2021-04-23

復星醫藥:復宏漢霖創新抗PD-1單抗斯魯利單抗上市註冊申請獲NMPA受理,擬納入優先審評程式

2021年4月22日,複宏漢霖(2696.HK)宣佈,自主研製的創新型PD-1抑制劑斯魯利單抗注射液(HLX10)針對經標準治療失敗的、不可切除或轉移性高度微衛星不穩定型(Microsatellite Instability-High,MSI-H)實體瘤適應症的上市註冊申請(NDA)正式獲得國家藥品監督管理局(NMPA)受理,並擬納入優先審評程式, 有望成為國內首個治療MSI-H實體瘤的抗PD-1單抗。 該適應症依據特定的MSI-H腫瘤標誌物進行篩查,不以癌種進行區分,覆蓋患者群體廣泛。 圍繞斯魯利單抗,企业採取了“Combo+Global”(聯合治療+國際化)的差异化開發戰畧,在適應症選擇和聯合治療上重點發力,已於全球範圍內同步開展10項臨床試驗。
斯魯利單抗單藥治療高度微衛星不穩定型或錯配修復缺陷型(MSI-H/dMMR)實體瘤的II期臨床研究聯合主要研究者,南京金陵醫院腫瘤中心秦叔逵教授表示:
“?
斯魯利單抗在臨床前研究和早期臨床研究中已展現出優秀的抗腫瘤活性,本次針對MSI-H實體瘤的II期臨床研究結果顯示產品療效及安全性優异。 期待質量、療效均有保證的國產創新型PD-1抑制劑早日上市,讓更多MSI-H實體瘤患者獲得高品質的免疫治療新選擇。
複宏漢霖執行董事、首席執行官兼總裁張文傑先生表示:
“?
斯魯利單抗是複宏漢霖覈心創新單抗產品,企业對其實施差异化開發,重點佈局免疫聯合療法和國際臨床研究,現各項研究正在加速推進中。 斯魯利單抗的NDA受理離不開所有受試者、研究人員的支撑以及團隊各位同事的努力,我們將儘快推進該產品更多適應症的上市行程,持續開拓海外市場,惠及更多患者。

適應症全面覆蓋高發癌種
多項研究進入關鍵臨床3期

圍繞“Combo+Global”的戰略部署,現時企业已開展斯魯利單抗的2項單藥及8項聯合療法臨床試驗,積極就化療、自有VEGF、EGFR靶點單抗等治療方案進行免疫聯合療法,不僅全面覆蓋了肺癌、食管癌、肝細胞癌、胃癌、頭頸癌等高發大瘤種,並針對中國的癌症發病人群特點實施差异化臨床開發。 其中,胃癌新輔助/輔助領域中PD-1抑制劑相關的探索較少,複宏漢霖聚焦該適應症開展3期臨床研究,在這一細分領域上處於國際領先地位,有望使胃癌患者在前線便從腫瘤免疫療法中獲益。 此外,針對一線鱗狀非小細胞肺癌、一線非鱗狀非小細胞肺癌及一線小細胞肺癌的斯魯利單抗聯合治療均已進入關鍵性3期研究階段,在肺癌一線治療中實現了全面佈局。 斯魯利單抗聯合化療一線治療鱗狀非小細胞肺癌的上市註冊申請有望於今年下半年遞交。


斯魯利單抗臨床研究進展

多方位國際化佈局,惠及新興國家市場
斯魯利單抗的研發嚴格按照國際標準,該產品的生產基地已通過歐盟和中國的GMP認證。 企业針對斯魯利單抗前瞻性地進行了國際佈局,已於中國、美國、歐盟等國家和地區獲得批准開展臨床試驗,並於中國、土耳其、波蘭、烏克蘭、俄羅斯等國家及地區累計入組近2000名受試者,印證了國際市場對企业產品品質的信心與認可。 同時,複宏漢霖也希翼憑藉豐富的國際臨床研究數據,通過國際合作等管道惠及歐盟、美國及新興市場的更多患者。 現時,企业已與PT Kalbe Genexine Biologics(KG Bio)達成合作協定,授予其斯魯利單抗首個單藥療法及兩項聯合療法在東南亞地區10個國家的獨家開發和商業化權利。

隨著“Combo+Global”戰畧的不斷深入,以斯魯利單抗為先導,複宏漢霖持續打造豐富的創新藥候選產品管線,積極加速多元化創新,提高創新效率,致力於持續為全球患者帶來可負擔的高品質創新生物藥。
關於MSI-H實體瘤
微衛星不穩定通常由於基因的錯配修復功能缺失,使DNA複製過程中微衛星序列堿基插入或錯配,造成錯誤堿基累積所致[1]。 其中,高度微衛星不穩定常發生在多個癌種中,如子宮內膜癌、結直腸癌、胃癌、腎細胞癌、卵巢癌等[2],有研究顯示MSI-H在所有癌種中的發生率約為14%[3],該類患者通常對於免疫檢查點抑制劑有較高的應答率-1,MSI-H也越來越成為預測實體瘤患者免疫治療效果的重要生物標誌物。 若患者被檢測出這一腫瘤標誌物呈陽性且符合治療標準,即可進行相應的腫瘤免疫治療,而不需要按照傳統的腫瘤原發灶部位與病理分型對患者進行篩選,符合精准治療的先進理念,適用癌種範圍廣泛。 現時美國食品藥品監督管理局(US FDA)已準予PD-1靶點藥物用於治療既往一線標準治療失敗的MSI-H/dMMR晚期實體瘤及一、二線MSI-H/dMMR結直腸癌等適應症,我國尚未有針對MSI-H/dMMR晚期實體瘤獲批的抗PD-1單抗,治療需求遠未被滿足。
關於複宏漢霖
複宏漢霖(2696.HK)是一家國際化的創新生物製藥企业,致力於為全球患者提供可負擔的高品質生物藥,產品覆蓋腫瘤、自身免疫疾病、眼科疾病等領域,已在中國上市3款產品,在歐盟上市1款產品,3款產品獲得中國上市註冊申請受理。 自2010年成立以來,複宏漢霖已建成一體化生物製藥平臺,高效及創新的自主核心能力貫穿研發、生產及商業運營全產業鏈。 企业已建立完善高效的全球研發中心,按照國際GMP標準進行生產和質量管控,位於上海徐匯的生產基地已獲得中國和歐盟GMP認證。

複宏漢霖前瞻性佈局了一個多元化、高品質的產品管線,涵蓋20多種創新單克隆抗躰,並全面推進基於自有抗PD-1單抗斯魯利單抗的腫瘤免疫聯合療法。 繼國內首個生物類似藥漢利康 ® (利妥昔單抗)、中國首個自主研發的中歐雙批單抗藥物漢曲優 ® (曲妥珠單抗,歐盟商品名:Zercepac ®)、 企业首個自身免疫疾病治療產品漢達遠 ® (阿達木單抗)相繼獲批上市,企业HLX04貝伐珠單抗及兩款創新藥HLX01利妥昔單抗類風濕關節炎新適應症、斯魯利單抗MSI-H實體瘤的上市註冊申請也正在審評中。 企业亦同步就10個產品、8個聯合治療方案在全球範圍內開展20多項臨床試驗,對外授權全面覆蓋歐美主流生物藥市場和眾多新興國家市場。

The NDA of the Novel Anti-PD-1 mAb Serplulimab of Henlius Accepted by NMPA and Proposed to be Granted Priority Review ?

Shanghai, China, April 22th, 2021 –Shanghai Henlius Biotech, Inc. (2696.HK) announced that the New Drug Application (NDA) of serplulimab injection (HLX10), a novel anti-PD-1 monoclonal antibody (mAb), for the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) solid tumors that fail to respond to the standard therapy, has been accepted by the National Medical Products Administration (NMPA) and proposed to be granted priority review. Serplulimab is potentially to be the first anti-PD-1 mAb in MSI-H solid tumors in China. For this indication, patients are screened for specific MSI-H tumor markers, rather than classifying the tumor types, covering a wide range of cancer types. Henlius adopts the “Combo+Global” development strategy for serplulimab, focusing on indication differentiation and combination therapy, with a total of 10 clinical trials conducted worldwide.

The co-leading principal investigator of serplulimab Phase 2 clinical trial in unresectable or metastatic microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) solid tumors, Professor Shukui Qin of Cancer Center of Nanjing Jinling Hospital, said, ” Serplulimab showed excellent anti-tumor activity in preclinical and early-stage clinical studies, and the results of the Phase 2 clinical study in MSI-H solid tumors also states the favorable safety and efficacy. We hope that this China-developed novel PD-1 inhibitor will be launched as soon as possible, so that more patients with solid tumors could be accessible to high quality immunotherapy new options.”

Executive Director, Chief Executive Officer and President of Henlius, Mr. Wenjie Zhang, said, “Serplulimab is the core innovative mAb of Henlius. Focusing on combination immunotherapy and international clinical trials, we have built up a differentiation development strategy for the product. Steady progress has been made in all clinical studies. We are very grateful to all the subjects, physicians and colleagues that have contributed to the NDA acceptance of serplulimab. We will push forward the clinical process in more indications as soon as possible and look forward to benefiting more patients around the world.”

Several pivotal Phase 3 clinical trials covering comprehensive cancer types with high incidence

With the"Combo+Global" strategy, steady progress has been made in the clinical studies of 2 monotherapies and 8 combination therapies of serplulimab with chemotherapy, in-house VEGF and EGFR targets mAbs. Henlius actively carries out combination therapies that cover a wide range of tumor types with high incidence such as lung cancer, esophageal cancer, hepatocellular cancer,gastric cancer, head and neck cancer, and implements differentiation clinical development based on the Chinese cancer characteristics. Among them, while there are few explorations in the gastric cancer neoadjuvant/adjuvant area of PD-1 inhibitors, Henlius has conducted Phase 3 clinical studies in this field, leading the clinical trial progress around the globe, with the aim of enabling gastric cancer patients to benefit from the early line of immunotherapy. What’s more, the company has achieved all-around layout in the first-line of lung cancer, and has entered pivotal Phase 3 clinical trials in first-line squamous non-small cell lung cancer (sqNSCLC), first-line non-squamous non-small cell lung cancer (nsqNSCLC) and first-line small cell lung cancer (SCLC). The NDA filing of HLX10 in combination with chemotherapy for the first-line treatment of sqNSCLC in China will also be expected in the second half of 2021.

The all-around international layout to benefit emerging markets
The manufacturing and development of serplulimab is strictly in accordance with international standards and its manufacturing facility based in Shanghai has passed the European Union (EU) and China GMP certification. Henlius developed the international layout for serplulimab, which has been approved for clinical trials in China, the United States, the EU and other countries and regions. About 2000 patients have been enrolled in China, Turkey, Poland, Ukraine, Russia, etc., which shows confidence and recognition on the quality of the product in the international market. Apart from conducting international trials of HLX10, Henlius also actively seeks for international cooperation opportunities with the aim of benefiting more patients in the world, especially patients in emerging markets. Henlius has reached a collaboration agreement with PT Kalbe Genexine Biologics (KG Bio), upon which KG Bio is granted exclusive rights to develop and commercialize serplulimab in relation to its first monotherapy and two combination therapies in 10 Southeast Asian countries.

With the continuous development of the "Combo+Global" strategy, Henlius continues to build a diversified pipeline of innovative drug candidates with serplulimab as the lead, actively accelerating innovation and improving innovation efficiency, and committing to bringing affordable and high-quality innovative biologics to patients around the world.
About MSI-H solid tumors
The defect of mismatch repair (MMR) that can lead to base mismatch or insert in microsatellites during DNA replication, and the accumulation of incorrect bases usually causes microsatellite instability (MSI)[1]. MSI-H often occurs in several cancer types, such as endometrial cancer, colorectal cancer, gastric cancer, renal cell carcinoma, ovarian cancer, etc[2]. Studies have revealed that the prevalence of MSI-H across all tumor types is 14%[3]. Patients who suffer from this disease usually have higher response rates for immune checkpoint inhibitors-1. Thus, MSI-H is becoming a more and more important biomarker for the immunotherapy predictions of patients with solid tumors. If the patient is MSI-H positive and meets the treatment criteria, the corresponding immunotherapy can be carried out without screening tumor sites and pathological classification, which aligns with the advanced concept of precision medicine and is applicable to a wide range of cancer types. Currently, the U.S. Food and Drug Administration (US FDA) has approved PD-1 target mAb for the treatment of second-line MSI-H/dMMR advanced solid tumors and first/second-line MSI-H/dMMR colorectal cancers. While there are still no anti-PD-1 mAb approved for MSI-H/dMMR advanced solid tumors in China, the treatment needs are far from being met.
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, 3 products have been launched in China, 1 in the European Union (EU), the New Drug Applications (NDA) of 3 products 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 commercialisation. It has established global R&D centers and a Shanghai-based manufacturing facility certificated by China and the EU Good Manufacturing Practice (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 serplulimab (anti-PD-1 mAb) as backbone. Apart from the launched products 漢利康 ® (rituximab), the first China-developed biosimilar, 漢曲優 ®(trastuzumab, Zercepac® in the EU), the first China-developed mAb biosimilar approved both in China and in the EU and 漢達遠 ® (adalimumab), the Company's first product indicated for autoimmune diseases, the NDA of HLX04 (bevacizumab) and the two innovative mAbs HLX01 (rituximab) for the treatment of rheumatoid arthritis and serplulimab indicated for MSI-H solid tumors are under review. What's more, Henlius has conducted over 20 clinical studies for 10 products and 8 combination therapies worldwide, expanding its presence in major market as well as emerging market.


【參考文獻】
[1] Yang G, Zheng RY, Jin ZS. Correlations between microsatellite instability and the biological behaviour of tumours. J Cancer Res Clin Oncol.2019 Dec;145(12):2891-2899.
[2] Hause, R., Pritchard, C., Shendure, J. et al. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med22, 1342–1350 (2016).
[3] Lorenzi M, Amonkar M, Zhang J, et al. Epidemiology ofMicrosatellite Instability High (MSI-H) and Deficient Mismatch Repair (dMMR) inSolid Tumors: A Structured Literature Review[J]. Journal of Oncology, 2020,2020.
[4] Michael J Overman, Ray McDermott, Joseph L Leach, et al. Nivolumab in patients with metastatic DNA mismatch repair deficient/microsatelliteinstability-high colorectal cancer (CheckMate 142): results of an open-label,multicenter, phase 2 study[J]. Lancet Oncology, 2017,18(9):1182-1191.
[5] Aurelien Marabelle, Dung T Le, Paolo A Asciert, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase IIKEYNOTE-158 Study[J]. J Clin Oncol, 2020, 38(1): 1-10.


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