百亿研发费用下,新一轮市场争夺战开始

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百济神州国际多中心临床有非小细胞肺癌临床期肝癌一线临床期食管癌一线二线临床期胃癌一线临床期III期非小细胞肺癌临床期肝癌二线三线临床期复发难治NKT细胞淋巴瘤临床期,在国际化临床上进度领先

【编者按】随着临床试验的推进、更多适应症的拓展,各家企业在PD-1上的研发投入都还将持续,未来市场的比拼更加多元化。


6月1日,备受关注的恒瑞医药PD-1终于正式拿到新药注册批件,国内PD-1赛道又增一个注射用卡瑞利珠单抗(商品名:艾立妥),适应症是复发或难治性经典霍奇金淋巴瘤。国产PD-1第一梯队仅剩百济神州的还未上市。

但百济神州在PD-1第二个适应症上市申请方面走得较快。近日百济神州PD-1继经典霍奇金淋巴瘤之后第二个适应症--治疗局部晚期或转移性尿路上皮癌的上市申请获得受理。

根据恒瑞公告披露,截至目前,其PD-1产品项目已投入研发费用约为5亿元人民币。而此前据君实生物向E药经理人透露,截至获批,君实在PD-1上累计研发投入为7亿元。

无疑,随着临床试验的推进、更多适应症的拓展,各家企业在PD-1上的研发投入都还将持续,未来市场的比拼更加多元化。近期,中信建投证券分析了不同企业科研投入结构的差异,是自主研发还是引进合作为主?是放眼海外还是立足本土?正在重点推进的品种是什么?这些数据可以精准反映不同公司的研发战略与模式差异,也能从中分析不同企业未来的竞争力所在。

研发费用去哪了?

行业整体研发投入正在持续上升,研发费用同比增速从2015年的17.08%提升到2018年的26.08%。分企业类型来看,研发费用增速比较为:新型Biotech公司>创新型龙头制药企业>行业平均水平。这与行业分化趋势贴合。

Biotech公司中,百济神州2018年以46.6亿元投入远远超过第二名信达生物,但基石药业以298.33%的增长率表现突出。传统制药企业中,恒瑞、复星、中国生物制药的研发投入位列前三甲,分别为26.7亿元、25.07亿元、20.91亿元,但石药集团以103.56%的增长率成为潜力股。

大量的研发投入分别去哪了?研发费用流向一般为研发人员数量和薪酬的提升、重要品种临床方案设计和临床试验实施,一些中小型Biotech公司还包括研发外包费用和品种license-in的授权费用。

从恒瑞2018年研发开支构成来看,占比最高的项目是临床设计试验费用及直接投入费用,分别占研发提升总额的48.34%和30.7%。另外,薪酬增长率为19.54%的同时股权激励费用增长率为692.29%,说明恒瑞着重使用股权激励策略调动核心员工积极性。这样的研发投入结构也能看出恒瑞医药坚持自主研发模式为主。

分品种来看,2018年恒瑞医药研发投入比例最高的品种是SHR1210(即PD-1),目前正在进行8个Ⅲ期临床试验,同时开展了多个二期临床试验。

百济神州占比最高的项目是临床阶段项目的外部成本及内部研发开支费用,主要是相应药物临床试验数目增多,员工薪酬、股权激励费用增加所致。此外,与2017年相比,非临床阶段项目的外部成本曾都较大,主要是推进临床前候选药物逐渐进入临床阶段。这说明百济神州在研管线丰厚。

值得注意的是,百济神州高研发投入背后隐含的是国际化战略。根据中信建投统计,近两年百济神州在海外开展临床试验数目增长最多,2018年在北美开展了10个临床试验,同时在澳洲、欧洲、日本均有开展多中心临床。临床试验数目远远领先于恒瑞医药、信达生物、君实生物。这也不难理解百济神州高额的研发投入增长,因为北美、欧洲等地区的临床试验成本远比中国要高。

近期百济神州吴晓滨接受媒体采访时提到,今后三年要在中国和世界各地递交20余个新药上市申请,平均每个月或一个半月一个,频率相当高。

信达生物研发费用增长占比最高的项目为外包费用及授权费用,分别占提升总额的31.35%和41.33%。主要原因是开展的临床试验数目增长引起研发外包活动增加,以及与Incyte签订一些产品的授权费用。对于信达来说,外部合作是重要的研发模式。

研发人员绝对数目的增长也是研发支出的重要一环。近两年恒瑞、复星、君实、贝达等研发人员数目都有明显提升。2018年,复星医药研发人员绝对数目最多,达4464人,恒瑞增速最快,增加43.79%达到3116人。君实生物研发人员占总员工的比例最高,237人占总员工数量的39.5%。

而Biotech企业中,百济神州、贝达、君实2018年临床医学人员增长均超过100%。君实的临床开发人员增加了好几倍。随着研发推进,药企对于临床试验需求越来越高。

差异化竞争

无论是PD-1还是其他创新药,随着竞争加剧,未来差异化竞争都是企业必须考量的方向。

同为在PD-1领域竞争,恒瑞、信达、百济神州、君实生物就选择了差异化道路。

恒瑞医药在大适应症和联用上全面领先。其中非小细胞肺癌一线单药处于临床Ⅲ期、非小细胞肺癌二线单药/联用阿帕替尼方案处于临床Ⅱ期,EGFR阳性非小细胞肺癌二线单药/联用阿帕替尼方案处于临床Ⅱ期。肝癌也是恒瑞医药布局较多的适应症,其中肝癌一线联用阿帕替尼处于临床Ⅲ期,肝癌二线联合阿帕替尼/化疗处于临床Ⅱ期,肝癌辅助联合TACE处于临床I期,除此之外,胃癌、食管癌均处于临床Ⅲ期。在中国目前支付能力弱、定价不高的情况下,创新药企进入大领域大病种仍然是性价比更高的选择。

百济神州率先布局PD-1耐药及国际多中心临床。百济神州国际多中心临床有非小细胞肺癌(临床Ⅲ期)、肝癌一线(临床Ⅲ期)、食管癌一线/二线(临床Ⅲ期)、胃癌一线(临床Ⅲ期)、III期非小细胞肺癌(临床Ⅲ期)、肝癌二线/三线(临床Ⅱ期)、复发难治NK/T细胞淋巴瘤(临床Ⅱ期),在国际化临床上进度领先。同时,公司率先布局PD-1耐药方案,联合Sitravatinib,适应症为肝癌、胃癌,目前处于临床I期。

Cinda Bio focuses on lung cancer and other major indications. The first and second lines of non-small cell lung cancer are in clinical phase III, and the second line of EGFR-positive non-small cell lung cancer is in clinical phase III with a combination of Beva monoantigen/chemotherapy regimen. In addition, stomach cancer, esophageal cancer and nasopharyngeal cancer are all in clinical phase III, and new aids of liver cancer are in clinical stage III. Cinda bio-combination program to joint chemotherapy-based, targeted drug combination is less.

Regent's biological differentiation and adequate external cooperation. Junshi biology in liver cancer assistance, liver cancer new auxiliary, urinary tract skin cancer, nasopharyngeal cancer, triple-yin breast cancer on the clinical progress of leading, and other domestic leaders to form differentiated competition. In addition, the company's external cooperation program is more, with Beida Pharmaceutical CM082 jointly used for lung cancer first-line, melanoma, and Zee-Zi biodonafini jointly for liver cancer, with stone pharmaceutical group albumin yewol for breast cancer, with Pfizer Axitini jointly for melanoma, and Hutchison Whampoa Sovantinib jointly for a variety of solid tumors.

Although the progress of domestic new drug research and development is behind the international, but due to the emerging fields or technology start-up differences are not big, there is still the possibility of overtaking the corner. Some head innovation companies have pioneered the me-too into the me-better or fast-follow phase. For example, in the field of immunotherapy, PD-1, CAR-T and other fields, unproven new targets have been domestic enterprises to carry out fast-follow strategic layout.

Zebtinib of Baxter is expected to become the third commercial BTK inhibitor in the world after Ibtiny and acalabrutinib. Ibtini went public at the end of 2013 and has achieved global sales of $6.205 billion in 2018, diastivoly a heavyweight. Zebutinib is the first independently developed cancer drug in China to be recognized by the FDA for breakthrough therapies. Baxter is conducting head-to-head Phase III clinical trials with Ibtini on two indications, most likely as a me-better or even Best-in-class variety.

The division is intensifying

According to Haitong Securities summary, 2018 is the second wave of domestic innovation drug harvest year. Since 2003, China's first returning scientists to do innovative drug research and development such as Beida, microcore, such as the first batch of local enterprises such as Hengrui also began to invest in innovative research and development, these enterprises after 2011 gradually began to enjoy the results of ten years of investment. After 2014, pharmaceutical reform attracted big wave of scientists, investors, pharmaceutical industry research and innovation began to show signs of blowout, 2018 is the harvest period of this wave of investment.

At the same time, some important participants in China's pharmaceutical industry, such as generics and generics, have been affected by a series of policies, such as volume procurement, product price reduction, control of complementary drugs, and so on, the growth rate has continued to slow. CITIC Jiantou compared the growth rate of different sectors such as biopharmaceuticals and chemicals in recent years, it is clear that there is internal differentiation, the overall growth of the chemical preparations sector slowed down, the growth rate of 2019Q1's homecoming net profit was only 2.9%, and the growth rate of the biopharmaceutical sector was as high as 46.3% due to the outstanding performance of growth hormone and vaccines.

The growth rate of multinational pharmaceutical companies has also started to pick up due to the rapid entry of a large number of heavy varieties into China and the catalysis of medical insurance access, with Q1 growth rates higher in 2018 and 2019 than those of local leading enterprises. Among them, Mercer east due to HPV vaccine and K drug approval in China, in 2018 in China's growth rate of 37%. AstraZeneca's rapid growth of oncology drugs, represented by Oxitinib, has boosted sales in China by 25 per cent, while price cuts and post-health-care releases of Roche's Merova, Hercesterin and Aventin have led to a 23 per cent increase in sales in China. Another trend is that the overall market growth of prescription drugs is higher than the growth rate of public hospital terminals, indicating that the growth rate of retail terminals and primary hospitals is increasing, and the second- and third-tier cities are growing faster than the first-tier city market, and as a result, multinational pharmaceutical companies are accelerating their decline. In 2018, multinational pharmaceutical companies will grow by more than 10% in both second- and third-tier cities, compared with significantly slower growth in local pharmaceutical companies.

In the past year, China's pharmaceutical industry is experiencing a period of class division before the chaos, scientists-led innovation and research and development companies, a large number of imitation pharmaceutical companies, multinational pharmaceutical companies, from imitation to the creation of traditional local pharmaceutical enterprises, Chinese medicine enterprises at the same stage into a period of strategic confusion, by anxiety and trends.


From July 25th to 27th, 2019, EOC Health will host the "GIIS 2019 4th China Great Health Industry Upgrade Summit", which willfocus on the market environment, investment hotspots and industrial change in the four segments of healthcare big data, pharmaceutical innovation, non-public health care and science and technology medical.