△至2020年，美國的濕性AMD（年齡相關性黃斑變性）患者很可能超過150萬人，而AMD是工業(yè)化國家致盲的主要原因
△此次申報數(shù)據(jù)主要是來自于Brolucizumab的HAWK和HARRIER III期研究的數(shù)據(jù)
△諾華使用了優(yōu)先審查通路獲得了Brolucizumab在美國的快速評審。若獲得FDA批準，預計該藥將于2019年底上市
昨日，諾華公司在巴塞爾宣布，美國食品藥品監(jiān)督管理局（FDA）已接受諾華公司用于治療濕性年齡相關性黃斑變性（AMD）的brolucizumab（RTH258）的生物藥許可證申請（BLA）。該種AMD亦稱為新生血管性AMD（nAMD）。為加速brolucizumab上市，諾華公司使用了優(yōu)先審查通路以期獲得快速審評。若得到FDA的批準，諾華預計將于2019年底上市brolucizumab。
據(jù)估計，至2020年，美國將有150萬至175萬人罹患濕性AMD，而濕性AMD是全球致盲的主要原因，也是一個日益嚴峻的公共衛(wèi)生問題1。隨著病情發(fā)展，患者可能會失去中心視力，導致無法進行日?；顒?。若不治療，視力會迅速惡化，可致失明2。
諾華制藥（美國）總裁Fabrice Chouraqui認為：“我們致力于重塑濕性AMD患者及其照護者的治療歷程。實現(xiàn)這一里程碑是其中重要一步。濕性AMD患者需要面對視力下降導致的巨大身心困擾，我們希望能夠為患者提供新的治療選擇?！?br>
“濕性AMD剝奪了人們的寶貴視力，對數(shù)百萬人的生活造成了巨大負擔。這些人不僅面臨視力喪失，而且還要承受對頻繁眼內(nèi)注射藥物的痛苦，”視力支持基金會執(zhí)行主任Dawn Prall George認為，“我們對這種前景光明的新治療方案十分期待，希望它們能幫助患者更好地控制這種嚴重損害性疾病?！?/p>
Brolucizumab（RTH258）是一種人源化單鏈抗體片段（scFv），是目前達到開發(fā)階段的臨床上最先進的人源化單鏈抗體片段。由于單鏈抗體片段體積小、組織滲透性強、從全身循環(huán)里快速清除及其藥物釋放特性，brolucizumab在藥物開發(fā)中受到高度關注7-9。
該專利創(chuàng)新結構使得藥物分子更小（26kDa），對所有血管內(nèi)皮生長因子VEGF-A異構體有強大抑制作用及高度親和力7-10。臨床前研究中，brolucizumab通過阻止配體-受體相互作用，抑制VEGF受體的激活7,9,10。VEGF信號通路增強的信號轉導與病理性眼部血管生成及視網(wǎng)膜水腫有關11。抑制VEGF通路已被證明能抑制脈絡膜視網(wǎng)膜血管疾病患者的新生血管病灶的生長，緩解視網(wǎng)膜水腫，改善視力12。
nAMD是北美、歐洲、澳大利亞和亞洲65歲以上人群嚴重失明和法定盲的主要原因，全球患者約2000萬至2500萬人2,13。nAMD是由異常血管形成于黃斑（視網(wǎng)膜中負責敏銳的中央視力的區(qū)域）下方所導致的。這些血管非常脆弱，有漏液現(xiàn)象，會破壞正常視網(wǎng)膜結構，最終導致黃斑的損害1,14,15。
nAMD的早期癥狀包括視物扭曲變形以及清晰視物的困難16。及時診斷及干預至關重要。隨著疾病發(fā)展，細胞損傷增加，視力進一步下降。如此下去，可致中央視力的完全喪失，使患者無法閱讀、駕駛或識別熟悉面孔14。若不治療，視力會迅速惡化2。
*Brolucizumab（RTH258）尚未在中國遞交新藥審批
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References
1. American Academy of Ophthalmology. Age-related macular degeneration preferred practice patterns. Available at: https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp-2015. Accessed March 2019.
2. van Lookeren Campagne M, et al. Mechanisms of age-related macular degeneration and therapeutic opportunities. J Pathol. 2014; 232(2):151-64. doi: 10.1002/path.4266.
3. ClinicalTrials.gov. Identifier NCT02307682. Available at https://clinicaltrials.gov/ct2/show/NCT02307682 (link is external). Accessed January 2019.
4. ClinicalTrials.gov. Identifier NCT02434328. Available at https://clinicaltrials.gov/ct2/show/NCT02434328 (link is external). Accessed January 2019.
5. Dugel P, et al. HAWK & HARRIER: 48-week results of 2 multi-centered, randomized, double-masked trials of brolucizumab versus aflibercept for neovascular AMD. Presented at: The American Academy of Ophthalmology 2017 Annual Meeting on November 10, 2017, New Orleans.
6. Dugel P, et al. Phase 3, randomized, double-masked, multi-center trials of brolucizumab versus aflibercept for neovascular AMD: 96-week results from the HAWK and HARRIER studies. Presented at: The American Academy of Ophthalmology on October 27, 2018, Chicago.
7. Escher D, et al. Single-chain antibody fragments in ophthalmology. Oral presentation at EURETINA congress. 2015. Abstract.
8. Nimz EL, et al. Intraocular and systemic pharmacokinetics of brolucizumab (RTH258) in nonhuman primates. The Association for Research in Vision and Ophthalmology (ARVO) annual meeting. 2016. Abstract 4996.
9. Gaudreault J, et al. Preclinical pharmacology and safety of ESBA1008, a single-chain antibody fragment, investigated as potential treatment for age related macular degeneration. ARVO Annual Meeting abstract. Invest Ophthalmol Vis Sci 2012;53:3025. http://iovs.arvojournals.org/article.aspx?articleid=2354604 (link is external). Accessed January 2019.
10. Tietz J, et al. Affinity and Potency of RTH258 (ESBA1008), a Novel Inhibitor of Vascular Endothelial Growth Factor A for the Treatment of Retinal Disorders. IOVS. 2015; 56(7):1501.
11. Qazi Y, et al. Mediators of ocular angiogenesis. J. Genet. 2009;88(4):495-515.
12. Kim R. Introduction, mechanism of action and rationale for anti-vascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol. 2007;55(6):413-415.
13. Wong, W.L. et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and met analysis. Lancet Glob Health. 2014 Feb;2 (2):e106-16.
14. World Health Organization. Priority eye diseases: Age-related macular degeneration. Available at http://www.who.int/blindness/causes/priority/en/index7.html (link is external). Accessed January 2019.
15. NHS Choices. Macular Degeneration. Available at http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Introduction.aspx (link is external). Accessed January 2019.
16. NHS Choices. Macular Degeneration - Symptoms. Available at http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Symptoms.aspx (link is external). Accessed January 2019.
