2023年2月10日，復(fù)宏漢霖（2696.HK）宣布公司與億勝生物合作開(kāi)發(fā)的重組抗血管內(nèi)皮生長(zhǎng)因子(Vascular endothelial growth factor, VEGF)人源化單克隆抗體注射液HLX04-O的國(guó)際多中心III期臨床研究(NCT04740671)完成美國(guó)首例患者給藥，擬用于濕性年齡相關(guān)性黃斑變性(wet age-related macular degeneration, wAMD)的治療。該臨床研究此前已在澳大利亞和歐盟完成首例患者給藥。另一項(xiàng)在wAMD患者中開(kāi)展的針對(duì)HLX04-O的III期臨床研究亦于中國(guó)完成首例患者給藥。
此研究是一項(xiàng)在濕性年齡相關(guān)性黃斑變性（wAMD）患者中開(kāi)展的旨在比較HLX04-O與雷珠單抗的有效性和安全性的隨機(jī)、雙盲、陽(yáng)性對(duì)照的全球III期研究。合格的受試者將以1:1的比例隨機(jī)分為兩組，分別于48周內(nèi)每四周玻璃體腔內(nèi)注射HLX04-O（1.25 mg）或雷珠單抗（0.5mg）。其主要目的為比較第36周HLX04-O與雷珠單抗在wAMD患者研究眼中的有效性，主要終點(diǎn)為第36周最佳矯正視力（Best corrected visual acuity，BCVA）較基線改善的平均字母數(shù)變化。次要目的包括評(píng)估其他療效終點(diǎn)、安全性、耐受性以及藥代動(dòng)力學(xué)特征等。
HLX04-O是復(fù)宏漢霖利用基因工程技術(shù)構(gòu)建的一款重組抗VEGF人源化單克隆抗體注射液，能夠特異性結(jié)合血管內(nèi)皮生長(zhǎng)因子（Vascular endothelial growth factor, VEGF），阻斷VEGF與內(nèi)皮細(xì)胞上的受體Flt1（VEGFR-1）和KDR（VEGFR-2）結(jié)合，抑制其酪氨酸激酶信號(hào)通路的激活，進(jìn)而抑制內(nèi)皮細(xì)胞增生，減少新生血管生成，從而實(shí)現(xiàn)對(duì)wAMD等血管增生性眼部疾病的治療。根據(jù)眼科用藥需求，公司在貝伐珠單抗?jié)h貝泰 的基礎(chǔ)上保持活性成分不變，對(duì)處方、包裝材料、規(guī)格和生產(chǎn)工藝等進(jìn)行優(yōu)化，開(kāi)發(fā)了新的眼科制劑產(chǎn)品HLX04-O?？杀刃匝芯勘砻魃a(chǎn)工藝和制劑處方的變更對(duì)藥物制劑的質(zhì)量、安全性和有效性未產(chǎn)生不利影響。
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除已完成首例患者給藥的歐盟、澳大利亞及美國(guó)，HLX04-O亦獲得包括新加坡在內(nèi)的多個(gè)國(guó)家和地區(qū)的臨床試驗(yàn)許可。復(fù)宏漢霖將攜手億勝生物持續(xù)推動(dòng)HLX04-O的國(guó)際多中心III期臨床試驗(yàn)，以期憑借相關(guān)研究結(jié)果實(shí)現(xiàn)HLX04-O在中國(guó)、澳大利亞、歐盟和美國(guó)等全球多個(gè)國(guó)家和地區(qū)上市，成為首批獲得批準(zhǔn)用于眼科相關(guān)疾病治療的貝伐珠單抗，惠及全球眾多眼科疾病患者。未來(lái)，復(fù)宏漢霖也將積極推動(dòng)創(chuàng)新生物藥品的開(kāi)發(fā)，憑借已經(jīng)建立起的完善的創(chuàng)新研發(fā)平臺(tái)，持續(xù)高效地為全球患者提供可負(fù)擔(dān)的、療效更好的治療方案。
關(guān)于濕性年齡相關(guān)性黃斑變性
年齡相關(guān)性黃斑變性（AMD）是造成老年人視力損害和不可逆失明的主要原因之一[1]，根據(jù)世界衛(wèi)生組織報(bào)告，全球約有3000萬(wàn)AMD患者，每年約有50萬(wàn)人因?yàn)锳MD而致盲[2]。AMD致盲患者中，以脈絡(luò)膜新生血管（Choroidal neovascularization，CNV）為特征的濕性年齡相關(guān)性黃斑變性（wAMD）比例高達(dá)90%。隨著老年人口比例的不斷上升，wAMD已經(jīng)成為一個(gè)日益嚴(yán)重的社會(huì)醫(yī)學(xué)問(wèn)題，存在著巨大的未滿足的臨床需求[3]。隨著眼底治療方法的突破與發(fā)展，抗VEGF藥物已成為wAMD的一線療法[4]，貝伐珠單抗玻璃體注射治療wAMD的有效性和安全性也已在多項(xiàng)臨床研究中得到驗(yàn)證[5-11]。
關(guān)于復(fù)宏漢霖
復(fù)宏漢霖（2696.HK）是一家國(guó)際化的創(chuàng)新生物制藥公司，致力于為全球患者提供可負(fù)擔(dān)的高品質(zhì)生物藥，產(chǎn)品覆蓋腫瘤、自身免疫疾病、眼科疾病等領(lǐng)域，已在中國(guó)上市5款產(chǎn)品，在國(guó)際上市1款產(chǎn)品，18項(xiàng)適應(yīng)癥獲批，1個(gè)上市注冊(cè)申請(qǐng)獲得中國(guó)藥監(jiān)局受理。自2010年成立以來(lái)，復(fù)宏漢霖已建成一體化生物制藥平臺(tái)，高效及創(chuàng)新的自主核心能力貫穿研發(fā)、生產(chǎn)及商業(yè)運(yùn)營(yíng)全產(chǎn)業(yè)鏈。公司已建立完善高效的全球創(chuàng)新中心，按照國(guó)際藥品生產(chǎn)質(zhì)量管理規(guī)范（GMP）標(biāo)準(zhǔn)進(jìn)行生產(chǎn)和質(zhì)量管控，不斷夯實(shí)一體化綜合生產(chǎn)平臺(tái)，其中，上海徐匯基地已獲得中國(guó)和歐盟GMP認(rèn)證，松江基地（一）也已獲得中國(guó)GMP認(rèn)證。
復(fù)宏漢霖前瞻性布局了一個(gè)多元化、高質(zhì)量的產(chǎn)品管線，涵蓋20多種創(chuàng)新單克隆抗體，并全面推進(jìn)基于自有抗PD-1單抗H藥漢斯?fàn)?的腫瘤免疫聯(lián)合療法。繼國(guó)內(nèi)首個(gè)生物類似藥漢利康 （利妥昔單抗）、中國(guó)首個(gè)自主研發(fā)的中歐雙批單抗藥物漢曲優(yōu) （曲妥珠單抗，歐洲商品名：Zercepac ，澳大利亞商品名：Tuzucip 和Trastucip ）、漢達(dá)遠(yuǎn) （阿達(dá)木單抗）和漢貝泰 （貝伐珠單抗）相繼獲批上市，創(chuàng)新產(chǎn)品漢斯?fàn)?（斯魯利單抗）已獲批用于治療微衛(wèi)星高度不穩(wěn)定（MSI-H）實(shí)體瘤、鱗狀非小細(xì)胞肺癌和廣泛期小細(xì)胞肺癌，成為全球首個(gè)獲批一線治療小細(xì)胞肺癌的抗PD-1單抗，其食管鱗狀細(xì)胞癌適應(yīng)癥的上市注冊(cè)申請(qǐng)也正在審評(píng)中。公司亦同步就16個(gè)產(chǎn)品、12個(gè)免疫聯(lián)合治療方案在全球范圍內(nèi)開(kāi)展20多項(xiàng)臨床試驗(yàn)，對(duì)外授權(quán)全面覆蓋歐美主流生物藥市場(chǎng)和眾多新興市場(chǎng)。
First Patient in the US Dosed in a Global Multicentre Phase 3 Clinical Study of Henlius Bevacizumab for Treatment of Ophthalmic Diseases Shanghai, China, Feburary 10th, 2023 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the first patient in the United States (US) was dosed in a global multicentre phase 3 clinical trial (NCT04740671) of HLX04-O, a recombinant anti-VEGF humanised monoclonal antibody injection jointly developed by the company and Essex, for the treatment of wet age-related macular degeneration (wAMD). Previously, the first patients in the European Union (EU) and Australia were dosed in the same global multicenter phase 3 clinical trial of HLX04-O. Meanwhile, the first patient has been dosed in another phase 3 clinical trial in China for HLX04-O for the treatment of wAMD.
This randomised, double-blind, active-controlled, global phase 3 study aims to compare the efficacy and safety of HLX04-O with ranibizumab in patients with wet age-related macular degeneration (wAMD). Eligible patients will be randomised 1:1 to receive intravitreal injection of HLX04-O (1.25 mg) or ranibizumab (0.5 mg) every 4 weeks for 48 weeks. The primary objective is to compare the efficacy of HLX04-O with ranibizumab at Week 36 in patient’s study eye with wAMD. The primary endpoint is the mean change from baseline in the best-corrected visual acuity (BCVA) at Week 36. Secondary objectives include the evaluation of other efficacy endpoints, safety, tolerability, and pharmacokinetic profiles.
HLX04-O is a recombinant anti-VEGF humanized monoclonal antibody injection constructed using genetic engineering technology independently developed by Henlius. HLX04-O can inhibit VEGF’s binding to its receptor Flt-1 (VEGFR-1) and KDR(VEGFR-2) on endothelial cells to inhibit the activation of its tyrosine kinase signalling pathway, inhibit endothelial cell proliferation and reduce angiogenesis, thereby treating eye diseases associated with angiogenesis. According to the requirements of ophthalmic drugs, the Company has developed HLX04-O which optimizes the prescription, specifications, and production processes of HANBEITAI, assuming that the active ingredients remain unchanged. Through a series of comparability analysis, it is proved that the changes in the production process and prescription of the preparation have no adverse impact on the quality, safety and efficacy of the preparation.
In addition to the EU and Australia, the clinical trial applications of HLX04-O had been approved in Singapore and other countries and regions. Through the cooperation with Essex, Henlius will speed up the global multicentre clinical trials of HLX04-O and apply marketing authorization in China, Australia, the EU, and the US around the globe based on the research results. HLX04-O has the potential to be one of the first bevacizumab approved for ophthalmic diseases, benefiting more patients with eye diseases worldwide. Looking forward, Henlius will continue advancing the development of innovative biologics based on its established and integrated innovation platform, underscoring its long-term commitment to providing affordable and effective therapies for patients worldwide.
About wAMD Age-related macular degeneration is one of the leading causes of visual impairment and blindness in the elderly worldwide[1]. According to the World Health Organization (WHO), about 30 million people have suffered from AMD globally, and about half a million people become blind due to AMD each year[2]. Wet age-related macular degeneration (wAMD) is characterized by the formation of subretinal choroidal neovascularization (CNV) and is responsible for approximately 90% of cases of AMD-related blindness. Due to an aging population, wAMD has become a serious social medical problem and indicated a huge burden of unmet need[3]. With the development of treatment for fundus diseases, anti-VEGF drugs are becoming the first-line therapy for the management of wAMD[4], and the efficacy and safety of vitreous injection of bevacizumab for wAMD have been verified in multiple clinical studies[5-11].
About Henlius Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases and ophthalmic diseases. Up to date, 5 products have been launched in China, 1 approved for marketing in overseas markets, 15 indications approved worldwide, and 4 New Drug Applications (NDAs) accepted for review in China. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centers and Shanghai-based manufacturing facilities in line with global Good Manufacturing Practice (GMP), including Xuhui Plant certificated by China and the EU GMP and Songjiang First Plant certificated by China GMP.
Henlius has pro-actively built a diversified and high-quality product pipeline covering over 20 innovative monoclonal antibodies (mAbs) and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab, trade name in Europe: Zercepac ; trade names in Australia: Tuzucip and Trastucip , the first China-developed mAb biosimilar approved both in China and Europe, HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumors, squamous non-small cell lung cancer (sqNSCLC), and extensive-stage small cell lung cancer (ES-SCLC). Its NDA for the treatment of esophageal squamous cell carcinoma (ESCC) is under review. What"s more, Henlius has conducted over 20 clinical studies for 16 products and 12 immuno-oncology combination therapies, expanding its presence in major markets as well as emerging markets.
【參考文獻(xiàn)】
[1] 歐陽(yáng)靈藝, 邢怡橋. 抗VEGF藥物在濕性年齡相關(guān)性黃斑變性中的應(yīng)用進(jìn)展[J]. 國(guó)際眼科雜志, 2020(1).
[2] Resnikoff S, Pascolini D, Etya"ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004 Nov;82(11):844-51.
[3] Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-116.
[4] Li X R , Liu J P . Recognition of anti-VEGF therapy base on the mechanism of VEGF in wet age-related macular degeneration[J]. Zhonghua Shiyan Yanke Zazhi/Chinese Journal of Experimental Ophthalmology, 2012, 30(4):289-292.
[5] Tufail A, Patel PJ, Egan C, Hykin P, da Cruz L, Gregor Z, Dowler J, Majid MA, Bailey C, Mohamed Q, Johnston R, Bunce C, Xing W; ABC Trial Investigators. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomized double masked study. BMJ. 2010 Jun 9;340:c2459.
[6] Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011 May 19;364(20):1897-908.
[7] Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Wordsworth S, Reeves BC. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012 Jul;119(7):1399-411.
[8] Kodjikian L, Souied EH, Mimoun G, Mauget-Fa sse M, Behar -Cohen F, Decullier E, Huot L, Aulagner G; GEFAL Study Group. Ranibizumab versus Bevacizumab for Neovascular Agerelated Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial. Ophthalmology. 2013 Nov;120(11):2300-9.
[9] Krebs I, Schmetterer L, Boltz A, Told R, Vécsei-Marlovits V, Egger S, Sch nherr U, Haas A, Ansari-Shahrezaei S, Binder S; MANTA Research Group. A randomized double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. Br J Ophthalmol. 2013 Mar;97(3):266-71.
[10] Berg K, Pedersen TR, Sandvik L, Bragadóttir R. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015 Jan;122(1):146-52.
[11] Schauwvlieghe AM, Dijkman G, Hooymans JM, Verbraak FD, Hoyng CB, Dijkgraaf MG,Peto T, Vingerling JR, Schlingemann RO. Comparing the Effectiveness of Bevacizumab to Ranibizumab in Patients with Exudative Age-Related Macular Degeneration. The BRAMD Study. PLoS One. 2016 May 20;11(5):e0153052.
