Leveraging aging models of pulmonary fibrosis; the efficacy of nintedanib in aging

Nintedanib is one of two FDA-approved treatments for idiopathic pulmonary fibrosis (IPF). The clinical efficacy of nintedanib for inhibiting the progression of lung fibrosis is well-established [1]. However, although nintedanib is overwhelmingly prescribed to elderly patients, the impact of aging on its efficacy is difficult to discern from clinical data due to the magnitude of confounding variables that exist among human subjects (genetics, gender, comorbidities, disease stage at the onset of treatment, etc.). A recent post-hoc meta analysis of five IPF clinical trials suggested that the effect of nintedanib in reducing the rate of forced vital capacity decline is consistent across patients with age (patients >75 versus patients 75) versus 64 (<75) years. Further, one could argue that patients in both cohorts represent the elderly population. This study highlights the complexity of evaluating the impact of aging on efficacy in a clinical setting. To date, all pre-clinical efficacy studies with nintedanib have been performed in young animals. We therefore sought to determine whether aging impacts the efficacy of nintedanib for inhibiting the development of lung fibrosis. Bleomycin-induced lung injury in young (2 month) and aged (18 month) mice was followed by treatment with nintedanib or vehicle from day 10–21 (figure 1a), using a previously described protocol [3]. We previously demonstrated in this injury model that the severity of lung fibrosis is identical in young and aged mice, in terms of the net increase in total lung collagen following injury [4]. Although some prior studies have reported seemingly contradictory results, indicating increased severity of fibrosis in aged mice [5, 6], this discrepancy could be attributed to increased baseline levels of collagen in aged mice and the methodology/analyses used for fibrosis assessment, as the net increase in collagen appear to be similar in both young and aged mice [5, 6]. In line with our previous findings, both young and aged vehicle-treated mice demonstrated similar levels of fibrosis severity and a similar decline in lung function at 3 weeks post-injury (figure 1b-d, g-h). Also consistent with numerous prior reports [7, 8], we found that in young mice, nintedanib demonstrated efficacy for inhibiting the development of fibrosis (figure 1b-g) and led to improved lung function (figure 1h). Interestingly, nintedanib also significantly inhibited the development of lung fibrosis in aged mice, to a similar extent as young cohorts (figure 1b-g). Although nintedanib treatment resulted in lung functional improvement to a similar extent in both young (49%) and aged (57%) mice (figure 1h), results did not reach statistical significance in aged mice. Of note, there is less than 47% power to detect mean differences between the aged-vehicle and aged-nintedanib groups given the observed effect and sample sizes of aged mice; the trending p -value of 0.06 is displayed to provide a better understanding of the results. No significant differences in survival rate were observed between nintedanib- versus vehicle-treated groups for both young (68% versus 72%, respectively) and aged mice (83% versus 76%, respectively) during this treatment period (day 10–21). Overall, these data indicate that aging does not impact the efficacy of nintedanib in terms of its ability to inhibit the development of de novo lung fibrosis. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: Kosuke Kato report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study Conflict of Interest: Yoon-Joo Shin report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study. Conflict of Interest: Sunny Palumbo report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study. Conflict of Interest: Ioannis Papageorgiou report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study. Conflict of Interest: Seongmin Hahn report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study. Conflict of Interest: Joseph D. Irish report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study. Conflict of Interest: Skye P. Rounseville report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study. Conflict of Interest: Robert Krafty reports grants from NIH, outside the submitted work. Conflict of Interest: Lutz Wollin report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study. Conflict of Interest: Maor Sauler report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study. Conflict of Interest: Louise Hecker report grants from Boehringer Ingelheim Pharma GmbH & Co. KG., during the conduct of the study.