https://orcid.org/0000-0002-4471-895X
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ABSTRACT
Introduction
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.
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 distance |
| AEC | = | alveolar epithelial cell |
| ALAT | = | alanine aminotransferase |
| ATS | = | American Thoracic Society |
| BAFF-R | = | B-cell activating factor receptor |
| cAMP | = | cyclic adenosine monophosphate |
| c-FMSR | = | colony stimulating factor-1 receptor |
| CI | = | confidence interval |
| COPD | = | chronic obstructive pulmonary disease |
| CTGF | = | connective tissue growth factor |
| CYP3A4 | = | Cytochrome P450 3A4 |
| DLCO | = | diffusing capacity of the lungs for carbon monoxide |
| DMD | = | Duchenne muscular dystrophy |
| DSP | = | desmoplakin |
| EMA | = | European Medicines Agency |
| ERS | = | European Respiratory Society |
| FDA | = | Food and Drug Administration |
| FGF-2 | = | fibroblast growth factor 2 |
| FGFR | = | fibroblast growth factor receptor |
| FVC | = | forced vital capacity |
| Gal | = | galectin |
| GPR84 | = | G-protein-coupled receptor 84 |
| HRCT | = | high resolution computed tomography |
| IFN | = | interferon |
| IGF-1 | = | insulin-like growth factor 1 |
| IgG1 | = | immunoglobulin G1 |
| IL | = | interleukin |
| ILD | = | interstitial lung disease |
| IPF | = | idiopathic pulmonary fibrosis |
| IV | = | intravenous |
| JRS | = | Japanese Respiratory Society |
| LAPC | = | locally advanced pancreatic cancer |
| LPA | = | lysophosphatidic acid |
| MET | = | hepatocyte growth factor receptor |
| mL | = | milliliter |
| MMRM | = | mixed model repeated measures |
| mTOR | = | mechanistic target of rapamycin |
| MUC5B | = | mucin 5B |
| NCT | = | national clinical trial number |
| NCT | = | national clinical trial number |
| OLE | = | open-label extension |
| PDE4B | = | phosphodiesterase 4B |
| PDGF | = | platelet-derived growth factor |
| PF-ILD | = | progressive fibrosing interstitial lung disease |
| PFD | = | pirfenidone |
| PI3K | = | phosphoinositide 3-kinase |
| QLF | = | quantitative lung fibrosis |
| RCTs | = | randomized clinical trials |
| rhPTX-2 | = | recombinant human pentraxin-2 |
| RNA | = | ribonucleic acid |
| SAE | = | serious adverse event |
| SAP | = | serum amyloid P |
| TEAE | = | treatment‐emergent adverse event |
| TERC | = | telomerase RNA component |
| TGF | = | transforming growth factor |
| TNF | = | tumor necrosis factor |
| TKI | = | tyrosine kinase inhibitor |
| UIP | = | usual interstitial pneumonia |
| VEGFR | = | vascular endothelial growth factor receptor |
| WGS | = | whole-genome sequencing |
Declaration of interest
L 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 disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.