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默克/GSK建立全球合作联盟,签订37亿欧元升级版PD-1开发协议

医药魔方 医药魔方 来源:医药魔方
2019-02-06
药企合作 PD-1
原文

2月5日,德国默克与GSK宣布双方达成全球战略合作联盟,联合开发靶向PD-L1/TGF-β的双功能融合蛋白类肿瘤免疫疗法M7824(bintrafusp alfa)。 


根据协议,默克可以从GSK获得3亿欧元首付款,基于肺癌临床数据的5亿欧元研发里程金,以及未来29亿欧元的上市和商业销售里程金,整个交易的总额达到37亿欧元。双方将共同负责M7824未来在全球范围内的临床开发及商业推广,由此产生的成本和利润也由双方平等分担。


M7824是一种双功能的融合蛋白,一端是能够识别结合PD-L1的抗体结构(Y),另一端是可以结合TGF-β的TGF-β受体II型融合蛋白(Trap),能够同时阻断PD-L1和TGF-β这两条信号通路,解除免疫系统的抑制状态,提高免疫系统对癌症细胞的杀伤作用。



截至目前,有10种以上不同癌症类型的近700例患者在I期研究中接受了M7824 的治疗。M7824在晚期NSCLC、人HPV病毒相关癌症、胆道癌、胃癌等多种难治性癌症中显示出了令人兴奋的临床数据。ASCO2018大会上公布的M7824的两项早期临床数据也成为大家关注的焦点。


1)接受过铂类药物化疗但未接受过PD-1抑制剂的IV期NSCLC患者,分别接受500mg(n=40)和1200mg(n=40)M7824单药治疗。数据显示,1200mg高剂量组患者的ORR为27.5%,其中PD-L1阳性(PD-L1>1%)患者的ORR达到40.7%(n=11/27)。PD-L1高表达(PD-L1>80%)患者的ORR高达71.4%(n=5/7),优于PD-1抑制剂一般20%-40%的应答率。


2)HPV相关癌症患者使用不同剂量的M7824进行治疗,其中12位确定携带HPV感染。对于这12位确定HPV感染的肿瘤患者,1例肿瘤完全消失,4例肿瘤明显缩小,1例肿瘤稳定,总有效率高达41.7%,优于PD-1抑制剂一般20%以下的应答率。


M7824可以降低联合用药的副作用,而且由于TGF-β通路对肺纤维化的发展也起着关键作用,抑制TGF-β通路不仅可以提高非小细胞肺癌的疗效,还有可能降低患者因放化疗引起的肺炎和肺纤维化。鉴于Y-Traps这种独特的作用机制,M7824被称为第2代PD-1抑制剂或者升级版PD-1抑制剂,目前有多项针对难治性癌症的临床研究正在进行,除了上述I期研究外,包括一项比较M7824和Keytruda作为单药一线疗法用于PD-L1高表达晚期NSCLC的疗效和安全性差异的II期研究。


默克医疗健康业务CEO Belén Garijo表示:“M7824有望给难治性癌症患者带来新的生机。GSK对肿瘤领域有强烈的投入意愿,是一个理想的合作伙伴。我们双方也有不同的优势可以互补合作,成为这类新型肿瘤免疫疗法的领军企业。我们期待全面发掘M7824 对一系列癌症的治疗潜力。”


GSK首席科学官&全球研发总裁Hal Barron表示:“尽管肿瘤治疗取得了很大的进步,仍有很多难治性癌症患者无法从当前的免疫疗法中获益。M7824是融合两种不同生物学功能的蛋白药物,在某些癌症患者中也显示出了令人兴奋的治疗效果。我很期待这种首创的免疫疗法能够改变癌症患者的命运。”


GSK重回肿瘤领域之后,刚刚宣布收购Tesaro。此次与默克达成合作也体现了GSK对I-O疗法、细胞疗法、表观遗传学、基因编辑等前沿领域的重视和投入。制药巨头在某个药物上建立合作联盟或者深度捆绑并不鲜见。默沙东就在2017年围绕奥拉帕利、仑伐替尼先后与阿斯利康、卫材达成了总额85亿美元和57.55亿美元的合作协议。


机器翻译

On February 5, Merck and GSK announced that they have reached a global strategic cooperation alliance to jointly develop a bifunctional fusion protein tumor immunotherapy M7824 (bintrafusp alfa) targeting PD-L1/TGF-β.

According to the agreement, Merck can receive 300 million euros in down payment from GSK, 500 million euros in R & D mileage based on lung cancer clinical data, and 2.9 billion euros in marketing and commercial mileage in the future, with the total amount of the whole transaction reaching 3.7 billion euros.Both parties will jointly be responsible for the future clinical development and commercial promotion of M7824 worldwide, and the resulting costs and profits will be shared equally by both parties.

M7824 is a bifunctional fusion protein, one end is able to recognize the antibody structure (Y) that binds to PD-L1, and the other end is a TGF-β receptor type II fusion protein (Trap) that can bind to TGF-β, which can block both PD-L1 and TGF-β signaling pathways, relieve the inhibitory state of the immune system, and improve the killing effect of the immune system on cancer cells.

Up to now, nearly 700 patients with more than 10 different cancer types have been treated with M7824 in phase I studies.M7824 in advanced NSCLC.Human HPV virus-associated cancer.Biliary tract cancer.Gastric cancer and other refractory cancers show exciting clinical data.The two early clinical data of M7824 presented at ASCO 2018 have also become the focus of attention.

1) patients with stage IV NSCLC who had received platinum-based chemotherapy but not PD-1 inhibitors received 500 mg (n = 40) and 1200 mg (n = 40) of M7824 monotherapy, respectively.The data showed that the ORR of patients in the 1200 mg high dose group was 27.5%, in which PD-L1 positive (PD-L1> 1%) patients achieved ORR of 40.7% (n = 11/27).Patients with high PD-L1 expression (PD-L1> 80%) have an ORR up to 71.4% (n = 5/7), which is superior to the general response rate of 20% -40% for PD-1 inhibitors.

2) Patients with HPV-related cancer were treated with different doses of M7824, of which 12 were identified to carry HPV infection.For these 12 patients with established HPV-infected tumors, 1 tumor completely disappeared, 4 tumors shrank significantly, and 1 tumor was stable, with an overall response rate of up to 41.7%, which is superior to the response rate of less than 20% in general for PD-1 inhibitors.

M7824 can reduce the side effects of the combination, and since the TGF-β pathway also plays a key role in the development of pulmonary fibrosis, inhibition of the TGF-β pathway can not only improve the efficacy of non-small cell lung cancer, but may also reduce patients with pneumonia and pulmonary fibrosis caused by chemoradiotherapy.In view of the unique mechanism of action of Y-Traps, M7824 is known as a 2nd generation PD-1 inhibitor or an upgraded PD-1 inhibitor, and there are several ongoing clinical studies for refractory cancer, including a phase II study comparing the efficacy and safety of M7824 and Keytruda as single-agent first-line therapy for advanced NSCLC with high expression of PD-L1 in addition to the above-mentioned phase I study.

Belén Garijo, CEO of Merck Healthcare, said: "M7824 is expected to bring new vitality to patients with refractory cancer.GSK has a strong willingness to invest in the field of oncology and is an ideal partner.We also have different strengths to complement each other and become the leader in this new type of cancer immunotherapy. We look forward to fully exploring the therapeutic potential of M7824 for a range of cancers. ”

Hal Barron, GSK's Chief Scientific Officer & Global R&D President, said: "Although cancer therapy has made great progress, there are still many patients with refractory cancer who cannot benefit from current immunotherapy. M7824 is a fusion of two different biological functions. The protein drug has also shown exciting therapeutic effects in some cancer patients. I am looking forward to this pioneering immunotherapy to change the fate of cancer patients.

GSK has just announced the acquisition of Tesaro.The cooperation with Merck also reflects the importance and investment of GSK in the frontier areas of IO therapy, cell therapy, epigenetics, gene editing, etc. It is not uncommon for pharmaceutical giants to establish cooperative alliances or deep-bundling on a drug. MSD revolved around Olapalil in 2017. Lenvatinib and AstraZeneca. Eisai reached a total of 8.5 billion US dollars and 5.755 billion US dollars in cooperation agreements.

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