Cinda/Lilly PD-1 was finally rejected, please keep the "going to sea" tips

On March 24, Eli Lilly received a complete response letter (CRL) from the FDA.
The FDA did not approve its new drug listing of sintilimab combined with pemetrexed and platinum for the first-line treatment of non-squamous non-small cell lung cancer.
apply
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According to Eli Lilly’s official website, the CRL also stated that Cinda/Lilly submitted the application without consulting the regulatory agency before the end of the trial, and there was no continuous communication with the regulatory agency (FDA) during the application process
.
Ask it to do another clinical trial, preferably a multi-center clinical trial
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Using the existing standard therapy as the control group, OS was selected as the primary endpoint, and a non-inferiority trial was conducted
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Mountains and heavy waters return to the road of "going to sea" Domestic generic drugs have already started the road to internationalization very early
.
Domestic companies such as Huahai, Qilu, Hengrui, and Shijiazhuang mainly start with APIs and export overseas, and then export to preparations
.
The internationalization of generic drugs often depends on cost, the bulk of which is in APIs
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If domestic enterprises want to take the road of internationalization of generic drugs, it is not feasible without the production bases of APIs and preparations that have passed the international certification
.
Since the competitors of generic drugs are mainly Indian companies, it is basically difficult to win the international competition if the production process is outsourced
.
The international outsourcing of generic drugs usually includes breakthroughs in outsourcing R&D of APIs and preparations with technical barriers, as well as situations where bioequivalence studies need to be completed for oral solid preparations
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In addition, first generic drugs often face patent litigation, which requires working with a law firm familiar with local regulations
.
There are not many products listed overseas by domestic biosimilar companies
.
In 2020, Henlius’ trastuzumab was approved for marketing in the EU, becoming the first “Chinese national” monoclonal antibody biosimilar to land in the EU
.
According to Henlius’ annual report, the domestic sales revenue of trastuzumab in 2021 will be about 868.
0 million yuan, the overseas sales revenue will be about 62.
2 million yuan, and the overseas licensing and R&D service revenue will be about 30.
2 million yuan.

.
Compared with chemical generic drugs, it is even more difficult for domestic biosimilars to be listed overseas
.
This is because the molecular weight of chemical drugs is small and the structure is simple, and generic drugs can completely imitate a chemical drug only by the same chemical structure
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Chemical generic drugs do not need to go through long-term animal experiments and clinical research like the original manufacturers before they can be used on the market, and their research and development costs are greatly reduced
.
Biosimilars have complex structures, and the molecular structure cannot be completely consistent with the original drug, which requires higher production, manufacturing processes and technological processes.
Analysis, testing and characterization of quality, safety and effectiveness (QSE) are also required.
Marketing registration often requires a head-to-head comparison with the original drug
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The history of biosimilars from domestic companies in the domestic market is very short.
In February 2019, the NMPA approved the listing of Henlius' rituximab injection, and domestic biosimilars achieved zero breakthroughs
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To sum up, the origin needs European and American certification, and it is necessary to complete phase III clinical research abroad with the original research head-to-head, and the cost of purchasing the original research drug as a reference has already exceeded 100 million.
Therefore, domestic biosimilars can go overseas.
There are not many companies
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The export registration of traditional Chinese medicines mainly faces regulatory issues.
To be marketed in Europe and the United States, there must be a clear chemical structure and a phase III clinical study that can prove that the drug meets the unmet clinical needs
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"Global New" Successful Cases At present, the R&D registration path for domestic new drugs and generic drugs to be marketed abroad is basically open.
The next goal is to be a leader instead of a follower! So, how to take advantage to expand and optimize the product pipeline of the enterprise? How to find new growth poles to enhance the competitiveness of enterprises? If a domestic new drug is approved by the US FDA as a successful node for "global new", then there are three recent successful cases in China: First, in March 2022, Nanjing Legend Bio and Johnson & Johnson cooperated with the BCMA-targeting CAR-T product West Dakiorenza was approved by the FDA for the treatment of patients with relapsed/refractory multiple myeloma
.
This is the first FDA-approved domestic CAR-T cell therapy
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Second, in February 2021, Junshi and Eli Lilly's double-antibody therapy, etesevimab (JS016) and bamlanivimab, obtained the FDA's EUA (emergency use authorization) for Treatment of mild-to-moderate COVID-19 patients 12 years of age and older at risk of progression to severe COVID-19 and/or hospitalization; FDA emergency use authorization in September 2021 for post-exposure prophylaxis in high-risk groups 12 years of age and older; In December 2021, it received FDA emergency use authorization for the treatment and post-exposure prophylaxis of mild to moderate COVID-19 from birth to under 12 years of age, becoming the first and only neutralizing antibody therapy in the world to receive EUA coverage for people under 12 years of age
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Third, in November 2019, BeiGene’s Brukinsa (zanubrutinib, zanubrutinib) was approved by the FDA for the treatment of previously treated mantle cell lymphoma indications.
This is the first Chinese local original anticancer drug approved by the FDA
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From a market perspective, the "global new" returns are good
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In 2021, the cumulative global sales of zanubrutinib will be about 1.
4 billion yuan, a year-on-year increase of 423%
.
Full-year sales in the U.
S.
were $115.
7 million, up 535% year over year
.
In 2021, Junshi and Eli Lilly's etesevimab/bamlanivima neutralizing antibody therapy sales will reach as high as 2.
2392 billion US dollars
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What are the ways to ensure compliance? From drug development to successful drug marketing registration, it is usually divided into two parts - preclinical and clinical stage research
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Pre-clinical applications are actually not difficult.
As long as the entire R&D chain is clear, the CMC data is complete, and is true and compliant, the application permission can usually be obtained
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Method 1: Introducing FDA technical officials How to improve the understanding of relevant regulations? One of the ways is to introduce technical officials who have served in the FDA, such as WuXi Biologics, Tasly, Luye Pharma, Junshi and other companies
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Inviting former FDA technical officials to join will help companies understand the approval rules and needs of overseas markets, and facilitate better deployment in the global market
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Taking Junshi as an example, in January 2018 Junshi introduced Li Ning, the former director of the FDA division, and currently serves as the CEO; in August 2019, Junshi introduced Wang Gang, the former chief scientist of the FDA, as the company's senior vice president of industrial affairs and chief quality officer.
Responsible for the company's production quality and related work; in August 2020, Patricia Keegan, former deputy director of the FDA Oncology Center of Excellence, was introduced as Chief Medical Officer (CMO) to manage the company's clinical development projects and be responsible for the strategy, direction and execution of clinical development plans.
And participate in the strategy formulation of the company as a whole
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Method 2: Licensing overseas markets to multinational companies Due to lack of experience in overseas registration and listing, it is a very mainstream cooperation method for domestic new drug companies to authorize overseas markets for their products to multinational companies.
For example, the cooperation between Junshi and Eli Lilly mentioned above Neutralizing antibodies, CAR-T co-operated by Nanjing Legend Bio and Johnson & Johnson, PD-1 co-operated by Innovent and Eli Lilly
.
In 2021, many similar cooperations have signed sky-high transaction volumes
.
Rongchang Bio's Vidicitumab was approved in China with conditions in June 2021 for the third-line treatment of HER2-overexpressing locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma), becoming the first domestic new ADC drug It is also the third ADC drug in China
.
With its excellent clinical performance, in August 2021, Vidicitumab won the favor of US ADC giant Seattle Gene, which obtained the commercialization rights of Vidicitumab outside of China with a total transaction value of US$2.
6 billion.
, which fully demonstrates the competitiveness and huge commercial value of the product
.
In December 2021, BeiGene announced an agreement with Novartis to jointly develop, manufacture and commercialize BeiGene's TIGIT inhibitor Ociperlimab in North America, Europe and Japan
.
In addition, the two parties also agreed to grant BeiGene the right to market, promote and sell 5 Novartis approved anti-tumor drugs in designated areas in China, with a total transaction value of approximately US$2.
895 billion, which once again set a new record for overseas authorization of Chinese biological companies.
The transaction value is as high as 2.
9 billion US dollars
.
In 2021, the top 5 Chinese pharmaceutical companies in terms of license-out transaction value will all have a transaction value of more than US$1 billion, and they are basically biological products; in 2020, there are only two projects with a transaction value of more than US$1 billion
.
What kind of outsourcing services do you need now? The pharmaceutical outsourcing service industry (CXO) is an outsourcing industry chain attached to drug R&D and production.
After more than 40 years of development, it has formed CRO (Contract Research Organization), CMO (Contract Manufacture Organization, contract manufacturing organization), CDMO (Contract Development and Manufacturing Organization), CSO (Contract Sales Organization, Contract Sales Organization) and many other sub-industries
.
Among them, CRO companies and CDMO/CMO companies run through the drug life cycle in R&D and production respectively
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According to the product type, CDMO can be divided into three sub-fields: small molecule CDMO, macromolecule CDMO, and cell gene therapy CDMO (CGT CDMO).
The required process technology, equipment and personnel requirements are different
.
1 Small molecule CDMO company Small molecule CDMO company's products include basic chemicals, non-GMP+GMP intermediates, APIs, preparations, etc.
The reaction apparatus is a reactor
.
Due to the strong disassembly of the chemical synthesis steps, the high stability of most compounds, and the convenient transportation, the product stages of small molecule CDMOs are obvious
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Usually, the research and development method of domestic me-too is to follow the research projects of large companies, understand the structure of the key compounds of the project through patents and conferences, carry out reasonable reconstruction through AI and other means, and analyze the activity of the compounds to determine the PCC, and then follow the Basic research and development path of the target compound from starting materials, non-GMP intermediates, GM intermediates, APIs to preparations
.
After years of development of overseas CDMOs, the products of leading companies are basically GMP intermediates, APIs, and preparations, that is, the integration of "API + preparations"
.
Due to labor costs, environmental pressures, and capacity distribution and allocation, the global small molecule CDMO industry continues to shift to China, India and other countries
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Comments: Recently, because a target can often have more than 10 me-too small molecules entering the clinic, and even 6 to 7 are approved for marketing, some people question the R&D model of this small molecule new drug generic drug
.
If it is not the first small molecule with a new target to be listed abroad, the proposition of "how to meet the unmet clinical needs" must be considered when going to the FDA for listing
.
2 Macromolecular CDMO Company Macromolecular CDMO Company's products include stock solution and biological preparations, and the reaction instruments are disposable reactors and stainless steel tanks
.
Because the preparation of biological drugs uses cell engineering, fermentation engineering and other technologies, the preparation process is mostly continuous fermentation and production, which is difficult to disassemble.
Compared with chemical small molecules, biological macromolecules have poor stability and high transport difficulties.
Therefore, macromolecule CDMO companies have the characteristics of high order stickiness and high barriers
.
The leading macromolecular CDMO companies gain a high market share with advantages in technology, production capacity, and customers, and have a high industry concentration
.
With the rise of Biotech, few project experience and the unique development background of biological products with asset-light operation pushing up the production outsourcing rate, many leading macromolecular CDMO companies have been achieved
.
In order to obtain CDMO orders, emerging macromolecule CDMO companies often start by laying out production capacity
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Comments: At present, the number of PD-1 products approved has exceeded 10, which is praised by the industry as "a high level of repeated construction"
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In fact, the domestic production capacity of monoclonal antibodies is saturated, and monoclonal antibody biosimilars are about to enter the centralized procurement mode
.
How to truly achieve unique innovation? This is a question that monoclonal antibody companies need to think about
.
3CGT CDMO Company CGT CDMO Company's products include plasmids, viruses, cells and final preparations.
The reaction instruments are cell culture and separation instruments
.
Due to the specificity of allogeneic immune rejection and gene therapy, cell gene therapy is mostly an individual precision treatment method, and there is no universal therapy.
The strict aseptic and pollution-free production conditions also limit the establishment of a universal production line by CGT CDMO
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At present, CGT CDMO's products are mostly plasmids, adenovirus (ADV), lentivirus (LV), adeno-associated virus (AAV), etc.
that must be used in cell gene therapy, and then special production lines are established according to orders
.
In view of the short development time of cell gene therapy, most of the companies are start-ups, and their R&D and production are difficult, high cost and long cycle, and they are very dependent on CGT CDMO
.
CDMO companies provide regulations, production capacity, and project management services, while start-ups help CDMOs familiarize themselves with and build CGT technology platforms, and both parties develop together in cooperation
.
Comments: At present, the number of gene therapy start-ups is very large, but most of them are in the stage before GMP industrial production
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Whoever can quickly solve the GMP industrial production and complete the clinical trial will stand out from many enterprises
.