ziritaxestat (GLPG1690) / Lakefront Biotherapeutics, Gilead - LARVOL DELTA

Autotaxin inhibitors: an updated patent review (2021-present). (PubMed, Expert Opin Ther Pat) - "Currently, beyond the Phase II candidates PAT409 and HW021199, ATX inhibitors FTP-198 and HNC1058 have entered Phase I clinical trials for pulmonary fibrosis, while IOA-289 and HNC664 have advanced to clinical studies for solid tumors, underscoring the immense therapeutic potential of ATX. Although the identification of type V and VI ATX inhibitors has broadened the design landscape, most emerging entities since 2020 remain analogs of GLPG1690 and PAT409, presumably being attributed to the unavailable data of most clinical candidates, and despite the absence of approved drugs, the continued evolution of drug design strategies and application of novel technologies would further facilitate the discovery of ATX candidates, ultimately offering more therapeutic options for patients."

Journal • Review • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor

Beyond attenuation: a translational review of curative-intent pharmacological targets in idiopathic pulmonary fibrosis. (PubMed, Front Med (Lausanne)) - "The current standard-of-care agents, pirfenidone and nintedanib, merely slow disease progression and are burdened by significant toxicity...Analysis reveals that targeting broad-spectrum enzymes (e.g., autotaxin via ziritaxestat) or downstream effectors (e.g., Connective Tissue Growth Factor (CTGF) via pamrevlumab) has failed, likely due to mechanistic redundancy or insufficient target engagement. In contrast, highly specific, next-generation inhibitors targeting upstream signal initiation points such as the lysophosphatidic acid receptor 1 (LPAR1) (admilparant) and local αvβ6 integrin-mediated activation of transforming growth factor-beta (TGF-β) (bexotegrast) have yielded promising Phase 2 data, demonstrating a sophisticated translational learning loop. Furthermore, the geroscience approach targeting cellular senescence (dasatinib/quercetin) has introduced a controversial new paradigm, while the recent approval of nerandomilast (a phosphodiesterase 4B (PDE4B)..."

Journal • Review • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CTGF • TGFB1

A multi-stage computational pipeline and in vitro validation for the discovery of small-molecule translation inhibitors targeting the bacterial ribosome. (PubMed, RSC Adv) - "Among these, Mitoxantrone (IC50 = 14.10 ± 0.38 µM) was identified as a translation inhibitor with a bacteriostatic effect comparable to the antibiotic Clindamycin. Whereas Plerixafor (IC50 = 62.30 ± 6.47 µM), Olcegepant (IC50 = 144.30 ± 16.41 µM), and Ziritaxestat (IC50 = 224.30 ± 25.02 µM) showed inhibitory effects at higher concentrations...The pharmacokinetic and toxicological profiles of these compounds are already well-characterized. Overall, this work illustrates a useful drug discovery strategy combining virtual screening, MD simulations, and experimental validation to identify ribosome-targeting inhibitors and can be extended to other challenging RNA targets and protein-RNA complexes."

Journal • Preclinical • Infectious Disease • Oncology

Investigating Sulfotransferase Mediated Drug Interactions of Ethinylestradiol using a Physiologically Based Pharmacokinetic Model. (PubMed, AAPS J) - "The developed PBPK models for etoricoxib and ziritaxestat can be used in future applications as probe SULT1E1 precipitants. Incorporation of SULT metabolism into the EE PBPK model may support a more comprehensive assessment of the DDI liability of investigational drugs that affect multiple EE metabolic pathways."

Journal • PK/PD data • CYP2C9 • CYP3A4 • SULT1E1 • UGT1A1

Rational design and identification of potent imidazole-fused Autotaxin inhibitors for treatment of idiopathic pulmonary fibrosis. (PubMed, Eur J Med Chem) - "Herein, in pursuit of expanding the chemical space of novel ATX inhibitors, a series of imidazole-fused (imidazo[1,2-b]pyridazine and benzo[d]imidazole) derivatives with aliphatic amine linkers were designed through integrating the structural features of GLPG-1690 and PF-8380. Significantly, in the Bleomycin-induced pulmonary fibrosis mouse model, 12 has certainly reduced collagen deposition and ameliorated lung fibrosis. Overall, compound 12 turned out to be a well-characterized potent ATX inhibitor warranting further investigation for the treatment of idiopathic pulmonary fibrosis."

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

Successive structural optimization of Ziritaxestat culminates in the discovery of orally bioavailable and in vivo potent imidazothiadiazole derivative for treating ATX-driven diseases. (PubMed, Eur J Med Chem) - "Herein, we communicate our medicinal chemistry campaign culminating in the discovery of imidazothiadiazole-based ATX inhibitor with oral bioavailability and potent in vivo efficacy. Moreover, 25 demonstrated promising therapeutic efficacy against bleomycin-induced systemic sclerosis in mice. Attributed to its attractive in vitro and in vivo performance in battling ATX-related diseases, 25 deserves further development as a potential candidate."

Journal • Preclinical • Immunology • Inflammation • Scleroderma • Systemic Sclerosis

"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