Reperfusion Injury • CCL2 • IL10 • MRC1

The effect of the WKYMVm peptide on promoting mBMSC secretion of exosomes to induce M2 macrophage polarization through the FPR2 pathway. (PubMed, J Orthop Surg Res) - "Our findings demonstrated the potential value of the WKYMVm peptide in promoting the secretion of exosomes by mBMSCs and eventually leading to M2 macrophage polarization. We believe that our study could provide a research basis for the clinical treatment of bone defects."

Journal • PCR

Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure. (PubMed, J Med Chem) - "In cellular assays 13c inhibited neutrophil chemotaxis, and stimulated macrophage phagocytosis, as well as increased cytokine IL-10 in human blood assays. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Immunology • IL10

"Nice to see Kyorin's FPR2 agonist (licensed to @bmsnews) revealed at the San Diego (home to Kyorin's subsidiary @KiNativPlatform) ACS meeting!" (@jsrosenblum)