An update on emerging drugs for the treatment of idiopathic pulmonary fibrosis: a look towards 2023 and beyond

ABSTRACTIntroduction Currently approved drug treatments for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, have been shown to slow lung function decline and improve clinical outcomes. Since significant advances in the understanding of pathogenetic mechanisms in IPF, novel potential agents are being tested to identify new targeted and better tolerated therapeutic strategies.Areas covered This review describes the evidence from IPF phase II and III clinical trials that have been completed or are ongoing in recent years. The literature search was performed using Medline and Clinicaltrials.org databases. Particular attention is paid to the new inhibitor of phosphodiesterase 4B (BI 1015550), being studied in a more advanced research phase. Some emerging critical issues of the pharmacological research are highlighted considering the recent outstanding failures of several phase III trials.Expert opinion An exponential number of randomized clinical trials are underway testing promising new molecules to increase treatment choices for patients with IPF and improve patients' quality of life. The next goals should aim at a deeper understanding of the pathogenic pathways of the disease with the challenging goal of being able not only to stabilize but also to reverse the ongoing fibrotic process in patients with IPF.KEYWORDS: Antifibrotic drugsBI 1015550idiopathic pulmonary fibrosispamrevlumabphase 2 clinical trialsphase 3 clinical trials Article highlights Although novel insights into the pathogenesis of idiopathic pulmonary fibrosis, the currently approved antifibrotic treatments are not able to stop disease progression.Pharmacological research accelerated with the aim to find new effective and targeted therapeutic strategies.Considering the outstanding failures in the last years of a significant number of phase III clinical trials, some critical issues need to be highlighted, such as the optimal study endpoint, the eligibility criteria used, and the differences in racial, ethnic, geographic, sex and genetic predisposition in the study populations.List of abbreviations 6MWD=6-minute walk distanceAEC=alveolar epithelial cellALAT=alanine aminotransferaseATS=American Thoracic SocietyBAFF-R=B-cell activating factor receptorcAMP=cyclic adenosine monophosphatec-FMSR=colony stimulating factor-1 receptorCI=confidence intervalCOPD=chronic obstructive pulmonary diseaseCTGF=connective tissue growth factorCYP3A4=Cytochrome P450 3A4DLCO=diffusing capacity of the lungs for carbon monoxideDMD=Duchenne muscular dystrophyDSP=desmoplakinEMA=European Medicines AgencyERS=European Respiratory SocietyFDA=Food and Drug AdministrationFGF-2=fibroblast growth factor 2FGFR=fibroblast growth factor receptorFVC=forced vital capacityGal=galectinGPR84=G-protein-coupled receptor 84HRCT=high resolution computed tomographyIFN=interferonIGF-1=insulin-like growth factor 1IgG1=immunoglobulin G1IL=interleukinILD=interstitial lung diseaseIPF=idiopathic pulmonary fibrosisIV=intravenousJRS=Japanese Respiratory SocietyLAPC=locally advanced pancreatic cancerLPA=lysophosphatidic acidMET=hepatocyte growth factor receptormL=milliliterMMRM=mixed model repeated measuresmTOR=mechanistic target of rapamycinMUC5B=mucin 5BNCT=national clinical trial numberNCT=national clinical trial numberOLE=open-label extensionPDE4B=phosphodiesterase 4BPDGF=platelet-derived growth factorPF-ILD=progressive fibrosing interstitial lung diseasePFD=pirfenidonePI3K=phosphoinositide 3-kinaseQLF=quantitative lung fibrosisRCTs=randomized clinical trialsrhPTX-2=recombinant human pentraxin-2RNA=ribonucleic acidSAE=serious adverse eventSAP=serum amyloid PTEAE=treatment‐emergent adverse eventTERC=telomerase RNA componentTGF=transforming growth factorTNF=tumor necrosis factorTKI=tyrosine kinase inhibitorUIP=usual interstitial pneumoniaVEGFR=vascular endothelial growth factor receptorWGS=whole-genome sequencingDeclaration of interestL Richeldi reports consulting activity for Roche, Boehringer Ingelheim, FibroGen, Nitto, Pliant Therapeutics, Bristol Myers Squibb, CSL Behring and research grants from Boehringer Ingelheim and Zambon, outside the submitted work. G Sgalla reports personal fees from Boehringer Ingelheim, outside 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 disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis paper was not funded.