德國(guó)殷格翰2019年7月23日 /美通社/ -- 勃林格殷格翰宣布INMARK®試驗(yàn)結(jié)果已于7月17日在柳葉刀醫(yī)學(xué)雜志上發(fā)表。INMARK®是一項(xiàng)隨機(jī)、雙盲，在特發(fā)性肺纖維化(IPF)患者中進(jìn)行的維加特®（尼達(dá)尼布）與安慰劑的對(duì)照研究（研究持續(xù)12周），隨后為40周的開放性研究，勃林格殷格翰是該試驗(yàn)的參與方之一。INMARK®試驗(yàn)是首個(gè)在特發(fā)性肺纖維化(IPF)患者中使用抗纖維化治療（尼達(dá)尼布），研究生物標(biāo)記物預(yù)測(cè)值的的臨床試驗(yàn)。研究結(jié)果進(jìn)一步證明，即使在肺功能保持良好的早期IPF患者中，接受尼達(dá)尼布和安慰劑治療12周后，兩組患者的用力肺活量(FVC)下降值也存在顯著差異。1,2
IPF是一種罕見但嚴(yán)重的，具有致命性的肺部疾病，全球約有300萬(wàn)人受累。3 該疾病可引起肺部瘢痕的不斷加重，導(dǎo)致肺功能持續(xù)且不可逆轉(zhuǎn)的退化以及呼吸困難。4由于IPF的不可預(yù)測(cè)性以及肺功能喪失的不可逆性，專家認(rèn)為患者應(yīng)獲得及時(shí)有效的治療。1,5
INMARK®評(píng)估了患者從入組到12周后生物標(biāo)記物 -- 降解C反應(yīng)蛋白的變化率。降解C反應(yīng)蛋白是一種生物標(biāo)記物，之前被證實(shí)可預(yù)測(cè)特發(fā)性肺纖維化(IPF)患者的死亡率。此外試驗(yàn)還評(píng)估了發(fā)生疾病進(jìn)展的入組患者比例，其定義為預(yù)測(cè)用力肺活量絕對(duì)下降>=10%，或在52周內(nèi)死亡。1
與安慰劑相比，接受尼達(dá)尼布治療12周后并未影響生物標(biāo)記物降解C反應(yīng)蛋白的變化率，但與用力肺活量下降率的降低有關(guān)1。
29%的入組患者在隨訪52周內(nèi)，用力肺活量下降>=10%或死亡，強(qiáng)調(diào)了特發(fā)性肺纖維化(IPF)疾病進(jìn)展也存在于用力肺活量≥80%的人群中。
在12周時(shí)間內(nèi)，與安慰劑組相比，尼達(dá)尼布組患者的用力肺活量下降率更低（尼達(dá)尼布組為5.9（18.5）ml/12周，安慰劑組為?70.2（13.1）ml/12周）。
“即使肺功能維持良好的患者在分別使用尼達(dá)尼布與安慰劑治療12周后，也展現(xiàn)出了用力肺活量下降的明顯差異?？紤]到特發(fā)性肺纖維化(IPF)的不可預(yù)測(cè)性以及肺功能喪失的不可逆性，越來(lái)越多的證據(jù)表明盡早治療特發(fā)性肺纖維化(IPF)才是最佳方案。” 英國(guó)倫敦皇家布朗普頓醫(yī)院呼吸內(nèi)科顧問兼該研究的主要研究者托比·馬赫教授評(píng)論道。
勃林格殷格翰呼吸醫(yī)學(xué)副主管Susanne Stowasser博士說道：“生物標(biāo)記物研究是現(xiàn)代醫(yī)學(xué)的一個(gè)關(guān)鍵驅(qū)動(dòng)力，對(duì)了解健康和疾病狀態(tài)、診斷、藥物開發(fā)以及疾病進(jìn)程或治療效果的預(yù)測(cè)都有著巨大的影響。INMARK是首個(gè)在使用抗纖維治療的特發(fā)性肺纖維化(IPF)患者中探索生物標(biāo)志物預(yù)測(cè)值的臨床試驗(yàn)。由于對(duì)IPF知之甚少，多年來(lái)生物標(biāo)志物研究一直是該病的研究熱點(diǎn)，其主要研究方向是識(shí)別疾病預(yù)后的標(biāo)記物?！彼a(bǔ)充道：“肺纖維化持續(xù)對(duì)人們的生活造成毀滅性的影響。勃林格殷格翰致力于諸如INMARK試驗(yàn)之類的研究，以便讓我們更好地了解間質(zhì)性肺疾?。ㄈ鏘PF）在個(gè)體患者中的進(jìn)展情況，并識(shí)別出那些可以獲得最佳治療效果的患者。”
關(guān)于INMARK®
INMARK®試驗(yàn)包含347名患者（其中116名使用尼達(dá)尼布治療，另外231名對(duì)照組患者使用安慰劑治療），評(píng)估從入組到第12周（以ng/mL/月表示）的降解C反應(yīng)蛋白變化率（斜率），以及疾病進(jìn)展的受試者比例。疾病進(jìn)展的定義為在52周內(nèi)FVC預(yù)測(cè)值的絕對(duì)下降>=10%或死亡。1
與安慰劑相比，接受尼達(dá)尼布治療12周并未影響新表位CRPM血藥濃度的變化率。1與安慰劑組相比，在12周內(nèi)，使用尼達(dá)尼布治療的患者的用力肺活量下降率較低。1在接受安慰劑治療12周的患者中， 12周內(nèi)降解C反應(yīng)蛋白水平的升高與52周內(nèi)疾病進(jìn)展相關(guān)。1
此次試驗(yàn)患者入組時(shí)平均用力肺活量預(yù)測(cè)值為97.5%，被認(rèn)為肺容量保持良好。超過四分之一的患者在52周內(nèi)出現(xiàn)疾病進(jìn)展（FVC預(yù)測(cè)值下降≥10%或死亡）。1 用力肺活量是一項(xiàng)肺功能測(cè)試，用于測(cè)量最大程度深呼吸后從肺部用力呼出的空氣量。5肺功能會(huì)隨著特發(fā)性肺纖維化(IPF)的進(jìn)展而逐步、不可逆轉(zhuǎn)地惡化，這就是用用力肺活量下降來(lái)衡量的。
關(guān)于維加特（尼達(dá)尼布）
尼達(dá)尼布（維加特），是一種小分子的酪氨酸激酶抑制劑，由勃林格殷格翰開發(fā)用于治療特發(fā)性肺纖維化(IPF)成人患者。6 2015年，尼達(dá)尼布被納入更新版的特發(fā)性肺纖維化(IPF)國(guó)際治療指南。在各種IPF患者類型中，維加特均可延緩疾病進(jìn)展，降低肺功能年下降率達(dá)50%。8-16維加特已在全球超過70個(gè)國(guó)家及地區(qū)獲批上市用于治療特發(fā)性肺纖維化(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.
