Editor's Note:
With the continuous improvement of the innovation strength of local pharmaceutical enterprises, China's contribution to global pharmaceutical innovation is also increasing, and under the impetus of multiple benefits such as policies, capital and talents, China is now accelerating from the second echelon of global pharmaceutical innovation to the first echelon of upgrading.
Especially under the impetus of the reform of the national new drug review and approval system, the pace of domestic innovative drug listing has been accelerating, and the innovative achievements of local biomedical enterprises have accelerated, gradually forming a benign pharmaceutical innovation industry ecology. However, internationalization is the only way for local innovative pharmaceutical companies to grow into a world-class Big Pharma.
At present, many innovative pharmaceutical companies have embarked on an international journey, although this road is not destined to be smooth, but their successful or unsuccessful experience is a valuable asset for the newcomers. In order to explore the path of local pharmaceutical companies to go to sea and summarize the experience, 21st Century Business Herald and 21st Century New Health Research Institute have specially planned to launch a series of reports on "Pharmaceutical Companies Going Overseas observation" for reference.
21st Century Business Herald reporter Zhu Ping Beijing reported that following the PD-1 of Cinda Biologics in February this year, two domestic innovative pharmaceutical companies have recently "broken through" the FDA and suffered setbacks.
On May 2, Junshi Bio issued an announcement that the listing application of the PD-1 antibody tereprimumab received a complete response letter (CRL) from the FDA, requesting a quality control process change.
In response to the setback to the application, Junshi Biotech pointed out in the announcement released on the morning of May 5 that this quality control process change is easier to complete, Junshi Bio plans to meet directly with the FDA, and expects to resubmit the biological product licensing application (BLA) before mid-summer 2022.
Also on the 2nd, Hehuang Pharmaceutical issued an announcement that the US FDA has issued a complete reply letter on the listing application of sorvatinib for the treatment of pancreatic and non-pancreatic neuroendocrine tumors. The FDA believes that the current data package based on two successful China Phase III studies and one U.S. bridging study is not sufficient to support the current approval of the drug in the United States. However, Hehuang Pharmaceutical also stressed that the rejection had nothing to do with any safety issues with the drug.
Although both companies have been frustrated by the FDA, the capital market has reacted differently. Hehuang Pharmaceutical's stock price has been falling since the announcement, on May 3, up or down nearly 18%; on May 2, US time, the US stock market closed at $12.23 / share, a decline of 18.95%; Junshi Bio closed up nearly 5% in the Hong Kong stock market on May 3, and Junshi Bio once over-rose by 9% in the intraday on May 5, closing up 5.49%.
A number of industry insiders interviewed by the 21st Century Business Herald reporter said that the reason why the capital market holds different attitudes is because the market has different judgments and expectations for the two. For Hehuang Pharmaceutical, the market believes that the uncertainty factors of making up international multi-center clinical trials are too large, and Junshi Bio does not need to supplement new clinical data, Guosheng Securities Comments is also optimistic about Junshi Bio, and it is expected that triprimumab is expected to become the first and only tumor immunotherapy drug used for nasopharyngeal cancer indications in the United States.
Liu Yugang, partner of Simon Guhe and head of the China region, pointed out to the 21st Century Business Herald that it was unexpected and reasonable for these two companies to be rejected by the FDA. "Because the company continues to communicate with the FDA, for Hehuang, it has previously reached an agreement with the FDA, but the current FDA not only requires bridged data, but also has global multi-center clinical data, the requirements are much higher, although there have been successful cases of bridging data before, but it was still rejected by the FDA, which is unexpected; previously, Richard Pazdur, director of the FDA Center of Excellence in Oncology, had publicly stated that he encouraged Chinese innovative drugs to apply for approval in the United States. Support Chinese companies to bring low-priceD PD-1 into the US market, through market competition to reduce drug prices, but this time Junshi Bio is also frustrated, although the market looks more optimistic, but by the international environment, FDA may also have different requirements, policies are also adjusting, there is still a lot of uncertainty, for this, companies need to do their best efforts, do the worst plan. ”
Liu Yugang pointed out that innovative pharmaceutical companies need to do a good job of global strategic planning and reasonable assessment of product value. "Innovative pharmaceutical companies need to do solid clinical trials, the more rigorous the better, the FDA will have fewer reasons for rejection, and international multi-center clinical trials have become a choice that China's new drugs must make to go overseas." But it requires a lot of money to be invested, so enterprises need to do a good job in the relevant strategies at the beginning, whether to find external cooperation forces, and what kind of partners to find. ”
One setback after another
Junshi Biotech announced that it received a complete reply letter from the FDA regarding the application for biologics License Application (hereinafter referred to as "BLA") from the FDA regarding the first-line treatment of patients with gemcitabine/cisplatin as a patient with advanced recurrent or metastatic nasopharyngeal cancer and a single drug for second-line and above treatment after platinum-containing treatment for relapsed or metastatic nasopharyngeal cancer (hereinafter referred to as "BLA").
Judging from the announcement, Junshi Bio is more optimistic, pointing out that the quality control process changes required by the FDA are a relatively easy project to complete, and plans to meet directly with the FDA and is expected to resubmit the BLA before the midsummer of 2022. The reply letter mentioned that the on-site verification to be completed was blocked due to travel restrictions related to the COVID-19 pandemic. The specific on-site verification time will be announced separately.
Junshi Bio also pointed out that since there is no tumor immunotherapy approved for the treatment of nasopharyngeal carcinoma in the United States, the BLA of the treatment of nasopharyngeal carcinoma with tripramineab meets the "unmet clinical needs". The FDA said it has flexibility in the regulation of this indication in terms of the adequacy of clinical data from individual countries. The FDA also noted that existing clinical data on triprilizumab could support the BLA's declaration. Junshi Bio has successfully completed the online part of the FDA on the on-site verification of the production base, and will maintain close communication with the regulatory authorities, actively prepare for the FDA on-site inspection in order to accept on-site verification at any time, and promote the commercialization of triprimumab in the United States as soon as possible.
Liu Yugang believes that from the perspective of clinical needs, due to the lack of this NPC drug in the US market, the drug may still be approved after resubmitting materials.
Guosheng Securities Comment also said that in the reply letter received by Junshi Biology this time, the FDA clearly pointed out that the existing clinical data on the treatment of nasopharyngeal carcinoma is enough to support the BLA declaration, so there is no need to resubmit BLA to supplement new clinical trial data, and it is expected that treprizumab is expected to become the first and only tumor immunotherapy drug for nasopharyngeal cancer indications in the United States.
However, the situation with Huang Pharma is not so optimistic, the FDA believes that the current data package based on two successful Chinese Phase III studies and a US bridging study is not enough to support the current approval of the drug in the United States, and more international multicenter clinical trials (MRCT) representing the U.S. patient population need to be included to support the approval of the United States, requiring an international multicenter clinical trial that is more representative of the U.S. patient population and in line with current U.S. medical practice. This also means that Hehuang Pharmaceutical will invest more money to support the clinical trial, and there will be more uncertainty.
However, this is not the first time that U.S. regulators have refused to approve innovative drugs in China. On February 11, the FDA held a tumor drug advisory committee on the application of sindili maclizumab jointly developed by Innovent Biologics and Eli Lilly for the treatment of first-line non-scaly non-small cell lung cancer, and finally recommended by a 14:1 vote not to approve the listing of sindili maclizumab in the United States. In addition to the need for more diverse clinical data, the FDA highlighted that the trial failed to meet the FDA's informed consent criteria because it did not explicitly list approved therapies or treatments involved in alternative studies.
In addition, on December 1 last year, the FDA also rejected the listing application of Wanchun Pharmaceutical Punabulin on the grounds that the FDA believed that a phase III registration clinic could not fully demonstrate the benefits of treatment, and required a second registered clinical trial to obtain sufficient evidence to support the approval of the CIN (Neutropenia) indication. The FDA considers the single-registry trial to be too thin to show clinical benefit to the drug.
In September 2021, Punabulin was awarded breakthrough therapy certification by the US FDA and included in the breakthrough treatment variety by the State Food and Drug Administration of China (NMPA). And previously, the market generally believed that purnabulin is expected to become a major breakthrough therapeutic variety in the field of CIN for 30 years.
Increased risk of uncertainty
"In addition to Junshi, it is all because of clinical data problems, exposing the shortcomings of international clinical multi-center trials of Chinese innovative pharmaceutical companies, and whether innovative drugs can succeed in the global market is a test of the ability of enterprises to globalize, especially the design and execution capabilities of international clinical trials that meet the standards." A senior person in the pharmaceutical industry analyzed to the 21st Century Business Herald reporter.
In fact, whether it is Cinda Pharmaceutical, Wanchun Pharmaceutical or Junshi Bio and Hehuang Pharmaceutical, they are the pioneers of innovative drugs in China, and in the active layout of overseas markets, Hehuang Pharmaceutical has established a US commercialization team around sofatinib to prepare for the potential approval of Sofatinib in the United States in 2022. At the March results meeting, its chief technology officer Su Weiguo mentioned that he was confident in the approval process of sulvatinib in the United States, and revealed that the team has 54 people on the job, and plans to reach 84 people by the end of June.
But going to sea is not smooth sailing, and there are many accidents. Judging from the announcement of Hehuang Medicine, it really felt unexpected.
The announcement said that sulfatinib was granted a fast-track qualification by the US FDA in April 2020 for the treatment of pancreatic and non-pancreatic neuroendocrine tumors, and in November 2019, it was granted orphan drug qualification for the treatment of pancreatic neuroendocrine tumors. In May 2020, he huang pharmaceuticals agreed with the FDA at the pre-marketing conference of the new drug that two Chinese phase III studies for the treatment of patients with pancreatic and non-pancreatic neuroendocrine tumors, together with the available data from the Sofatinib US bridging study, can form a basis to support the submission of new drug listing applications in the United States. On June 30, 2021, the FDA accepted a new drug listing application submitted by sulfatinib.
Dr. Li Changqing, who served as the FDA's senior medical review officer, said in an interview with the media that in the United States, pharmaceutical companies generally hold a meeting with the US FDA before completing the phase II clinical trial of the drug and entering the phase III clinical trial. At this meeting, pharmaceutical companies need to discuss with the FDA whether clinical trial design options are feasible, including the control of standard treatment regimens. If other new drugs in the same field are approved during the Phase III clinical trial, the pharmaceutical company and the FDA need to reach a consensus agreement before the clinical trial is carried out, and if anything happens subsequently, it will be directly carried out in accordance with the consensus agreement between the two parties.
In contrast to the FDA's attitude, in a conference call held on the evening of May 2, HeHuang Said That the reasons behind this problem will not be discussed too much. For them, the FDA's refusal to "go to sea" of suffotinib is extremely sad news, but the results of the data still show that suffotinib is beneficial for the clinical treatment of rare diseases pancreatic and non-pancreatic neuroendocrine tumors, and the cooperation between Huang Medicine and the FDA can continue.
The reversal encountered with Huang is not an isolated case, and the above-mentioned Xinda is more typical. In 2019, Dr. Pazdur of the FDA said that it would introduce the "catfish" of China's innovative drug to lay the price of PD-1 drugs in the United States. Based on this, Innovent Bio/Eli Lilly Dielizumab begins to break through.
But in the new situation, the FDA's attitude has reversed. In order to increase the approved chips, Eli Lilly directly played the price card, and the day before the "meeting", Eli Lilly said that after regulatory approval, Xindili monoclonal antibody will be sold at a price of 40% off similar products. However, it was still rejected by the FDA.
In the view of Song Ruilin, executive chairman of the China Pharmaceutical Innovation Promotion Association, the change in the FDA's attitude towards China's innovative pharmaceutical companies going overseas is a key point that touches the industry, which means that in the future, domestic pharmaceutical companies will go international, in addition to the known technical quality, there are many uncertain factors.
Song Ruilin also stressed to the 21st Century Business Herald reporter that the core and essence of pharmaceutical innovation are clearer, that is, to solve unmet clinical needs based on clinical value.
In the view of the above-mentioned industry veterans, there are still many difficulties to be overcome on the road of China's innovative drugs to the sea, especially the problem of clinical data. "Previously, overseas markets had certain prejudices and doubts about Chinese pharmaceutical companies, in addition, many Chinese innovative drugs were only based on the Chinese market when they were previously developed, and in terms of clinical design, they were also based on Chinese patients, and in recent years, After China accelerated its integration with the international market, it began to target the international market, but this is a big gap with the international especially the multi-center clinical requirements required by the US FDA, so there will be some supplementary clinical data and other issues." This situation of clinical supplement design first makes Chinese enterprises very passive when they go to sea. ”
The above-mentioned senior person also expressed a similar view to Song Ruilin, believing that the FDA's decision to approve a drug mainly depends on the design of clinical trials and the results of clinical trials, based on this, in the context of FDA tightening, some companies that apply for approval in the United States still need to be cautious. For example, the CurrentLy In Progress BeiGene PD-1 also needs attention.
According to public information, BeiGene has fully communicated with the drug administration regulatory authorities, including the FDA, before conducting the global phase III clinical trial (NCT03430843) of terelizumab contrast chemotherapy for the treatment of second-line esophageal squamous cell carcinoma (ESCC).
From the perspective of patient source, BeiGene meets the requirements of international clinical multicenters: a total of 512 patient enrollment trials from 11 countries or regions in Asia, Europe and North America in clinical trials, but this clinical control group is chemotherapy, one of the standard treatments at the beginning of clinical trials, the primary endpoint is overall survival, and if there is a lack of head-to-head trials with chemotherapy, there are still uncertainties in the context of tightening approval of PD-1 monoclonal antibodies in the United States.
It is worth noting that this time, Huang and Junshi both mentioned that because of the epidemic in China, the FDA could not conduct on-site inspections. On the evening of May 2, in a conference call with Huang Pharmaceutical, the real factor of the epidemic was also mentioned many times, although the FDA had completed two reviews at the end of last year, but the remaining two reviews could not be continued due to location restrictions (Suzhou, Shanghai). Junshi also mentioned in the announcement that Triplizumab has successfully completed the FDA's online part on the on-site verification of production bases, and the on-site verification has been blocked due to travel restrictions related to the new coronavirus pneumonia epidemic, and the specific time will be notified separately.
On March 31, Yifan Pharmaceutical also issued an announcement that due to travel restrictions, the FDA could not conduct on-site inspections of its holding subsidiary Yiyi Bio in the current review cycle, and would postpone the approval of the application for the listing of innovative drugs in the United States until the on-site inspection was completed.
Liu Yugang pointed out to the 21st Century Business Herald reporter that the epidemic has indeed caused a great impact on clinical and FDA on-site reviews, and is also an uncertain factor in clinical progress, especially for innovative drugs such as macromolecules and biologics.
On the evening of May 5, BeiGene also mentioned in its 2022 quarterly report that it is expected that the world health crisis caused by the new crown pneumonia epidemic will continue to have a certain negative impact on BeiGene's business, including commercial sales, drug policy communication, inspection and declaration, production, clinical trial patient enrollment, participation and data release. Due to the constraints imposed by the pandemic and the potential impact on clinical, production and commercial operations, the future impact of the epidemic remains uncertain globally and in China. BeiGene is working to reduce work delays and disruptions due to the pandemic and has put in place agreements and processes to ensure that the company continues to work in accordance with its commercialization, pharmaceutical affairs, production and clinical development goals set globally.
Strategic layout
The approval of the FDA is also a stepping stone to help Chinese pharmaceutical companies quickly open up the global market, and the FDA's recognition is equivalent to the recognition of many markets such as Europe and the United States. However, Liu Yugang also pointed out that in order to list new drugs in the United States, it is necessary to carry out international multi-center clinical trials and related requirements according to the expected standards of the US FDA, which also means that the cost of enterprises should be increased, and various uncertainties during the period are also a test for enterprises.
For example, according to the requirements of the FDA, Wanchun Pharmaceutical next needs to conduct a second well-controlled trial to verify the efficacy obtained in the first trial, which is also a test of funds for Wanchun Pharmaceutical.
According to the financial report, as of 2021, Wanchun Pharmaceutical's net loss attributable to the company was 64.2 million US dollars, and the reason for the company's net loss expanding year-on-year was that the company's operating loss in the current period reached 66.24 million US dollars, of which R & D investment reached 36.9 million US dollars.
At the same time, as of December 31, 2021, Wanchun Pharmaceutical held only $72.4 million in cash, cash equivalents and short-term investments. At present, the ratio of Wanchun Pharmaceutical's cash reserves to annual losses is less than 2, although this does not mean that the company's real survival support time, but this value is less than two years, but also absolutely represents the urgency of time.
In fact, for innovative pharmaceutical companies, especially those without products, their demand for funds is particularly urgent. If only cash reserves and R&D expenditure are considered (based on the 2021 annual report data), although It has cash and cash equivalents of nearly 30 billion yuan in BeiGene, it can only burn for 3 years; it is 3.4 years for Huang Pharmaceutical and 1.7 years for Junshi Biotech.
Liu Yugang pointed out to the 21st Century Business Herald reporter that enterprises that want to go to sea must do a good job in global strategic layout, especially for the US market. Innovative drugs can obtain more markets when they go overseas, but enterprises need to carefully consider and investigate according to their own situation, and then decide the importance, necessity and feasibility of going to sea for their enterprises.
Liu Yugang believes that enterprises need to make a reasonable assessment of the value of their own products. To gain a foothold in the U.S. innovative drug market, me better, first in class is needed. If it is a new global target, ranking in the first echelon of the world, related products have the potential to solve the global unmet clinical needs, and it is worth considering and trying to go to the FDA.
"The form of Chinese enterprises going to sea can also be considered diversified, and they can choose to be easy first and then difficult, or they can be difficult and easy." From the perspective of funds and other considerations, cooperation with American companies, the choice of large pharmaceutical companies or large CRO companies; or enterprises themselves to hire professionals with international clinical experience, their own clinical, the latter cost will be higher, but in the long run may dilute the cost. Liu Yugang pointed out.
As mentioned above, the BeiGene PD-1 tirelizumab is its choice to cooperate with Novartis. According to the above-mentioned quarterly report released by BeiGene, it has partnered with Novartis to provide support for the submission of terelizumab in the United States for the treatment of NPCs and the submission of marketing applications for the treatment of NSCLCs in the United States in 2022; and cooperation with Novartis to continue to support the application for marketing authorization (BLA) for new drugs for second-line treatment ESCC that is under FDA review. According to PDUFA, the target date for fda to make a decision on this listing application is July 12, 2022; however, the completion of the regulatory review may be delayed due to covid-19 restrictions.
It is also understood that recently, BeiGene announced that its new production base and clinical research and development center in the Princeton West Innovation Park in Hopewell, New Jersey, have officially broken ground, which will promote late-stage research and clinical development capabilities.
Yiyi Bio chose a different path from BeiGene. Liu Jubo, CEO of Yiyi Biology, pointed out to the 21st Century Business Herald reporter: "The model of Yiyi Biology is to do the most difficult work first, and insist on doing all clinical stages. If a phase is sold, the success of the new drug has nothing to do with the company, because the money has already been earned. However, the company cannot understand how to do the second and third phases in the United States through this drug, how to list it, and whether the manufacturer can obtain the GMP review of the US FDA through my drug. ”
Liu Jubo frankly said that Yiyi Bio chose this difficult way, but it can make the company grow faster. Yiyi Bio is also the first Chinese biopharmaceutical company in China to rely entirely on its own team to complete global Phase I to III clinical trials, and submit a BLA (Biological Product Licensing Application) application to the US FDA as the main body of the declaration and obtain formal acceptance.
In Liu Yugang's view, no matter what model the company chooses to "break through" the FDA, the most important thing is that the company must have a clear understanding of itself, make a strategic layout from the beginning, or choose a partner, choose what kind of partner, or break through by itself. "Although it is not easy, it does not need to be too pessimistic, clinical demand orientation has always existed, as long as the product itself has value, the market will also recognize."
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