BMS-986020 / Duke TMI, BMS - LARVOL DELTA

Design, Synthesis and Discovery of a second-generation PET Ligand for Lysophosphatidic Acid Receptor 1 (LPA1) to Measure Target Engagement of LPA1 Antagonists in Lung Tissues (SNMMI 2025) - "Ligand candidates were successfully synthesized with either C-11 or F-18, with high radiochemical purity (>95%), molar activities above 37 MBq/nmol, higher free fractions (> 10% free in rodent plasma) and demonstrated high LPA1 affinity. From these studies, [18F]BMS-986327 demonstrated the highest signal to noise within the bleomycin treated rodent model (a 58% increase compared to WT). Target engagement PET studies showed a clear correlation between radioligand signal in the lung of bleomycin treated rats and the plasma concentration of an administered LPA1 antagonist (either BMS-986278 and BMS-986020)."

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

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice. (PubMed, EBioMedicine) - "These findings indicate that TYK2i has beneficial effects on both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2is in human T1D."

Journal • Preclinical • Diabetes • Immunology • Inflammation • Metabolic Disorders • Type 1 Diabetes Mellitus • IFNA1 • IL23A • TYK2

Autotaxin/lysophosphatidic acid axis through Rho/ROCK signal-induced lung fibroblasts-mediated fibrotic mechanisms (APSR 2024) - "The ATX/LPA axis represents a key therapeutic target for inhibiting the Rho/ROCK signaling-induced lung fibrosis in lung fibroblasts."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • FN1 • RHOA • TGFB1

Lysophosphatidic Acid Receptor 1 Plays a Pathogenic Role in Permanent Brain Ischemic Stroke by Modulating Neuroinflammatory Responses. (PubMed, Biomol Ther (Seoul)) - "A selective LPA1 antagonist (AM152) was used as a pharmacological tool for this investigation...As underlying effector pathways, NF-κB, MAPKs (ERK1/2, p38, and JNKs), and PI3K/Akt were found to be involved in LPA1-dependent pathogenesis. Collectively, these results demonstrate that LPA1 can contribute to brain injury by permanent ischemic stroke, along with relevant pathogenic events in an injured brain."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Vascular Neurology

In vitro pharmacological characterization of standard and new lysophosphatidic acid receptor antagonists using dynamic mass redistribution assay. (PubMed, Front Pharmacol) - "KI 16425, RO 6842262, and BMS-986020 behaved as LPA inverse agonists in DMR experiments and as LPA antagonists in calcium mobilization assays...Compared to the classical calcium mobilization assay, DMR offers some advantages, in particular allowing the identification of inverse agonists. Finally, in the frame of this study, a new LPA inverse agonist has been identified."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Fibrosis • Metabolic Disorders • Neuralgia • Oncology • Pain • Type 2 Diabetes Mellitus

Preclinical Ex Vivo and In Vivo Evidence Supporting Selective Inhibition of Tyrosine Kinase 2-Dependent, IL-12-Mediated Signaling as a Novel Pharmacological Strategy for Alopecia Areata Management (ISDS 2023) - "When AA lesions were induced in scalp skin biopsies from healthy donors grafted onto severe combined immunodeficient/beige mice by injecting IL-2 preactivated, autologous peripheral blood mononuclear cells enriched in CD56+NKG2D+ cells, BMS-986202 treatment significantly increased hair regrowth and the number of anagen HFs, decreased hair matrix keratinocyte apoptosis and HF dystrophy, restored IP, and reduced infiltration of major histocompatibility complex class II+, and CD3+ and CD8+ T cells in AA-affected HFs. Ex vivo and in vivo data support TYK2 inhibition as a novel, pharmacologic strategy for managing AA that deserves clinical investigation."

Preclinical • Alopecia • Immunology • Inflammation • CD8 • HLA-DRB1 • IFNG • IL12A • IL18 • IL2 • NCAM1 • NKG2D • TYK2

External Control Arms in Idiopathic Pulmonary Fibrosis Using Clinical Trial and Real World Data Sources. (PubMed, Am J Respir Crit Care Med) - "IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, while ECs from real-world data sources, including registry or EHR data, do not. RCT-ECs may serve as a potentially useful supplement to future IPF RCTs."

Clinical • Journal • Real-world • Real-world evidence • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases

Recent progress on tyrosine kinase 2 JH2 inhibitors. (PubMed, Int Immunopharmacol) - "Interest in TYK2 JH2 inhibitors has increased as a result of safety concerns with JAK inhibitors. This overview introduces TYK2 JH2 inhibitors that are already on the market, including Deucravactinib (BMS-986165), as well as those currently in clinical trials, such as BMS-986202, NDI-034858, and ESK-001."

Journal • Review • Immunology • IFNA1 • IL12A • TYK2

Structure Based Discovery and Anti-fibrotic Activity of Novel Antagonists of Lysophosphatidic Acid Receptor 1 (LPAR1) (ATS 2023) - "The 1st generation LPAR1 antagonist, BMS-986020, demonstrated a significant reduction in forced vital capacity (FVC) decline in a 6-month phase II trial in IPF patients but was terminated due to compound-specific hepatobiliary toxicity...Lead compounds were evaluated for LPAR1 antagonist activity in a mouse model of LPA-mediated histamine release, anti-fibrotic efficacy in a mouse model of bleomycin induced lung fibrosis, and toxicity in preclinical species. Structure-based drug design and Schrödinger FEP modeling dramatically shortened compound synthesis and testing cycles resulting in the identification of multiple novel LPAR1 antagonist chemical series with nanomolar potency in LPAR1 Ca2+ flux assay...Two lead compounds LTSE A and B showed potent in vitro activity with nanomolar IC50 in Ca2+ flux assay and fibroblast migration inhibition... Novel oral LPAR1 antagonists were discovered through structure-based drug design. The advanced leads with superior potency..."

Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases • ABCC3

Predicting the preclinical efficacy of anti-fibrosis agents using a force-sensing fibrosis on chip system. (PubMed, Biosens Bioelectron) - "Two anti-fibrosis drug candidates that are currently under clinical trials (KD025 and BMS-986020) were tested for their potential anti-fibrosis efficacy and the results were compared to those of FDA-approved anti-fibrosis drugs pirfenidone and nintedanib. Both pre-approval drugs were effective in inhibiting transforming growth factor beta 1 (TGF-β1) induced increases in tissue contractile force, stiffness and expressions of fibrotic biomarkers, which are similar to the effects of FDA-approved anti-fibrosis drugs. These results demonstrated the potential utility of the force-sensing fibrosis on chip system in the pre-clinical development of anti-fibrosis drugs."

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

Tyrosine Kinase 2 Inhibition Ameliorates the Phenotype of Lesional Alopecia Areata Scalp Skin Ex Vivo, and Reverses the Induction of Human Alopecia Areata in a Humanized Mouse Model (ESDR 2022) - "We have previously shown that treatment with IL-12 and IL-18 induces IFNγ-dependent, immune privilege collapse of the hair bulb, which can be inhibited by blocking IL-12 receptor signaling with the TYK2 inhibitor, BMS-986202 (BMS), in human microdissected HFs. In the humanized mouse model, treatment with BMS or tofacitinib significantly increased hair shaft numbers and microscopically detected anagen I-VI HFs, reduced HM keratinocyte apoptosis and HF dystrophy, decreased MHC class I and II expression, and diminished numbers of MHC class II+ cells and infiltrating CD3+ T cells. Taken together, our results suggest TYK2 inhibition is a novel, pharmacological strategy for AA management, deserving clinical exploration."

Preclinical • Alopecia • Inflammation • IFNG • IL12A • IL18 • TYK2

LPA antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis. (PubMed, Respir Res) - P2 | "BMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA dependent and inhibited by BMS-986020. Together these data elucidate a novel antifibrotic mechanism of action for pharmacological LPA blockade. Trial registration ClinicalTrials.gov identifier: NCT01766817; First posted: January 11, 2013; https://clinicaltrials.gov/ct2/show/NCT01766817 ."

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

Mechanism of hepatobiliary toxicity of the LPA antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278. (PubMed, Toxicol Appl Pharmacol) - "The data indicate that this toxicity was unrelated to LPA antagonism since the mechanisms that likely influenced the adverse clinical outcome of BMS-986020 were not observed with equipotent LPA antagonists BMS-986234 and BMS-986278. This conclusion is consistent with the lack of hepatobiliary toxicity in nonclinical and clinical safety studies with BMS-986278."

Journal • Fibrosis • Gastroenterology • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • ABCC3

Structure dependence and species sensitivity of in vivo hepatobiliary toxicity with lysophosphatidic acid receptor 1 (LPA) antagonists. (PubMed, Toxicol Appl Pharmacol) - "BMS-986020, BMS-986234 and BMS-986278, are three lysophosphatidic acid receptor 1 (LPA) antagonists that were or are being investigated for treatment of idiopathic pulmonary fibrosis (IPF). Mixed effects on plasma bile acids in both rat and monkey has made this biomarker not a useful predictor of the hepatobiliary toxicity. In conclusion, the nonclinical data indicate the hepatobiliary toxicity observed clinically and in monkeys administered BMS-986020 is compound specific and not mediated via antagonism of LPA."

Journal • Preclinical • Cholestasis • Developmental Disorders • Fibrosis • Gastroenterology • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases. (PubMed, J Med Chem) - P2 | "The structure-activity relationship (SAR) studies starting from the LPA antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681)."

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

The development of modulators for lysophosphatidic acid receptors: A comprehensive review. (PubMed, Bioorg Chem) - "While no drugs targeting LPARs have been approved by the FDA thus far, at least three antagonists have entered phase Ⅱ clinical trials for idiopathic pulmonary fibrosis (BMS-986020 and BMS-986278) and systemic sclerosis (SAR100842), and one radioligand (BMT-136088/F-BMS-986327) has entered phase Ⅰ clinical trials for positron emission tomography (PET) imaging of idiopathic pulmonary fibrosis. This article provides an extensive review on the current status of ligand development targeting LPA receptors to modulate LPA signaling and their therapeutic potential in various diseases."

Journal • Review • Cardiovascular • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Neuralgia • Oncology • Pain • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis

[VIRTUAL] Selective inhibition of tyrosine kinase 2 prevents and restores interleukin-12- induced hair follicle immune privilege collapse: a novel approach to alopecia areata therapy? (ESDR 2021) - "Given the critical role of interleukin (IL)-12 in priming Th1 responses, we investigated whether IL-12 could be directly involved in inducing HF-IP collapse and whether the selective tyrosine kinase 2 (TYK2) inhibitor, BMS-986202, could prevent or reverse the process. By quantitative immunohistomorphometry, we showed that ex vivo treatment of microdissected HFs with IL-12 (3 ng/mL) + IL-18 (20 ng/mL) upregulated MHC-I and II as well as MICA/B expression in the hair bulb (cardinal features of IP collapse), increased the numbers of CD3+ or CD56+ cells in HF epithelium and mesenchyme, and selectively enriched IFNginducible genes...Therefore, our data demonstrate that local IL-12 directly promotes perifollicular immune cell expansion, IFNg secretion, and HF-IP collapse. These findings support a potential role of IL12 signaling in AA pathogenesis and highlight IL-12 as a potential new target for pharmacologic AA therapy"

Alopecia • Inflammation • IFNG • IL12A • IL18 • NCAM1 • TYK2

The value of imaging and clinical outcomes in a phase II clinical trial of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis. (PubMed, Ther Adv Respir Dis) - "This study assessed quantitative scores from high-resolution computed tomography (HRCT) developed by machine learning as a secondary efficacy endpoint in a 26-week phase II study of BMS-986020 - an LPA receptor antagonist - in patients with IPF...Significant correlations were found between changes in QLF and changes in percent predicted FVC, diffusing capacity for carbon monoxide (DLCO), and shortness of breath at week 26 (ρ = -0.41, ρ = -0.22, and ρ = 0.27, respectively; all p < 0.01). This study demonstrated the utility of quantitative HRCT as an efficacy endpoint for IPF in a double-blind, placebo-controlled clinical trial setting.The reviews of this paper are available via the supplemental material section."

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

Lysophosphatidic acid mediated PI3K/AKT activation contributed to esophageal squamous cell cancer progression. (PubMed, Carcinogenesis) - "Treatment of KYSE30 cell xenografts with Lpar1 inhibitor BMS-986020 significantly repressed tumor growth. Our results shed light on the important role of LPA in ESCC, and Lpar1 might be a potential treatment target for ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2. (PubMed, J Med Chem) - "A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented."

Clinical • Journal • Dermatology • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Arthritis • Lupus • Psoriasis • TYK2

BMS-986020, a Specific LPA Antagonist, Provides Neuroprotection against Ischemic Stroke in Mice. (PubMed, Antioxidants (Basel)) - "A single administration of BMS provided similar long-term neuroprotection except survival rate. Collectively, BMS provided neuroprotection against both acute and sub-acute injuries of ischemic stroke, indicating that BMS might be an appealing therapeutic agent to treat ischemic stroke."

Journal • Cardiovascular • CNS Disorders • Dermatology • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Ischemic stroke • Psoriasis • Respiratory Diseases • Vascular Neurology

[VIRTUAL] Discovery of LPA receptor antagonist clinical candidate BMS-986278 for the treatment of idiopathic pulmonary fibrosis: Preclinical pharmacological in vitro and in vivo evaluation (ACS-Fall 2020) - "BMS-986278 exhibits: 1) potent in vitro activity (including in lung fibroblasts); 2) inhibition of acute LPA-stimulated histamine release in mice in vivo; and 3) antifibrotic activity, as demonstrated by histopathological analysis (e.g. decreases in picrosirius red staining area) of lung tissue in chronic studies in the rodent bleomycin lung fibrosis model. In contrast to BMS-986020, BMS-986278 has negligible activity at bile acid and other clinically relevant drug transporters such as BSEP and MDR3 (IC50 >100 µM). BMS-986278 is thus a novel, promising LPA1 receptor antagonist for the treatment of IPF and other fibrotic diseases."

Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases

[VIRTUAL] Discovery of BMS-986202, a clinical Tyk2 JH2 inhibitor for the treatment of autoimmune and inflammatory diseases (ACS-Fall 2020) - "We have previously reported that targeting the Tyk2 pseudokinase domain (JH2) is an innovative and effective approach to selectively mediating the Tyk2-dependent signaling cascade, leading to a compound currently in phase III clinical development for the treatment of psoriasis. We now report the discovery and pre-clinical studies of the clinical backup Tyk2 JH2 inhibitor BMS-986202."

Clinical • Dermatology • Dermatopathology • Immune Modulation • Immunology • Inflammation • Psoriasis • IL12A • TYK2

[VIRTUAL] Discovery of LPA receptor antagonist clinical candidate BMS-986278 for the treatment of idiopathic pulmonary fibrosis: Preclinical pharmacological in vitro and in vivo evaluation (ACS-Fall 2020) - "BMS-986278 exhibits: 1) potent in vitro activity (including in lung fibroblasts); 2) inhibition of acute LPA-stimulated histamine release in mice in vivo; and 3) antifibrotic activity, as demonstrated by histopathological analysis (e.g. decreases in picrosirius red staining area) of lung tissue in chronic studies in the rodent bleomycin lung fibrosis model. In contrast to BMS-986020, BMS-986278 has negligible activity at bile acid and other clinically relevant drug transporters such as BSEP and MDR3 (IC50 >100 µM). BMS-986278 is thus a novel, promising LPA1 receptor antagonist for the treatment of IPF and other fibrotic diseases."

Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases

[VIRTUAL] Evaluation of Collagen Neoepitope Biomarkers in a Phase 2 Trial of BMS-986020, A Lysophosphatidic Acid Receptor Antagonist, for the Treatment of Idiopathic Pulmonary Fibrosis (ATS-I 2020) - "To further support the association of C3M and C6M with FVC and lung fibrosis, respectively, categorical analysis indicated that FVC responders displayed a trend of larger mean decrease in C3M than did nonresponders (-18% vs -6%), and whole lung QLF responders displayed a trend of larger mean decrease in C6M than did nonresponders (-18% vs 3%). Conclusions : The data suggest that LPA 1 pathway antagonism can impact collagen turnover and matrix remodeling in IPF lung and that C3M, PRO-C4 and C6M may have potential value as biomarkers to monitor treatment response and disease progression/regression in future clinical trials."

Biomarker • P2 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases