GLPG1205 / Lakefront Biotherapeutics, Gilead - LARVOL DELTA

Pharmacological modulation of GPR84 revealed by dual states structures and immune functional assays. (PubMed, Exp Mol Med) - "Immune functional assays in THP-1 cells demonstrated that ZQ-16 elicited GPR84-dependent activation and cytokine production, which were effectively abrogated by GLPG1205. Mutagenesis combined with functional assays validates key ligand interactions, providing a framework for the rational design of pathway selective GPR84 modulators."

Journal • Fibrosis • Inflammation

GPR84 and Neuroinflammation: A Receptor Worth Targeting, or A Target Worth Reconsidering? (PubMed, Mol Neurobiol) - "However, the most clinically advanced antagonist, GLPG1205, failed to meet primary endpoints in Phase II trials in ulcerative colitis and idiopathic pulmonary fibrosis. This review argues that these translational failures reflect deeper methodological limitations - including supraphysiological agonist concentrations, constitutive knockout models that conflate microglial and peripheral macrophage contributions, species selectivity gaps in available antagonists - that have produced conflicting preclinical evidence and impeded clinical translation. Resolving GPR84's context-dependent biology will require conditional genetic models, CNS-penetrant pharmacological tools, and integration of spatial and temporal multiomics approaches before the receptor's therapeutic potential can be meaningfully evaluated."

Journal • Review • Alzheimer's Disease • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Neuralgia • Pain • Pulmonary Disease • Respiratory Diseases • Ulcerative Colitis • IL1B • NLRP3 • TNFA

Mechanistic insight into signal bias by the agonist-dependent conformational dynamics of GPR84. (PubMed, Nat Commun) - "Here, we present the cryo-electron microscopy structures of the GPR84-Gi complex bound to the G protein-biased agonist DL-175, and the inactive state of GPR84 bound to the antagonist GLPG1205...Notably, steric interactions between DL-175 and L3366.52 selectively preclude the conformational changes required for efficient β-arrestin recruitment without compromising G protein activation. These structural insights provide a structural context for the rational design of GPR84-targeted therapeutics with precisely tuned signaling profiles."

Journal • Inflammation

Next-Generation Neuroinflammation PET: Development of a New Brain-Penetrant GPR84 Tracer 18F-MGX-38 and Evaluation in Mice and Non-Human Primate (SNMMI 2026) - "Blocking with GPR84 antagonist (GLPG1205, 35 M), significantly reduced tracer binding to hGPR84-HEK293 cells by 64.87%, demonstrating high specificity of 18FMGX-38 (P <0.0001, n= 8)... We have developed a novel brain-penetrant PET radiotracer, 18FMGX-38, for imaging the promising neuroinflammation biomarker GPR84. 18FMGX-38 demonstrates specific binding to human GPR84–expressing cells, robust blood–brain barrier penetration in mice and rhesus macaques, and favorable in vivo pharmacokinetics. IND-enabling studies—assessing the utility of 18FMGX-38 for imaging innate immune activation in preclinical models of CNS disease—are ongoing."

Preclinical • Cardiovascular • CNS Disorders • Inflammation • Neuralgia • IL4

GPR84-PET imaging with 18F-MGX-110S reveals innate immune activation with greater sensitivity than TSPO-PET in an Alzheimer's disease mouse model (SNMMI 2026) - "Binding affinity and specificity were assessed by saturation and competitive assays (with GPR84 antagonist GLPG1205) in human GPR84-expressing HEK cells... We report the development and validation of the first 18F-labeled GPR84-PET tracer as a highly sensitive tool for imaging innate immune activation in AD. 18F-MGX-110S crosses the intact mouse BBB and demonstrates superior sensitivity for detecting early neuroinflammation compared with TSPO-PET. Clinical translation of GPR84-PET tracers is underway and holds significant potential to advance our understanding of AD pathology and inform the development and evaluation of targeted immunomodulatory therapies."

Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • CD68 • GPRC6A

GPR84 antagonism shifts liver macrophage polarization from M1 to M2, increases liver triiodothyronine, and improves cholesterol levels and hepatic steatosis in a high-fat diet metabolic dysfunction-associated steatohepatitis mouse model (EASL 2026) - "The GPR84 antagonist GLPG1205 was used to evaluate the efficacy of GPR84 inhibition in a high-fat diet (HFD) metabolic dysfunction-associated steatohepatitis (MASH) mouse model... Pharmacological inhibition of GPR84 in HFD-fed mice significantly reduced liver leukocytes, neutrophils, and promoted a shift from M1 (pro-inflammatory) to M2 (anti-inflammatory, pro-tissue repair) polarized liver macrophages, increased liver T3 levels, reduced serum and liver cholesterol, and improved liver weight/body weight, fat mass composition, and liver steatosis. These findings suggest that GPR84 inhibition is a promising target in MASLD and hypercholesterolemia."

Preclinical • Dyslipidemia • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming. (PubMed, Cancer Immunol Res) - "Pharmacological antagonism with GLPG1205 or genetic deletion of GPR84 promoted T cell differentiation, proliferation, cytokine production, and cytotoxicity, whereas agonism with DL175 reduced these functions...Furthermore, antagonism or deletion of GPR84 in antigen-specific CD8+ T cells in adoptive cellular therapy models enhanced their antitumor effects in vivo. Thus, GPR84 inhibition improves CD8+ T cell function and may further enhance adoptive cellular therapies."

Journal • Oncology • CD8

Revealing the suppressors: A new PET imaging approach for detecting MDSCs before and after immunotherapy in a model of brain metastases (SNMMI 2025) - "A subset of vehicle mice was blocked with GPR84 antagonist GLPG1205 (2 mg/kg; n=11) to assess tracer specificity. Organs of interest were analyzed via gamma counting and autoradiography, and quantitative polymerase chain reaction (qPCR) was used to assess Gpr84 and Tspo expression in whole brains of vehicle (n=5), treated (n=5), and sham (n=5) mice... PET imaging and autoradiography revealed localization of immunosuppressive MDSCs in both brain and extracranial tumors of vehicle-treated mice (Fig. 1B-C, Fig. S1A)."

IO biomarker • Melanoma • Oncology • Solid Tumor

Targeting GPR84 to alleviate acute immune-mediated liver injury. (PubMed, Mol Med) - "Our findings suggest that GPR84 plays a pivotal role in immune-mediated liver injury, primarily through its expression on hematopoietic cells. Targeting GPR84, particularly with the antagonist GLPG1205, offers a promising therapeutic strategy for treating immune-related liver diseases."

Journal • Hepatology • Inflammation • Liver Failure • ITGAM • STAT3 • TNFA

Targeting Medium Chain Fatty Acid Metabolism to Control Chronic Gvhd (TCT-ASTCT-CIBMTR 2025) - P2 | "GPR84 is a valid target for the prevention and treatment of cGVHD. Because GLPG1205 has been found safe in a phase 2 trial (NCT03725852) for idiopathic pulmonary fibrosis (IPF), testing this GPR84 antagonist and a diet low in MCFAs for cGVHD treatment is possible in clinical settings."

Bone Marrow Transplantation • Chronic Graft versus Host Disease • Fibrosis • Graft versus Host Disease • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis • CD8

Development and comparison of two novel PET tracers for imaging pro-inflammatory receptor GPR84 in human cells and tissues (SNMMI 2024) - "Co-incubation with GPR84 antagonist (GLPG1205, 1000x by mass) reduced tracer binding in hGPR84-HEK293 cells by >90% (Fig 1D, p<0... Both tracers enable specific detection of GPR84 and innate immune activation in cells and UC tissue. [18F]MGX-110S shows high potential for translation given its favorable half-life, in vivo distribution, and specificity for GPR84."

Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • Septic Shock • Ulcerative Colitis

The GPR84 Antagonist GLPG1205 Reduces Features of Disease in Experimental Severe Asthma. (PubMed, Am J Respir Cell Mol Biol) - No abstract available

Journal • Asthma • CNS Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

PET Imaging of Innate Immune Activation Using C Radiotracers Targeting GPR84. (PubMed, JACS Au) - "Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro...When compared with C-DPA-713-an existing radiotracer used to image innate immune activation in clinical research studies-C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology."

Journal • CNS Disorders • Inflammation

Human IPF lung tissue implanted on the chick chorioallantoic membrane as a novel in vivo model for antifibrotic drug testing (ICLAF 2022) - "Daily treatments of the xenografts with nintedanib and PBI-4050 significantly reduce their size, fibrosis-associated gene expression, and collagen deposition. Similar effects are found with GLPG1205 and fenofibric acid, two drugs that target the immune microenvironment. Our CAM-IPF model represents the first in vivo model of IPF that uses human lung tissue. This rapid and cost-effective assay could become a valuable tool for predicting the efficacy of antifibrotic drug candidates for IPF."

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

GLPG1205 for idiopathic pulmonary fibrosis: a Phase 2 randomised placebo-controlled trial. (PubMed, Eur Respir J) - P2 | "Treatment with GLPG1205 did not result in a significant difference in FVC decline versus placebo. GLPG1205 demonstrated a poorer safety and tolerability profile than placebo."

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

GLPG1205 shows reduction in lung volume decline over 26 weeks vs placebo when measured with novel volumetric CT analysis in IPF patients (ERS 2022) - P2 | "The PINTA trial (NCT03725852) was a double-blind placebo (PBO)-controlled study of GLPG1205 in 68 IPF patients...Novel imaging quantification software may provide alternative trial endpoints allowing for smaller trial sizes. These will require standardised imaging protocols and power calculations."

Clinical • Idiopathic Pulmonary Fibrosis

Human Lung Tissue Implanted on the Chick Chorioallantoic Membrane as a Novel In Vivo Model of IPF. (PubMed, Am J Respir Cell Mol Biol) - "Daily treatments of the xenografts with nintedanib and PBI-4050 significantly reduce their size, fibrosis-associated gene expression, and collagen deposition. Similar effects are found with GLPG1205 and fenofibric acid, two drugs that target the immune microenvironment. Our CAM-IPF model represents the first in vivo model of IPF that uses human lung tissue. This rapid and cost-effective assay could become a valuable tool for predicting the efficacy of antifibrotic drug candidates for IPF."

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

[VIRTUAL] Results of a phase 2 study of GLPG1205 for idiopathic pulmonary fibrosis (PINTA) (ERS 2021) - P2 | "IPF patients received oral GLPG1205 100mg or PBO once daily, on top of standard of care (nintedanib/pirfenidone/neither) for 26 weeks. This along with the observed safety profile for GLPG1205 alone supports further development. Funding Galapagos"

P2 data • Fibrosis • Gastrointestinal Disorder • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] SESSION 134: The future of idiopathic pulmonary fibrosis (ERS 2021) - "The live session is scheduled from September 5-7 and each presenter will have a 5-minutes live, slide show presentation followed at the end of the session by 30-minutes general discussion. This session includes the Best Abstract for Assembly 12 - Interstitial Lung Diseases, entitled "Results of a phase 2 study of GLPG1205 for idiopathic pulmonary fibrosis (PINTA)”"

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

GLPG1205, a GPR84 Modulator: Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Subjects. (PubMed, Clin Pharmacol Drug Dev) - "GPR84 receptor occupancy with GLPG1205 vs placebo confirmed target engagement. These results support further clinical development of GLPG1205."

Clinical • Journal • PK/PD data

Effect of GLPG1205, a GPR84 Modulator, on CYP2C9, CYP2C19, and CYP1A2 Enzymes: In Vitro and Phase 1 Studies. (PubMed, Clin Pharmacol Drug Dev) - P1 | "GLPG1205 may be concomitantly administered with pirfenidone in future clinical development; therefore, the potential for GLPG1205 to interact with enzymes involved in the metabolism of pirfenidone (cytochrome P450 [CYP] 1A2, CYP2C9, 2C19) was evaluated...GLPG1205 had no effect on the exposure of CYP2C9 and CYP1A2 substrates or metabolites; however, a trend toward increased omeprazole (CYP2C19 substrate) exposure was observed...GLPG1205 had a favorable safety and tolerability profile. In conclusion, GLPG1205 100 mg once daily does not interact with CYP2C9, CYP2C19, or CYP1A2 to a clinically relevant extent and may be administered concomitantly with drugs metabolized by these enzymes."

Clinical • Journal • P1 data • Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CYP1A2 • CYP2C19 • CYP2C9

GLPG1205: Expiry of patents related to composition-of-matter and method of treatment in US/ex-US, EU, Australia, China, Canada and Japan in 2032 (Galapagos) - Annual Report 2020: Expiry of patents related to method of treatment using GLPG1205 in further indications in 2038; Expiry of patents related to improved methods for treating lung disorders using GLPG1205 in EU in 2041

Patent • Idiopathic Pulmonary Fibrosis

Evaluation of Mass Balance and Absolute Bioavailability of GLPG1205 (clinicaltrials.gov) - P1; N=12; Completed; Sponsor: Galapagos NV; Recruiting ➔ Completed

Clinical • Trial completion

Evaluation of Mass Balance and Absolute Bioavailability of GLPG1205 (clinicaltrials.gov) - P1; N=12; Recruiting; Sponsor: Galapagos NV; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

Evaluation of Mass Balance and Absolute Bioavailability of GLPG1205 (clinicaltrials.gov) - P1; N=12; Not yet recruiting; Sponsor: Galapagos NV

Clinical • New P1 trial