The chronic and ultimately fatal disease, idiopathic pulmonary fibrosis (IPF) is a specific type of interstitial lung disease characterized by the progressive deposition of fibrotic tissue in the alveoli of the lungs.1 The cause of IPF still remains elusive, although the disease generally occurs in adults 50–70 years of age. IPF is currently estimated to affect between 132,000 and 200,000 people in the United States.2 With an aging global population, the incidence of IPF is expected to rise, along with the already high healthcare utilization and cost burden of the disease.3 Currently only two treatments that have been demonstrated to impact disease progression have been approved by the US Food and Drug Administration and recommended for use by the IPF Clinical Practice guidelines: nintedanib, a tyrosine kinase inhibitor from Boehringer Ingelheim, and pirfenidone, an anti-fibrotic from Roche.4–6 Presentations on IPF at the 103rd American Thoracic Society (ATS) International Congress, held in San Diego, CA, US, on May 18–23, 2018, continued to build on the existing evidence for currently available treatments, as well as providing early stage data for new therapies.
Boehringer presented new data on the efficacy of nintedanib using a pooled analysis of 1,128 patients who received treatment with nintedanib or placebo in the phase III INPULSIS (NCT01335464 and NCT01335477) and phase II TOMORROW (NCT00514683) trials. The analysis compared the observed number of deaths with the predicted mortality rate for patients based on Gender-Age-Physiology (GAP) stage, a method for predicting IPF prognosis based on mortality risk factors including gender, age and lung function. Fewer deaths were observed in each treatment group than predicted by baseline GAP stage—there were 46.7% of the number of GAP-predicted deaths in the nintedanib group and 63.9% in the placebo group. This difference suggested a 26.8% relative reduction in the risk of death with nintedanib compared with placebo.7 Additionally, the safety and tolerability profile of nintedanib was further confirmed in an analysis of data from six clinical trials, including a total of 1,126 patients.8
Boehringer also highlighted the importance of minimizing IPF disease progression in two pooled analyses of data from the nintedanib clinical development program. Both analyses demonstrated an association between lung function decline and decreased health-related quality of life, with reductions in forced vital capacity greater than 10%, a particular risk factor.9 Previously, the INPULSIS trials demonstrated that nintedanib reduces the decline in forced vital capacity, suggesting that nintedanib treatment response may translate into meaningful impact on quality of life for patients with IPF.10 Further studies are required to directly assess this.
Prometic presented key data on PBI-4050, an anti-fibrotic compound currently entering phase III clinical development for IPF. In an exploratory study, the effect of PBI-4050 on antifibrotic biomarkers was assessed. PBI-4050 produced statistically significant increases in interleukin (IL)-9, IL-7, and macrophage inflammatory protein-1β (p<0.05), all of which are known to have either direct or indirect anti-fibrotic activity. A positive effect of PBI-4050 on IL-1Ra and plasminogen, factors which may have protective roles in fibrotic disease, was also found (p=0.08). Additionally, PBI-4050 administered in combination with nintedanib significantly decreased levels of the chemokine and marker of disease severity, CCL-18 (p<0.01).11 The latter result is of particular interest given the potential of combination therapy to maximize disease outcomes for patients with IPF.
Prometic also presented data from their pre-clinical development program evaluating the use of plasminogen, a regulator of hemostasis through the degradation of fibrin. In a mouse model of lung fibrosis, subcutaneous plasminogen alone or in combination with pirfenidone or nintedanib significantly reduced the percentage of collagen in areas of the lung with inflammation compared with the control group. Similar reductions were not seen with pirfenidone or nintedanib alone. Small reductions in plasminogen activator inhibitor-1 were observed with plasminogen alone, but significantly reduced with the combination of plasminogen and pirfenidone.12 Further work is required to see if these promising results translate into humans with IPF.
In summary, the data presented at the ATS international congress 2018, highlights the ongoing work to further investigate the clinical benefits of nintedanib. Evidence presented suggests that nintedanib reduces IPF-related mortality and also highlights the importance of avoiding declines in lung function, which are associated with poor quality of life. Finally, several compounds in clinical and pre-clinical development targeting new fibrotic pathways, suggest that the treatment landscape for IPF, previously a largely untreatable disease will continue to evolve.
1. Sgalla G, Iovene B, Calvello M, et al. Idiopathic pulmonary fibrosis: pathogenesis and management. Respir Res. 2018;19:32.
2. Pulmonary Fibrosis Foundation. Pulmonary fibrosis patient information guide. Available at: //www.pulmonaryfibrosis.org/docs/default-source/patient-information-guides/patient_info_guide_eng_2013.pdf (accessed May 30, 2018).
3. Diamantopoulos A, Wright E, Vlahopoulou K, et al. The Burden of illness of idiopathic pulmonary fibrosis: a comprehensive evidence review. Pharmacoeconomics. 2018;36:779–807.
4. Boehringer-Ingelheim. OFEV® (nintedanib) capsules, Highlights of prescribing information. Available at: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Ofev/ofev.pdf (accessed May 30, 2018).
5. Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015;192:e3–19.
6. Roche. ESBRIET® (pirfenidone) capsules and film-coated tablet, Highlights of prescribing information. Available at: https://www.gene.com/download/pdf/esbriet_prescribing.pdf (accessed May 30, 2018).
7. Ryerson CJ, Wijsenbeek M, Bonella F, et al. Predicted versus observed mortality in clinical trials of nintedanib in idiopathic pulmonary fibrosis (IPF). Am J Respir Crit Care Med. 2018;197:A2534.
8. Lancaster LH, Hernandez P, Inoue Y, et al. Safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis (IPF): pooled data from six clinical trials. Am J Respir Crit Care Med. 2018;197:A1642.
9. EPG Online. Pooled data on Ofev shows efficacy, safety and tolerability in idiopathic pulmonary fibrosis – Boehringer. Available at: https://www.epgonline.org/global/news/pooled-data-on-ofev-shows-efficacy--safety-and-tolerability-in-idiopathic-pulmonary-fibrosis---boehringer-.html (accessed May 30, 2018).
10. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–82.
11. Gagnon L, Grouix B, Laverdure A, et al. Evaluation of the effect of PBI-4050 alone or in combination with pirfenidone or nintedanib on blood biomarkers linked to the fibrotic process in IPF patients. Am J Respir Crit Care Med. 2018;197:A2439.
12. Gagnon L, Tremblay M, Grouix B, et al. Plasminogen reduces lung fibrosis in the bleomycin-induced lung fibrosis model. Am J Respir Crit Care Med. 2018;197:A2663.