2023年12月27日，复宏汉霖（2696.HK）宣布，基于与宜联生物的合作，公司开发的EGFR靶向抗体偶联药物（antibody-drug-conjugate, ADC）注射用HLX42获得美国食品和药物监督管理局（FDA）授予快速通道资格（fast track designation, FTD），用于治疗经第三代EGFR酪氨酸激酶抑制剂治疗后疾病进展的EGFR突变的晚期/转移性非小细胞肺癌（NSCLC）。此前，HLX42用于治疗晚期/转移性实体瘤治疗的临床试验申请已经相继获得中国国家药品监督管理局（NMPA）、美国FDA许可。

复宏汉霖全球创新中心总经理单永强博士

很高兴我们在ADC开发领域接连取得重要进展。此次HLX42获得FDA授予快速通道资格，标志着其在治疗重大疾病和未满足临床需求中的潜力得到认可。未来，复宏汉霖也将持续聚焦未满足的临床需求，加速更多创新产品的研发步伐，让更多、更好的治疗方案早日惠及全球患者。

FDA授予的快速通道资格认定适用于有潜力治疗严重疾病及解决重要未满足临床需求的药物，并给予促进开发和加快审评的政策支持，包括但不限于（1）获得与FDA更多会议讨论、书面沟通的机会，从而在药物研发、临床试验设计等方面获得更加密切的指导；（2）在符合相关标准条件时获得优先审评和加速批准；（3）可通过滚动审评方式递交新药上市申报材料。

据GLOBOCAN 2020数据显示，肺癌是全球发病率第二大、死亡率第一的恶性肿瘤，2020年全球约有超过220万新发肺癌病例，占癌症新发病例的11.4%[1]。NSCLC约占所有肺癌的80%-85%[2]，其中EGFR突变比例在亚裔NSCLC患者中高达50%，在高加索人群中约占10%[3]。目前，包括EGFR酪氨酸激酶抑制剂（TKI）在内的EGFR靶向治疗是EGFR突变的晚期NSCLC患者的标准一线治疗，然而经治疗后出现疾病进展的患者，在后续治疗中选择有限，存在巨大未被满足的临床需求[4,5]。

HLX42为一款靶向表皮生长因子受体（EGFR）的新型ADC候选药物，是复宏汉霖首批进入临床阶段的ADC产品之一。兼具抗体分子的高度靶向性和细胞毒素的强大杀伤力，HLX42已经在临床前药效研究、药代动力学研究及安全性评价中展现出良好的抗肿瘤活性和安全性。在第三代EGFR TKI（奥希替尼）或抗EGFR单克隆抗体（西妥昔单抗）耐药的非小细胞肺癌、结直肠癌等肿瘤模型中，HLX42显示出良好的肿瘤杀伤效果，有望克服现有靶向EGFR治疗的耐药机制，填补更多晚期/转移性实体瘤患者未满足的临床需求。公司也计划启动一项I期临床研究，评估HLX42在晚期/转移性实体瘤患者中的安全性、耐受性及药代动力学特征。

此外，基于公司丰富的多元化产品管线和具备差异化优势的免疫基石产品H药汉斯状®（抗PD-1单抗），HLX42的开发也将为公司开展ADC联合免疫治疗，突破现有药物的治疗瓶颈提供更多可能。未来，复宏汉霖也将持续立足于未满足的临床需求，以抗体技术为核心，加速释放新型偶联技术发展动能，积极探索新靶点、新机制，不断拓展疾病领域和新药物分子类型，为全球患者带来更多高质量、可负担的创新治疗方案。

关于HLX42

HLX42为一款靶向表皮生长因子受体（EGFR）的新型ADC候选药物，由高度特异性的人源化lgG1 EGFR抗体分子、可裂解的新型连接子-荷载毒素偶联制备而成，其药物抗体比（drug-to-antibody ratio, DAR）约为8。HLX42的荷载毒素为一种新型DNA拓扑异构酶I（Topoisomerase I）小分子抑制剂，通过造成DNA双链断裂，阻断DNA复制，从而导致肿瘤细胞凋亡。静脉输注后，HLX42的连接子-毒素能够在肿瘤微环境中特异性裂解释放，具备较强的旁观者杀伤效应，独特的作用机制使得HLX42较同类ADC产品具有更大的治疗窗口，增强ADC在实体肿瘤中的治疗效果。

关于复宏汉霖

复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已在中国上市5款产品，在国际上市1款产品，19项适应症获批，3个上市申请分别获中国NMPA、美国FDA和欧盟EMA受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，上海徐汇基地和松江基地（一）均已获得中国和欧盟GMP认证。

复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖20多种创新单克隆抗体，并全面推进基于自有抗PD-1单抗H药汉斯状®的肿瘤免疫联合疗法。继国内首个生物类似药汉利康®（利妥昔单抗）、中国首个自主研发的中欧双批单抗药物汉曲优®（曲妥珠单抗，欧洲商品名：Zercepac®，澳大利亚商品名：Tuzucip®和Trastucip®）、汉达远®（阿达木单抗）和汉贝泰®（贝伐珠单抗）相继获批上市，创新产品汉斯状®（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、广泛期小细胞肺癌和食管鳞状细胞癌，并成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。公司亦同步就16个产品在全球范围内开展30多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴市场。

FDA Grants Fast Track Designation to Henlius’ EGFR-Targeting ADC HLX42 for NSCLC Patients with Disease Progression on EGFR Targeted Therapies

Shanghai, China, December 27, 2023 – Shanghai Henlius Biotech, Inc. (2696. HK) announced that the U.S. Food and Drug Administration (FDA) granted Fast Track Designation(FTD) for HLX42, an investigational EGFR-Targeting ADC that developed by the company based on the collaboration with MediLink Therapeutics, for the treatment of patients with advanced or metastatic EGFR-mutated non-small cell lung cancer whose disease has progressed on a 3rd-generation EGFR tyrosine kinase inhibitor.  Previously, HLX42 was approved for conducting clinical trial by the National Medical Products Administration (NMPA) and FDA.

Yongqiang Shan, general manager of Henlius’ Global Innovation Center, said: “I am glad to see the continuous progress we have made in advancing our ADC portfolio. The grant of FTD represents FDA's recognition of HLX42's potential in addressing serious diseases that filled unmet medical needs. In the future, Henlius will maintain our focus on areas of unmet medical needs and accelerate the development and delivery of innovative treatments, providing safe and effective care for patients worldwide.”

Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. According to the FDA, a drug that receives Fast Track designation is eligible for certain policy support, including but not limited to: 1) more opportunities for meetings and written communication with FDA to obtain closer guidance in drug development, clinical trial design, etc.; 2) eligibility for Accelerated Approval and Priority Review if relevant criteria are met; 3) accelerate path to FDA submission through Rolling Review.

According to GLOBOCAN data, lung cancer (LC) is the second commonly diagnosed cancer globally with the highest mortality rate. It is estimated that there are more than 2,200,000 new cases with LC and accounts for 11.4% of the global cancer incidence in 2020[1]. About 80%-85% of LC are NSCLC[2], and EGFR mutations are found in approximately 10% of white patients with NSCLC and up to 50% of Asian patients[3]. At present, EGFR targeted therapies, including EGFR tyrosine kinase inhibitors (TKIs), are the first-line treatment for advanced NSCLC patients with EGFR mutations, yet patients who experience disease progression after treatment have limited options for subsequent therapies[4,5]. Therefore, an great unmet medical need exists and new therapeutic approaches are required.

HLX42 is a novel antibody-drug conjugate (ADC) candidate that targeting epidermal growth factor receptor (EGFR) and being one of the first ADC products of Henlius to enter into clinical development. Combining the selectivity of targeted mAb with the highly potent cytotoxic agent, HLX42 has exhibited good anti-tumour effects and a favorable safety profile in preclinical efficacy studies, pharmacokinetic studies and safety evaluation. Meanwhile, HLX42 has shown potent tumour suppression in several CDX and PDX models that were EGFR TKIs or cetuximab resistant, which is expected to overcome the resistance of existing EGFR targeted therapies and fill the unmet clinical needs of more patients with advanced/metastatic solid tumours. And a phase 1 clinical trial will be initiated to evaluate the safety, tolerance and pharmacokinetics of HLX42 in patients with advanced/metastatic solid tumours.

With Henlius’ diversified portfolio and cornerstone product HANSIZHUANG, the company will further explore the potential of ADCs combining immunotherapies to provide more effective treatment options to fulfill the unmet clinical needs. Looking forward, Henlius will further take efforts to promote the layout of our innovative portfolio by focusing on antibody and novel conjugating technologies, bringing more high-quality and affordable therapeutics for patients worldwide.

About HLX42

HLX42 is a novel EGFR-targeting ADC candidate, comprised of a high-affinity humanised IgG1 mAb targeting EGFR conjugated with a novel cytotoxic payload through cleavable linkers, with the drug-to-antibody ratio is about 8. The cytotoxic payload of HLX42 is a novel DNA topoisomerase-I inhibitor which can cause double-strand breaks (DSBs) of DNA, block the replication machinery, thus trigger cancer cell apoptosis. When injected intravenously into the body, HLX42 linker-payload will be cleaved and released in tumour microenvironment (TME) with strong bystander killing effects. This unique mechanism of TME activation and payload release allows HLX42 to possess a higher therapeutic index and potency for treatment of solid tumours.

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 has been approved for marketing in overseas markets, 19 indications are approved worldwide, and 3 marketing applications have been accepted for review in China, the U.S., and the EU, respectively. 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 Facility and Songjiang First Plant, both certificated by China and the EU 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 for injection, 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), and esophageal squamous cell carcinoma (ESCC), making it the world's first anti-PD-1 mAb for the first-line treatment of SCLC. What's more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets.

【参考文献】

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249.

[2] About Lung Cancer. American Cancer Society. https://www.cancer.org/content/dam/CRC/PDF/Public/8703.00

[3] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Non-Small Cell Lung Cancer. Version 3.2023

[4] Cooper, A.J., Sequist, L.V. & Lin, J.J. Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol 19, 499–514 (2022).

[5] Ricordel, C., et al. "Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer." Annals of Oncology 29 (2018): i28-i37.