德国殷格翰2019年7月23日 /美通社/ -- 勃林格殷格翰宣布INMARK®试验结果已于7月17日在柳叶刀医学杂志上发表。INMARK®是一项随机、双盲，在特发性肺纤维化(IPF)患者中进行的维加特®（尼达尼布）与安慰剂的对照研究（研究持续12周），随后为40周的开放性研究，勃林格殷格翰是该试验的参与方之一。INMARK®试验是首个在特发性肺纤维化(IPF)患者中使用抗纤维化治疗（尼达尼布），研究生物标记物预测值的的临床试验。研究结果进一步证明，即使在肺功能保持良好的早期IPF患者中，接受尼达尼布和安慰剂治疗12周后，两组患者的用力肺活量(FVC)下降值也存在显著差异。1,2
IPF是一种罕见但严重的，具有致命性的肺部疾病，全球约有300万人受累。3 该疾病可引起肺部瘢痕的不断加重，导致肺功能持续且不可逆转的退化以及呼吸困难。4由于IPF的不可预测性以及肺功能丧失的不可逆性，专家认为患者应获得及时有效的治疗。1,5
INMARK®评估了患者从入组到12周后生物标记物 -- 降解C反应蛋白的变化率。降解C反应蛋白是一种生物标记物，之前被证实可预测特发性肺纤维化(IPF)患者的死亡率。此外试验还评估了发生疾病进展的入组患者比例，其定义为预测用力肺活量绝对下降>=10%，或在52周内死亡。1
与安慰剂相比，接受尼达尼布治疗12周后并未影响生物标记物降解C反应蛋白的变化率，但与用力肺活量下降率的降低有关1。
29%的入组患者在随访52周内，用力肺活量下降>=10%或死亡，强调了特发性肺纤维化(IPF)疾病进展也存在于用力肺活量≥80%的人群中。
在12周时间内，与安慰剂组相比，尼达尼布组患者的用力肺活量下降率更低（尼达尼布组为5.9（18.5）ml/12周，安慰剂组为−70.2（13.1）ml/12周）。
“即使肺功能维持良好的患者在分别使用尼达尼布与安慰剂治疗12周后，也展现出了用力肺活量下降的明显差异。考虑到特发性肺纤维化(IPF)的不可预测性以及肺功能丧失的不可逆性，越来越多的证据表明尽早治疗特发性肺纤维化(IPF)才是最佳方案。” 英国伦敦皇家布朗普顿医院呼吸内科顾问兼该研究的主要研究者托比·马赫教授评论道。
勃林格殷格翰呼吸医学副主管Susanne Stowasser博士说道：“生物标记物研究是现代医学的一个关键驱动力，对了解健康和疾病状态、诊断、药物开发以及疾病进程或治疗效果的预测都有着巨大的影响。INMARK是首个在使用抗纤维治疗的特发性肺纤维化(IPF)患者中探索生物标志物预测值的临床试验。由于对IPF知之甚少，多年来生物标志物研究一直是该病的研究热点，其主要研究方向是识别疾病预后的标记物。”她补充道：“肺纤维化持续对人们的生活造成毁灭性的影响。勃林格殷格翰致力于诸如INMARK试验之类的研究，以便让我们更好地了解间质性肺疾病（如IPF）在个体患者中的进展情况，并识别出那些可以获得最佳治疗效果的患者。”
关于INMARK®
INMARK®试验包含347名患者（其中116名使用尼达尼布治疗，另外231名对照组患者使用安慰剂治疗），评估从入组到第12周（以ng/mL/月表示）的降解C反应蛋白变化率（斜率），以及疾病进展的受试者比例。疾病进展的定义为在52周内FVC预测值的绝对下降>=10%或死亡。1
与安慰剂相比，接受尼达尼布治疗12周并未影响新表位CRPM血药浓度的变化率。1与安慰剂组相比，在12周内，使用尼达尼布治疗的患者的用力肺活量下降率较低。1在接受安慰剂治疗12周的患者中， 12周内降解C反应蛋白水平的升高与52周内疾病进展相关。1
此次试验患者入组时平均用力肺活量预测值为97.5%，被认为肺容量保持良好。超过四分之一的患者在52周内出现疾病进展（FVC预测值下降≥10%或死亡）。1 用力肺活量是一项肺功能测试，用于测量最大程度深呼吸后从肺部用力呼出的空气量。5肺功能会随着特发性肺纤维化(IPF)的进展而逐步、不可逆转地恶化，这就是用用力肺活量下降来衡量的。
关于维加特（尼达尼布）
尼达尼布（维加特），是一种小分子的酪氨酸激酶抑制剂，由勃林格殷格翰开发用于治疗特发性肺纤维化(IPF)成人患者。6 2015年，尼达尼布被纳入更新版的特发性肺纤维化(IPF)国际治疗指南。在各种IPF患者类型中，维加特均可延缓疾病进展，降低肺功能年下降率达50%。8-16维加特已在全球超过70个国家及地区获批上市用于治疗特发性肺纤维化(IPF)。
References
1. REF TO BE UPDATED WHEN FULL DETAILS AVAILABLE
2. Kolb M, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung function. Thorax, 2017; 72(4): 340-346.
3. Ley B, et al. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-40.
4. NHLBI, NIH. What Is Idiopathic Pulmonary Fibrosis? Accessed at: www.nhlbi.nih.gov/health/health-topics/topics/ipf/ Accessed April 2017.
5. Data on file. Boehringer Ingelheim. 2016.
6. Hilberg F, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774-4782.
7. Raghu G, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guidelines: Treatment of Idiopathic Pulmonary Fibrosis: Executive Summary. Am J Respir Crit Care Med. 2015; 192(2)238 – 248.
8. OFEV Summary of Product Characteristics. Boehringer lngelheim International GmbH. July 2017.
9. Richeldi L, et al; for the INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Eng J Med. 2014;370(22):2071-2082.
10. Kolb M, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. 2016. doi:l0.1136/thoraxjnl-2016-208710.
11. Raghu G, et al. Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am Journal Respir and Critl Care Med. 2016. doi:l0.1164/rccm.201602-04020C.
12. Cottin V, et al. Effect of baseline emphysema on reduction in FVC decline with nintedanib in the INPULSIS® trials. Abstract presented at: the 18th International Colloquium on Lung and Airway Fibrosis; Mont Tremblant, Canada, September 20-24, 2014.
13. Ryerson CJ, et al. Effect of baseline GAP index stage on decline in lung function with nintedanib in patients with idiopathic pulmonary fibrosis (IPF). Abstract presented at: the lllth American Thoracic Society Conference; San Francisco, California, May 13-18, 2016..
14. Wells A, et al. Effect of baseline composite physiologic index on benefit of nintedanib in IPF. Abstract presented at: the European Respiratory Society International Congress; London, England, September 3-7, 2015.
15. Maher TM, et al. No effect of baseline diffusing capacity of lung for carbon monoxide on benefit of nintedanib. Abstract presented at: the European Respiratory Society International Congress; London, England, September 3-7, 2015.
16. Keating GM. Nintedanib: a review of its use in patients with idiopathic pulmonary fibrosis. Drugs. 2015;75(10):1131-1140.
17. REF TO BE UPDATED WHEN FULL DETAILS AVAILABLE
18. Kolb M, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung function. Thorax, 2017; 72(4): 340-346.
19. Ley B, et al. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-40.
20. NHLBI, NIH. What Is Idiopathic Pulmonary Fibrosis? Accessed at: www.nhlbi.nih.gov/health/health-topics/topics/ipf/ Accessed April 2017.
21. Data on file. Boehringer Ingelheim. 2016.
22. Hilberg F, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774-4782.
23. Raghu G, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guidelines: Treatment of Idiopathic Pulmonary Fibrosis: Executive Summary. Am J Respir Crit Care Med. 2015; 192(2)238 – 248.
24. OFEV Summary of Product Characteristics. Boehringer lngelheim International GmbH. July 2017.
25. Richeldi L, et al; for the INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Eng J Med. 2014;370(22):2071-2082.
26. Kolb M, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. 2016. doi:l0.1136/thoraxjnl-2016-208710.
27. Raghu G, et al. Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am Journal Respir and Critl Care Med. 2016. doi:l0.1164/rccm.201602-04020C.
28. Cottin V, et al. Effect of baseline emphysema on reduction in FVC decline with nintedanib in the INPULSIS® trials. Abstract presented at: the 18th International Colloquium on Lung and Airway Fibrosis; Mont Tremblant, Canada, September 20-24, 2014.
29. Ryerson CJ, et al. Effect of baseline GAP index stage on decline in lung function with nintedanib in patients with idiopathic pulmonary fibrosis (IPF). Abstract presented at: the lllth American Thoracic Society Conference; San Francisco, California, May 13-18, 2016..
30. Wells A, et al. Effect of baseline composite physiologic index on benefit of nintedanib in IPF. Abstract presented at: the European Respiratory Society International Congress; London, England, September 3-7, 2015.
31. Maher TM, et al. No effect of baseline diffusing capacity of lung for carbon monoxide on benefit of nintedanib. Abstract presented at: the European Respiratory Society International Congress; London, England, September 3-7, 2015.
32. Keating GM. Nintedanib: a review of its use in patients with idiopathic pulmonary fibrosis. Drugs. 2015;75(10):1131-1140.
