Experimental autotaxin inhibitors for the treatment of idiopathic pulmonary fibrosis

ABSTRACT

Introduction

Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible, and fatal lung disease with unmet medical needs. Autotaxin (ATX) is an extracellular enzyme involved in the generation of lysophosphatidic acid (LPA). Preclinical and clinical data have suggested the ATX-LPAR signaling axis plays an important role in the pathogenesis and the progression of IPF.

Areas Covered

The aim of this review is to provide an update on the available evidence on autotaxin inhibitors in IPF and further details on the ongoing clinical studies involving these molecules.

Expert Opinion

The development of autotaxin inhibitors as a potential therapy for idiopathic pulmonary fibrosis has gained attention due to evidence of their involvement in the disease. Preclinical and early-phase clinical studies have explored these inhibitors’ efficacy and safety, offering a novel approach in treating this disease. Combining autotaxin inhibitors with existing anti-fibrotic agents is considered for enhanced therapeutic effects. 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.

KEYWORDS:

• Idiopathic pulmonary fibrosis
• targeted therapy
• inhibitors
• lysophosphatidic acid
• lung fibrosis
• Ziritaxestat

Article highlights

• IPF is the most frequent and severe form of idiopathic interstitial pneumonia, with a poor prognosis and limited treatment options.

• Autotaxin (ATX) and Lysophosphatidic Acid (LPA) play an essential role in mediating the abnormal responses to tissue injury and are implicated in the pathogenesis of IPF.

• Over the last few decades, many ATX and LPAR inhibitors have been tested as potential therapies for various diseases, particularly for IPF.

• GLPG1690, also known as Ziritaxestat, was the first autotaxin inhibitor to be evaluated in terms of efficacy and safety in two parallel phase 3 randomized control trials (RCTs) as a treatment for IPF. However, Ziritaxestat was shown to be ineffective in reducing the rate of decline for FVC over 52 weeks.

• There are currently two autotaxin inhibitors and one LPAR antagonist undergoing interventional clinical trials for treatment against IPF. BBT-887 and BLD-0409 two orally available autotaxin inhibitors, are currently undergoing a phase-2, multicenter, randomized, double-blind, placebo-controlled studies (NCT05483907;NCT05373914). BMS-986278 is a LPAR inhibitor currently being evaluated in a multicenter, randomized, double-blind, placebo-controlled, phase 2 study (NCT0408681).

• Due to the absence of current drugs that can completely block the progression of IPF, continued clinical research is needed to find molecules that can modulate or inhibit specific signaling pathways involved in the development and progression of pulmonary fibrosis.

Declaration of interests

G Sgalla and J Simonetti report fees from Chiesi Farmaceutici and Boehringer Ingelheim outside the submitted work. L Richeldi has received grants and personal fees from Chiesi Farmaceutici, Boehringer Ingelheim and InterMune, and personal fees from Biogen-Idec, ImmuneWorks, MedImmune, Roche, Sanofi-Aventis, Shionogi, and Takeda outside of the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.