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Leveraging ageing models of pulmonary fibrosis: the efficacy of nintedanib in ageing
European Respiratory Journal ( IF 16.6 ) Pub Date : 2021-11-25 , DOI: 10.1183/13993003.00759-2021
Kosuke Kato 1 , Yoon-Joo Shin 1 , Sunny Palumbo 2 , Ioannis Papageorgiou 1 , Seongmin Hahn 2 , Joseph D Irish 2 , Skye P Rounseville 2 , Robert T Krafty 3 , Lutz Wollin 4 , Maor Sauler 5 , Louise Hecker 6, 7
Affiliation  

Nintedanib is one of two US Food and Drug Administration (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 ageing 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 years of age) [2]. However, it is important to note that the average age of IPF diagnosis is 66 years and the average patient ages in these cohorts were 78 (>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 ageing 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 ageing 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 ageing does not impact the efficacy of nintedanib in terms of its ability to inhibit the development of de novo lung fibrosis.



中文翻译:

利用肺纤维化的衰老模型:尼达尼布在衰老中的功效

尼达尼布是美国食品和药物管理局 (FDA) 批准的两种特发性肺纤维化 (IPF) 治疗药物之一。尼达尼布抑制肺纤维化进展的临床疗效已得到公认[1]。然而,尽管尼达尼布绝大多数开给老年患者,但由于人类受试者中存在大量混杂变量(遗传、性别、合并症、发病时的疾病阶段),很难从临床数据中辨别出衰老对其疗效的影响。治疗)。最近对五项 IPF 临床试验的事后荟萃分析表明,尼达尼布在降低用力肺活量下降率方面的作用在不同年龄的患者中是一致的(患者 > 75 岁对比<75 岁的患者)[2]。然而,值得注意的是,IPF 诊断的平均年龄为 66 岁,这些队列中的平均患者年龄为 78 岁(>75 岁),而64 (<75) 岁。此外,有人可能会争辩说,这两个队列中的患者都代表老年人群。本研究强调了在临床环境中评估衰老对疗效影响的复杂性。迄今为止,所有尼达尼布的临床前疗效研究均在幼年动物中进行。因此,我们试图确定衰老是否会影响尼达尼布抑制肺纤维化发展的功效。博来霉素诱导的年轻(2 个月)和老年(18 个月)小鼠肺损伤后,使用先前描述的方案 [3],从第 10 天到第 21 天用尼达尼布或载体治疗(图 1a)。我们之前在该损伤模型中证明,就损伤后总肺胶原蛋白的净增加而言,年轻和老年小鼠的肺纤维化严重程度是相同的 [4]。尽管一些先前的研究报告了看似矛盾的结果,表明老年小鼠的纤维化严重程度增加 [5, 6],但这种差异可能归因于老年小鼠胶原蛋白基线水平的增加以及用于纤维化评估的方法/分析,因为在年轻和老年小鼠中,胶原蛋白的净增加似乎相似 [5, 6]。与我们之前的研究结果一致,年轻和老年载体治疗的小鼠在损伤后 3 周表现出相似水平的纤维化严重程度和相似的肺功能下降(图 1b-d,g-h)。同样与许多先前的报道一致 [7, 8],我们发现在年轻小鼠中,尼达尼布显示出抑制纤维化发展的功效(图 1b-g)并导致肺功能改善(图 1h)。有趣的是,尼达尼布还显着抑制老年小鼠肺纤维化的发展,其程度与年轻小鼠相似(图 1b-g)。尽管尼达尼布治疗在年轻 (49%) 和老年 (57%) 小鼠中导致肺功能改善程度相似(图 1h),但在老年小鼠中结果未达到统计学意义。值得注意的是,鉴于观察到的效应和老年小鼠的样本量,检测老年车辆组和老年尼达尼布组之间的平均差异的功效不到 47%;趋势 p 鉴于观察到的效应和老年小鼠的样本量,检测老年车辆组和老年尼达尼布组之间的平均差异的功效低于 47%;趋势 p 鉴于观察到的效应和老年小鼠的样本量,检测老年车辆组和老年尼达尼布组之间的平均差异的功效低于 47%;趋势 p-显示 0.06 的值是为了更好地理解结果。在此治疗期间(第 10-21 天),年轻小鼠(分别为 68%72%)和老年小鼠(分别为 83%对76%)的尼达尼布治疗组载体治疗组之间的存活率没有显着差异. 总体而言,这些数据表明,就尼达尼布抑制新生肺纤维化发展的能力而言,衰老不会影响尼达尼布的疗效。

更新日期:2021-11-25
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