Changes in Biomarkers in Patients with Idiopathic Pulmonary Fibrosis Treated with Nintedanib and Sildenafil - European Medical Journal
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Changes in Biomarkers in Patients with Idiopathic Pulmonary Fibrosis Treated with Nintedanib and Sildenafil

Authors:
*Eric S. White,1 Bruno Crestani,2 Andreas Günther,3 Toby M. Maher,4,5 Carina Ittrich,6 Claudia Diefenbach,6 Klaus B. Rohr,7 Manuel Quaresma,7 Martin Kolb8
Disclosure:

The INSTAGE trial was funded by Boehringer Ingelheim. Prof White has served as a consultant to Boehringer Ingelheim, Translate Bio, and Xfibra; and as a principal/co-investigator for clinical trials in ILD for Afferent Pharmaceutical, Boehringer Ingelheim, EMD Serono, Galapagos, Genentech, Mallinckrodt, and the Pulmonary Fibrosis Foundation. Prof Crestani has received travel grants from Apellis, AstraZeneca, Boehringer Ingelheim, Roche, and Sanofi; research grants from Boehringer Ingelheim, MedImmune, and Roche; and honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Roche, and Sanofi. Prof Günther has nothing to disclose. Prof Maher has received grants from GlaxoSmithKline, the National Institute for Health Research, and UCB; has served as a consultant to Apellis, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, Galecto, GlaxoSmithKline, Indalo, Pliant, Prometic, Roche, Samumed, and UCB; has received personal fees from Celgene; and has received speakers fees from Boehringer Ingelheim and Roche. Ms Ittrich, Ms Diefenbach, Mr Rohr, and Mr Quaresma are employees of Boehringer Ingelheim. Prof Kolb has received grants from Actelion, Alkermes, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Pharmaxis, Prometic, Respivert, and Roche; has served as a consultant to Boehringer Ingelheim, Genoa, Gilead, GlaxoSmithKline, Indalo, Prometic, Roche, and Third Pole; and has received honoraria for lecturing from Boehringer Ingelheim and Roche.

Acknowledgements:

Editorial assistance, supported financially by Boehringer Ingelheim, was provided by Elizabeth Ng of FleishmanHillard Fishburn, London, UK, during preparation of this article. The authors were fully responsible for all content and editorial decisions, were involved at all stages of development, and have approved the final version. Boehringer Ingelheim was given the opportunity to review this article for medical and scientific accuracy as well as intellectual property considerations.

Citation
EMJ Respir. ;7[1]:66-67. Abstract No AR05.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND

Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF). Sildenafil is a phosphodiesterase-5 inhibitor approved for the treatment of pulmonary arterial hypertension. Exploratory analyses of data from the INSTAGE trial in patients with IPF and severely impaired gas exchange suggested that treatment with nintedanib plus sildenafil may be associated with a reduced rate of decline in forced vital capacity compared with nintedanib alone.1 In the INSTAGE trial, changes in biomarkers of inflammation, epithelial cell damage, and extracellular matrix turnover were investigated.

METHODS

Patients with IPF and diffusing capacity of the lungs for carbon monoxide (DLco) ≤35% predicted were randomised 1:1 to receive nintedanib 150 mg twice a day plus sildenafil 20 mg three times a day, or nintedanib 150 mg twice a day plus placebo for 24 weeks. Blood samples were taken at baseline and Weeks 4, 8, 12, 18, and 24. In prespecified analyses, fold changes from baseline in adjusted mean levels of C-reactive protein (CRP) degraded by matrix metalloproteinase-1/8 (CRPM), CRP, Krebs von den Lungen-6 (KL-6), and surfactant protein D were analysed using a mixed model for repeated measures with fixed effects for treatment-by-visit and batch. Data were log10 transformed before analysis and estimates of changes from baseline were back-transformed.

RESULTS

Of the 273 patients treated in the INSTAGE trial, 163 (59.7%) were naïve to nintedanib therapy before entering the trial. At baseline, mean (standard deviation) forced vital capacity was 67.9% (19.3) and 66.1% (18.7) predicted, and mean (standard deviation) DLco was 25.8% (6.8) and 25.6% (7.0) predicted, in the nintedanib plus sildenafil and nintedanib plus placebo groups, respectively. Levels of CRPM appeared to be slightly reduced with nintedanib plus sildenafil compared with nintedanib alone. Levels of CRP were highly variable, with no consistent pattern observed in changes over 24 weeks in either treatment group. KL-6 levels were reduced with nintedanib plus sildenafil compared with nintedanib alone, while levels of surfactant protein D fell slightly, to a similar extent in both treatment groups over 24 weeks.

CONCLUSION

In the INSTAGE trial in patients with IPF and severely impaired gas exchange, biomarkers of extracellular matrix turnover (CRPM) and epithelial injury (KL-6) appeared to be reduced in subjects treated with nintedanib plus sildenafil compared with nintedanib alone for 24 weeks. These results are supportive of the potential clinical benefit of this combination suggested by clinical endpoints such as decline in forced vital capacity. The mechanisms by which nintedanib plus sildenafil might reduce KL-6 are unknown, but it is possible that the vascular effects of sildenafil2 might reduce pulmonary pressure and thus reduce lung injury and inflammation. Further analyses of data from the INSTAGE trial and other clinical trials such as the INMARK trial3 are needed to understand the changes in biomarkers observed in patients treated with nintedanib alone and nintedanib plus sildenafil.

References
Kolb M et al. Nintedanib plus sildenafil in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2018;379(18):1722-31. Milara J et al. Vascular effects of sildenafil in patients with pulmonary fibrosis and pulmonary hypertension: An ex vivo/in vitro study. Eur Respir J. 2016;47(6):1737-49. Maher TM et al. Biomarkers of extracellular matrix turnover in patients with idiopathic pulmonary fibrosis given nintedanib (INMARK study): A randomised, placebo-controlled study. Lancet Respir Med. 2019;7(9):771-9.