Why go to sea?
At a forum on innovative drugs going overseas in mid-April, a person in charge of R&D of domestic innovative pharmaceutical companies frankly said: Under the pressure of medical insurance negotiations, China's drug market is so large, and there is more profit space when going abroad.
The effects of health care negotiations were immediate. For example, Novartis' 2017 list of leizumab, which was included in the national medical insurance directory, fell from 9800 yuan to 5750 yuan per bottle, and sales fell by 33.626 million yuan in the first quarter of 2018.
The choice of innovative drugs to go to sea is already a last resort. However, there are few successful people, and more are the lessons of those who have hit the wall.
Just on May 2, 2022, Hehuang Pharmaceutical announced that the US FDA has postponed the listing application of sofatinib for the treatment of pancreatic and non-pancreatic neuroendocrine tumors, and needs to be supplemented by an international multicenter trial.
This is exactly the fate of the sea similar to that of Sindec's biological lung cancer treatment drug sindilizumab in early February: the FDA believes that the clinical trial of sindilizumab is only conducted in China, which does not meet the requirements of international multicenter trials.
This is not a small blow to domestic pharmaceutical companies going to sea. It should be known that sindilizumab is the only PD-1 monoclonal antibody drug that was successfully listed in the national medical insurance list in 2019. Fortunately, at the end of February, Siddhartha Olincy, a cell therapy product used by Legendary Biology for the treatment of relapsed or refractory multiple myeloma, was approved by the US FDA for listing, which finally eased the tension of domestic pharmaceutical companies.
The previous successful case is that in November 2019, BeiGene's zebutinib was approved for listing by the US FDA, becoming the first domestic anti-cancer innovative drug to successfully go to sea.
Hu Huiguo, former general manager of the overseas business of Sunshine Guojian and chief commercial officer of Maiwei Biologics, told the Health Bureau that innovative pharmaceutical companies cannot follow the trend when they go to sea, and they must have a full understanding and preparation for their own advantages and going to sea, and summarize the experience and lessons of other enterprises.
So, what is experience? What are the lessons?
Playing iron also needs to be hard, and the ability to differentiate and innovate is the key
"Everything else is an afterthought, and doing a good job of the product is the last word", the R&D leaders of many innovative pharmaceutical companies expressed similar views.
Zhang Xiaojing, deputy general manager and chief medical officer of Hengrui Pharmaceutical, said: "Having good differentiated products is the first hard indicator for new drugs to go to sea.
Two successful products at sea, whether it is Baan's BTK inhibitor zebutinib, or legendary biocar-T therapy Sidakiolaronse, meet this gold standard.
Taking zebutinib as an example, the drug is superior to the world's first BTK inhibitor ibutinib in three aspects: target share, selectivity and inhibition persistence, and has achieved a better response rate. Wang Lai, senior vice president of BeiGene, said in an interview: First of all, ibutinib is a good drug, but there is a lot of room for improvement, so Baekje decided to set up a project to do BTK inhibitors.
There are also pharmaceutical companies that are not satisfied with the best in their class. A group of Innovative Chinese Pharmaceutical Companies represented by Jiacosi have set their sights on the world's first innovative drug. Its founder Wang Yinxiang said in a forum: To achieve the world's top three in the field of segmentation, the clinical treatment of the target must be fast, otherwise it will not become the world's first. The Health Bureau learned that Jiakesi mainly focuses on small molecule drugs and has identified some old targets that are difficult to make drugs, such as SHP2 inhibitors with poor selectivity, and Jiakesi is the second in the world to be clinical.
The research of old targets is also valued by Hengrui, and compared to Jiakesi, Hengrui aims to be more old targets with the best potential of the same kind, and the success rate of making differentiated advantages is higher, similar to the development strategy of Zebutinib in BeiGene.
Good products do not mean that they must be completely different, Hu Huiguo explained to the Health Bureau: There are still too few innovative drugs in China, and enterprises that produce products with differentiated advantages have the competitiveness of going to sea.
In contrast, a key factor in the failure of Cinda Bio PD-1 to go overseas is that it has not really achieved differentiated innovation. In the view of many industry insiders, compared with the standard therapy of K drugs in the United States, the clinical trial data of Cinda PD-1 does not have obvious advantages, and it is far from cheap.
According to an analysis by Liu Fang and others in the First Affiliated Hospital of Chengdu Medical College, among the 138 patients who used K medicine, the number of patients with serious adverse reactions was as high as 33, accounting for nearly one-fourth, and even patients died of serious adverse reactions.
If Cinda PD-1 can make a breakthrough in the incidence of serious adverse reactions while ensuring non-inferior treatment effects, it can still be regarded as an important differentiated innovation to meet the actual clinical needs.
Advance the layout of internationalization, do not fight the battle of unpreparedness
The earlier you lay out, the more you can navigate the road to sea.
Zhang Lianshan, deputy general manager of Hengrui Pharmaceutical, said at an innovative drug forum: Innovative pharmaceutical companies have many commonalities when they go to sea, and every time they go to sea is a learning process. At the same time, he said that while overcoming cultural differences, innovative pharmaceutical companies must strengthen communication with regulators when they go overseas, package data well, and the quality of data is crucial.
This is a valuable experience summed up by pharmaceutical companies that have encountered many walls, and it is also a lesson for the failure of The Cinda PD-1 to go to sea.
Failure to plan ahead or a decisive factor in Cinda's failure. At the beginning of the design of clinical trials in the United States, Cinda and Eli Lilly did not fully communicate with the US Food and Drug Administration. According to the report of the per-economic network, Innovent Biologics only considered the possibility of listing in the United States after the release of China's Phase 3 clinical trial data. The Health Bureau asked Cinda for confirmation, but the other party did not respond.
Similar to what happened to Cinda, the FDA noted that the data package for Huang Pharma's Sulfantinib China Phase 3 study and a U.S. bridging study were not sufficient to support approval in the U.S. and needed to include more international multicentre clinical trials representing the U.S. patient population.
Since the strategy of going to sea is chosen, enterprises must make corresponding comprehensive adjustments. Hu Huiguo believes that innovative drugs going to sea is a systematic project, not which drug can be sold well in China can go directly to the sea, because the opponent of pharmaceutical companies is a global innovative company, and all aspects of talent, team, and management methods must be matched in advance.
In Zhang Xiaojing's view, if there is no research and development system and layout that supports overseas research, the success rate of going to sea will not be too high.
The reason for Baekje's success in going to sea is inseparable from the support of a huge overseas team. Wang Lai said in an interview: BeiGene's global clinical team of more than 1,000 people, the United States alone has more than 300 people, this scale is rare among anti-tumor innovative pharmaceutical companies.
Not only that, the early preparation of the international layout has also allowed BeiGene to catch up with China's accelerated reform of drug review in 2015, and also to catch up with China's accession to the International Coordination Conference on The International Coordination Conference on Technical Requirements for the Registration of Human Drugs ICH, and international data mutual recognition and reduction of some procedures have provided key help to zebutinib's approval in the United States.
Zhang Xiaojing believes that innovative pharmaceutical companies need firm international confidence to go global, and they need continuous and effective investment, and the teams in China and overseas should be seamlessly connected, while meeting overseas registration standards and regulatory requirements.
Correctly understand yourself and choose the mode of going to sea that suits you
More pharmaceutical companies have chosen license out, that is, to borrow ships to go to sea.
Nuocheng Jianhua, Jiakesi, Junshi Biological and other enterprises have chosen this model. In June 2017, the year after joining the ICH, the license out of Innovative Drugs in China began to erupt, with 9 cases in 2018 alone and more than 30 in 2021.
By granting patents overseas, pharmaceutical companies can reduce the risk of local R&D failure, and at the same time, they can quickly withdraw funds. Through license-out, Gacos received a $45 million down payment in 2020. In Wang Yinxiang's view, in addition to tens of millions of dollars in down payments, future hundreds of millions of dollars of milestone payments and overseas sales shares, this model can also save pharmaceutical companies from paying excessive sales fees.
Innovative pharmaceutical companies can also choose to cooperate with multinational pharmaceutical companies. For example, Yasheng Pharmaceutical, which was an early global innovative drug, has cooperated with Pfizer, AstraZeneca and other companies to develop orphan drugs, and obtained more than 10 orphan drug qualifications in the United States. In the view of Yang Dajun, CEO of Yasheng Pharmaceutical, having a clear understanding of the company's own value and insisting on making characteristics in small and refined fields will also have great returns.
But the requirements for this way of going to sea are also quite high. The Health Bureau learned that multinational pharmaceutical companies generally choose products that they do not have, and do not want to have too many risks in the future, not only need to cooperate in products to enter clinical phase 2, but also have overseas local trial data.
Before the innovative pharmaceutical companies go to sea, they still have to weigh their own pounds and a few pairs, and the innovative pharmaceutical companies that are not ready are still cautious to follow the trend. Hu Huiguo told the Health Bureau that after having differentiated products, it then chooses the appropriate mode of going to sea according to its own conditions, and then matches resources and talents to decide whether to do it yourself or find a partner.
Going to sea requires a lot of time and money. In 2018, before zebutinib was approved in the United States, BeiGene invested as much as 4.6 billion yuan in research and development, almost twice that of Hengrui.
However, whether the shoes fit or not is known only to the person who wears the shoes. In a forum, the host asked Zhang Lianshan what suggestions he had for innovative pharmaceutical companies that wanted to go to sea, and one of Zhang Lianshan's answers was: It is difficult for enterprises to achieve internationalization by relying on the money in their pockets.
Text | David operates | 23 Figure | Visual China