ziritaxestat (GLPG1690) / Galapagos, Gilead - LARVOL DELTA

"Regression to the truth": lessons learned from negative IPF trials. (PubMed, Breathe (Sheff)) - "Despite the approval of pirfenidone and nintedanib that slow disease progression, IPF remains a disease with poor survival...We examine three pivotal trials of novel IPF therapies, zinpentraxin alfa, ziritaxestat and pamrevlumab, that failed in late-stage clinical development...Negative trials are not failures but opportunities for learning. By recognising and addressing these challenges, while also embracing novel trial methodologies, we can enhance drug development and improve IPF outcomes."

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

Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode. (PubMed, Bioorg Med Chem) - "Type VI inhibitors 4 and 41 showed cellular and phenotypic activity similar to type IV inhibitor GLPG1690. Identification of this new binding mode completes this combinatorial puzzle in inhibitor design and calls for further investigation to characterize potential therapeutic benefit."

Journal • Fibrosis • Immunology • Oncology

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

EFFICACY AND SAFETY OF ZIRITAXESTAT FOR THE MANAGEMENT OF IDIOPATHIC PULMONARY FIBROSIS IN ADULTS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS (CHEST 2024) - "There was no significant change observed in FVC, SGRQ total score, or >1 TEAEs among the patients included in the analyzed trials. This suggests that ziritaxestat did not have a statistically significant impact on these outcomes. Further research may be needed to confirm these results and explore potential explanations for the lack of significant effects."

Retrospective data • Review • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases

Evidence from recent clinical trials in fibrotic interstitial lung diseases. (PubMed, Curr Opin Pulm Med) - "Despite recent frustrating negative results, there is a growing portfolio of candidate drugs developed in both IPF and PPF."

Journal • Review • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • CTGF

The future of clinical trials in idiopathic pulmonary fibrosis. (PubMed, Curr Opin Pulm Med) - "Advances in study design, end point selection and statistical analysis, and innovative strategies for more efficient enrolment of study participants have the potential to increase the likelihood of success of late-phase clinical trials in IPF."

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

Prediction of Disease Progression and Clinical Response in Systemic Sclerosis: Experience From a Proof-of-Concept Trial. (PubMed, ACR Open Rheumatol) - "Disease progression and drug effect could be predicted beyond the range of observed data. This modeling and simulation approach may inform future trial design, including study duration, and predict the probability of success."

Journal • Immunology • Scleroderma • Systemic Sclerosis

Experimental autotaxin inhibitors for the treatment of idiopathic pulmonary fibrosis. (PubMed, Expert Opin Investig Drugs) - "Large phase III trials assessed Ziritaxestat but yielded disappointing results, highlighting the importance of long-term observation and clinical outcomes in clinical research. Patient stratification and personalized medicine are crucial, as pulmonary fibrosis is a heterogeneous disease. Ongoing research and collaboration are essential for this advancement."

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

Design, synthesis and evaluation of novel UDCA-aminopyrimidine hybrids as ATX inhibitors for the treatment of hepatic and pulmonary fibrosis. (PubMed, Eur J Med Chem) - "Among them, 12a and 12h exhibited the strongest ATX inhibitory activities with IC values of 7.62 ± 0.62 and 7.51 ± 0.72 nM respectively, which were 9-fold more effective than the positive control drug GLPG-1690...Preliminary mechanistic studies indicated that 12a and 12h exerted anti-hepatic fibrosis and anti-pulmonary fibrosis effects by inhibiting the TGF-β/Smad signaling pathway. Overall, our findings suggested that 12a and 12h might be two promising anti-fibrotic agents, or might serve as two new lead compounds for the further development of anti-fibrotic agents."

Journal • Fibrosis • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases • COL1A1 • TGFB1

ISABELA studies: plasma exposure and target engagement do not explain the lack of efficacy of ziritaxestat in patients with IPF. (PubMed, Clin Pharmacol Ther) - P3 | "Ziritaxestat exposure in patients with IPF was numerically lower in those who received ziritaxestat on top of pirfenidone than in those who received ziritaxestat on top of nintedanib or ziritaxestat alone. Based on these evaluations, exposure and target engagement are not thought to have contributed to the lack of efficacy observed. We hypothesize that the lack of efficacy of ziritaxestat in the ISABELA program, despite adequate LPA reduction, could be due to the involvement of an alternative pro-fibrotic pathway."

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

Anti-fibrotic Effects of MT-5562, a Novel Potent Selective Autotaxin Inhibitor, in Preclinical Studies: Roles of Lysophosphatidic Acid in Autoimmune Diseases and Clues to Treat Skin and Lung Fibrosis in Systemic Sclerosis (ACR Convergence 2023) - " We examined the inhibitory effects of MT-5562 and its free form (MT-5562F) in comparison to other autotaxin inhibitors such as ziritaxestat and cudetaxestat on ATX activity using the choline assay...The effects of MT-5562F on skin and lung fibrosis were evaluated using murine SSc models induced by bleomycin (BLM) and the plasma concentrations of MT-5562F and LPA were also determined... Our results suggest that multiple LPA species are elevated in plasma of SSc patients and that MT-5562 is a selective and potent ATX inhibitor with a good preclinical safety and efficacy profile. It may offer a good option to treat lung and skin fibrosis in SSc, which has to be analyzed in clinical trials. H."

Preclinical • Fibrosis • Immunology • Inflammatory Arthritis • Lupus • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Scleroderma • Sjogren's Syndrome • Systemic Lupus Erythematosus • Systemic Sclerosis • CTGF • IL6

Drug-drug interaction prediction of ziritaxestat using a physiologically based enzyme and transporter pharmacokinetic network interaction model. (PubMed, Clin Transl Sci) - "DDIs with rifampin, itraconazole, voriconazole, pravastatin, and rosuvastatin were predicted, followed by validation against a test dataset...Model-based predictions for ziritaxestat as a victim of DDIs with a moderate CYP3A4 inhibitor (fluconazole) suggested a 2.6-fold increase in the AUC of ziritaxestat, while multiple doses of a strong inhibitor (voriconazole) would increase the AUC by 15-fold. Efavirenz would yield a three-fold decrease in the AUC of ziritaxestat. As a perpetrator, ziritaxestat was predicted to increase the AUC of the CYP3A4 index substrate midazolam by 2.7-fold. An overarching PBPK model was developed that could predict DDI liability of ziritaxestat for both CYP3A4 and the transporter pathways."

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

INHIBITION OF THE LYSOPHOSPHATIDIC ACID PATHWAY IMPROVES HEPATIC FIBROSIS AND PORTAL HYPERTENSION IN EXPERIMENTAL ADVANCED CHRONIC LIVER DISEASE (AASLD 2023) - " Cirrhotic rats with ascites (16 weeks CCl4) randomly received either an inhibitor of autotaxin (ATXi, GLPG1690; 60 mg/kg/BID), an LPA receptor-1 antagonist (LPAR1i, AM095; 30 mg/kg/BID) or vehicle for 14 days (n=12/group). This study demonstrates that inhibition of the LPA pathway exerts beneficial effects in a pre-clinical model of decompensated cirrhosis, which lead to marked amelioration in fibrosis and portal hypertension. Our results encourage its clinical evaluation for the treatment of advanced chronic liver disease."

Metastases • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immunology • Inflammation • Liver Failure • Portal Hypertension • CASP8 • IL10 • IL6 • VCAM1

Autotaxin-lysophosphatidic acid receptor 5 axis evokes endothelial dysfunction via reactive oxygen species signaling. (PubMed, Exp Biol Med (Maywood)) - "Interestingly, pharmacological inhibition of autotaxin (ATX) by GLPG1690 partially reversed the endothelial dysfunction, suggesting that lysophosphatidic acid (LPA) derived from LPC may be involved in the effect...Our findings indicate that the ATX-LPA-LPA receptor axis is involved in the development of LPC-induced impairment of endothelium-dependent vasorelaxation via LPA receptor-mediated reactive oxygen species production. Taken together, in this study, we identified a new pathway contributing to the development of LPC-induced endothelial dysfunction."

Journal • LPAR5

Dual role of autotaxin as novel biomarker and therapeutic target in pancreatic neuroendocrine neoplasms. (PubMed, Cancer Sci) - "An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target."

Biomarker • Journal • Endocrine Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Immunology • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Pancreatitis • Solid Tumor

Ziritaxestat and Lung Function in Idiopathic Pulmonary Fibrosis. (PubMed, JAMA) - No abstract available

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

Ziritaxestat and Lung Function in Idiopathic Pulmonary Fibrosis-Reply. (PubMed, JAMA) - No abstract available

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

ENPP2 inhibitor improves proliferation in AOM/DSS-induced colorectal cancer mice via remodeling the gut barrier function and gut microbiota composition. (PubMed, Pharmacol Res) - "In this study, the role of ENPP2 in CRC has been demonstrated using established in vitro and in vivo models including ENPP2 gene knockdown, and use of the ENPP2 inhibitor, GLPG1690...Finally, results of metabolomic analysis implicated mainly the gut microbiota-derived metabolites of aromatic amino acids in CRC progression. These findings may provide novel insights into the development of small-molecule ENPP2 inhibitors for the treatment of CRC."

Clinical • Journal • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • Transplantation • CLDN1 • OCLN • TJP1

Ziritaxestat fails to improve lung function in patients with idiopathic pulmonary fibrosis (Healio) - "'It's worth noting that ziritaxestat has a drug-drug interaction with nintedanib, and it actually increases plasma exposure to the nintedanib,' Maher said during the presentation. 'So, when you look at the breakdown of adverse events, the majority of nausea and diarrhea occurred in patients on nintedanib, presumably because we were increasing plasma exposure to a drug that has a known dose relationship with diarrhea.'" 'We're still digging into the data and doing more work with the blood samples and the biomarkers to try and understand what it was that led to failure in this study,' Maher concluded."

Media quote • Idiopathic Pulmonary Fibrosis

Effect of Ziritaxestat, a Novel Autotaxin Inhibitor, on Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials (ATS 2023) - "There is no abstract associated with this presentation.There is no abstract associated with this presentation."

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

[F]ONO-8430506: A novel radioligand for PET imaging of autotaxin (ATX). (PubMed, Bioorg Med Chem Lett) - "The binding mode for compound 8 inside the catalytic pocket of ATX using computational modelling and docking protocols revealed that compound 8 resembled a comparable binding mode to that of ATX inhibitor GLPG1690. However, PET imaging studies with radioligand [F]8 showed only relatively low tumour uptake and retention (SUV 0.21±0.03) in the tested 8305C human thyroid tumour model reaching a tumour-to-muscle ratio of ∼2.2 after 60 min."

Journal • Endocrine Cancer • Oncology • Thyroid Gland Carcinoma

Ziritaxestat Fails to Demonstrate Efficacy for Treatment of IPF in 2 Trials (HCPLive) - "For this investigation, a team led by Toby Maher, MD, PhD...aimed to assess the efficacy and safety of the autotaxin inhibitor ziritaxestat among this patient population....'Even though the ISABELA trials failed, they demonstrate the potential value of observing data for 52 weeks or longer and provide information regarding the utility of different clinical outcomes,' investigators noted."

Media quote • Idiopathic Pulmonary Fibrosis • Pulmonary Disease

ANTI-FIBROTIC EFFECTS OF MT-5562, A NOVEL POTENT SELECTIVE AUTOTAXIN INHIBITOR, IN PRECLINICAL STUDIES: CLUES TO TREAT SKIN AND LUNG FIBROSIS IN SYSTEMIC SCLEROSIS (EULAR 2023) - "The effects of MT-5562F on skin and lung fibrosis were evaluated in murine SSc models induced by bleomycin (BLM). Results MT-5562F, ziritaxestat, and cudetaxestat inhibited the enzyme activity of human ATX with IC50s of 0.45, 49.3, and 2.77 nmol/L, respectively...Conclusion Our results suggest that MT-5562 is a selective and potent ATX inhibitor. It is expected to be a safer compound comparing other ATX inhibitors under development, and it may offer a good option to treat lung and skin fibrosis in SSc."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis • CRP • CTGF • EGFR • IL6R • POSTN • TGFB1

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials. (PubMed, JAMA) - P3 | "Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444."

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

A 24-Week, Phase IIa, Randomized, Double-blind, Placebo-controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis (NOVESA). (PubMed, Arthritis Rheumatol) - "Ziritaxestat resulted in significantly greater reductions in mRSS at Week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is available in the Supplement."

Clinical • Journal • P2a data • Fibrosis • Immunology • Pain • Scleroderma • Systemic Sclerosis