“The United States is not the only market in the world. As long as we can get convincing data, it will always be recognized.”
At 3:30 a.m. Beijing time on February 11, tens of thousands of practitioners and investors from the field of biomedicine stayed up late to wait in the live studio. They are watching a medical review meeting online.
This meeting was the first direct confrontation between Chinese PD-1 pharmaceutical enterprises and the oncological Drugs Advisory Committee (hereinafter referred to as “ODAC”) of the FDA. The discussion focused on whether to recommend the listing of cindilimab, a PD-1 inhibitor of Eli Lilly (ly. US) and Cinda Biology (01801. HK).
This is destined to be a sleepless night. After five hours of intense discussion, the independent investigation team voted 14:1 and concluded that Lilly and Cinda biology needed supplementary clinical trials to obtain approval.
Before February 11, Cinda biology issued an announcement and responded that FDA did not have any doubts about the safety and effectiveness of cindilimab. The company will continue to cooperate with Lilly to complete the review of new drug listing, and stressed that “FDA will adopt ODAC’s voting opinions in the process of new drug approval, but ODAC’s voting opinions will not be binding on FDA’s decision-making”.
As an effective support platform for FDA’s scientificity and fairness, although the discussion results of ODAC meeting cannot be equated with the final approval results, in general, the final opinions of both parties will be consistent.
In fact, this result did not surprise the market. As early as before the review meeting, ODAC disclosed the meeting materials in advance. In this 32 page document, FDA raised some doubts about the clinical trial of cindilimab. Therefore, before the results were published, the industry was generally pessimistic about the approval results of cindilimab.
On the follow-up application and clinical trial arrangement, times finance called and sent a letter to Xinda biology, but as of press time, no reply was received.
On February 11, Cinda biological fell all the way after the opening, and finally closed at HK $31.60 / share, down 7.47%, which has fallen by more than 68% compared with the historical high in January 2021.
Among all the domestic PD-1 products sent to the US FDA, cindilimab is the fastest and leading one. The halberd of cindilimab has undoubtedly brought more uncertainty to China’s innovative drug “going to sea”.
“The United States is not the only market in the world. As long as we can get convincing data, it will always be recognized.” Lai Yankun, commercial director at home and abroad, told times finance.
Domestic PD-1 lost its first battle at sea
In the review meeting, ODAC’s objections mainly include three points: first, the control group of the trial is not the current standard therapy in the United States; Second, instead of OS (overall survival), PFS (progression free survival) was selected as the end point of the clinical study; Third, whether the “single China data” can prove to be applicable to American patients.
On May 18, 2021, Cinda biology and Lilly jointly announced that FDA has officially accepted the application for the listing of new drugs jointly developed by the two sides for the first-line treatment of non squamous non-small cell lung cancer (NSCLC).
The declared data are based on a study called “orient-11”, which is only carried out in China, not a global multicenter clinical study. The FDA therefore believes that the findings do not reflect the diversity of the U.S. population and cannot explain the impact of racial factors on treatment outcomes.
Orient-11 chose PFS as the clinical endpoint, while the previous similar drug, keytruda (commonly known as “K drug”), used OS when it was approved by FDA. Compared with OS, PFS has a shorter observation time, which can save time and research funds for enterprises. However, PFS is an artificially set evaluation standard and subjective, so FDA questions whether PFS is sufficient as a clinical endpoint.
On the other hand, the control group set up by orient-11 is chemotherapy, not other approved PD-1 monoclonal antibodies. Before orient-11 was launched, the first-line therapy for non squamous NSCLC in the United States has changed from chemotherapy to immunotherapy + chemotherapy.
“Too cruel.” A biomedical R & D person lamented to times finance, “FDA has approved many PD-1 monoclonal antibodies before this. It is difficult for subsequent estimates to escape the ‘head-to-head’ comparison, which is a great test.”
“I’m very disappointed that there was a lack of communication between the applicant and the sponsor at the beginning of the trial design. If there was sufficient communication, I don’t think we need to do these discussions today.” A member of the committee said at the meeting.
In this regard, Cinda biology argued and submitted the minutes of the meeting, saying that before submitting the application for bla (biological product license application), Cinda biology had made three formal communications with FDA. At that time, FDA agreed to Cinda biology’s BLA application.
Lilly representative was even more directly disappointed with this result. In his opinion, cindilimab could have benefited more American patients with lower prices. Lilly has previously revealed that its product pricing will be 40% lower than that of similar products in the U.S. market. It is understood that the annual treatment cost of drug K in the U.S. market is about 150000 US dollars, but after the medical insurance negotiation, the price of cindilimab in the Chinese market is less than 1 / 20 of the price of drug K in the U.S. market.
However, the FDA made it clear in the pre meeting information that the market price factor will not be considered in this discussion.
China’s inner roll, innovative drugs appear in the tide
PD-1 inhibitor is the most popular anticancer drug in recent two years. PD-1, or programmed death receptor-1, is a protein on human immune T cells. Different from the therapeutic mechanism of traditional drugs, PD-1 inhibitors do not directly target tumor cells. Their main mechanism is to activate human T cells and other immune cells, and then fight and eliminate tumor cells through immune response.
Cindilimab was approved to be listed in China on December 24, 2018. At the end of November 2019, it became the first PD-1 monoclonal antibody to successfully “sprint” the national medical insurance catalogue with a price decrease of 64%, and the annual treatment cost decreased from 280000 yuan to 96700 yuan.
In less than a year, in 2020, Jiangsu Hengrui Medicine Co.Ltd(600276) (600276. SH) carrelizumab, Baiji Shenzhou (688235. Sh, 06160. HK, bgne. US) tirelizumab and Shanghai Junshi Biosciences Co.Ltd(688180) (688180. Sh, 01877. HK) treprizumab all entered the medical insurance catalogue. This made the price advantage of cindilimab disappear for a time.
With the fierce competition in the local PD-1 market, the price has been going down.
In January 2022, the new medical insurance catalogue was officially implemented. The annual treatment cost of four domestic PD-1 mAbs included in the medical insurance catalogue, including cindilimab, treprizumab, tirelizumab and carrelizumab, has been reduced to 30000 ~ 50000 yuan. According to 70% of the medical insurance reporting proportion, the patient pays only 10000 ~ 15000 yuan.
PD-1 products outside the medical insurance catalogue can not escape the price war.
In August 2021, the paianpulimab of kangfang Biology (09926. HK) was approved for listing, and the product price was 4875 yuan / piece. After adding the drug gift scheme, the annual treatment cost directly broke through the floor price of 39000 yuan. The price of cyprimab of Harbin Gloria Pharmaceuticals Co.Ltd(002437) (002437. SZ) is also as low as 3300 yuan / piece.
In the face of a fierce price war, low prices may not be able to exchange for high growth.
Due to the different implementation time of cizumab in 2020, the sales of cizumab, cizumab and other products increased by 276% {in the first half of the year, but cizumab were successful in 2021, and cizumab entered the {6001} in 2021.
In the extreme environment, the overseas market seems to have become a must for innovative pharmaceutical enterprises.
“China’s innovative drugs are too convoluted. If a drug wants to get better revenue, it has to go overseas. For many enterprises, the United States is a priority market, because the United States and Europe have a certain demonstration effect on the global market. If it can be approved in Europe and the United States, it will be relatively easy to approve and sell in other countries.” Lai Yankun told times finance.
According to the statistics of times finance and economics, at present, there are 8 approved PD-1 monoclonal antibodies in China. Except for the imported products of Bristol Myers Squibb’s “O drug” (nabuliu monoclonal antibody), Merck’s “K drug” and cyprimab, the other 5 domestic products have submitted marketing applications to FDA or obtained clinical trial approval.
The United States has “changed its face” and the road ahead for new drugs to go to sea is uncertain
In the view of many people in the industry, the reason why the United States has become the first stop of many Chinese pharmaceutical enterprises overseas is that the FDA’s listing license means that the drug has passed the most stringent review in the world.
In April 2019, Richard pazdur, director of the FDA oncology center of excellence, publicly expressed support for Chinese companies to bring low-cost PD-1 / PD-L1 into the U.S. market, reduce drug prices through market competition, and said that they could approve the listing according to the clinical trial data conducted in China.
In March 2021, Shanghai Junshi Biosciences Co.Ltd(688180) announced that it had submitted a new drug marketing application of treprizumab for the treatment of recurrent or metastatic nasopharyngeal carcinoma to FDA and obtained the rolling review of FDA. This indication has previously obtained FDA Orphan Drug Certification and breakthrough therapy recognition.
Treprizumab became the first domestic PD-1 to submit a new drug listing application to FDA. Then, represented by PD-1 inhibitors, many Chinese innovative drugs, including Btk inhibitors and CD47 monoclonal antibodies, set sail for the FDA.
“Small molecule drugs, antibodies and car-t are all global markets, so many enterprises choose to declare abroad, and many car-t in China will basically declare in the United States.” The above-mentioned R & D personnel told times finance.
According to FDA statistics, at least 25 cancer drug applications at different drug development stages, planned to be submitted or currently under review will be based entirely or mainly on clinical data from China in the future.
However, in less than three years, the FDA’s attitude has suddenly changed.
In December 2021, Richard pazdur first pointed out in his paper the problem of cluster development of PD-1 / L1 products around the world, and expressed his concern about clinical trials conducted entirely or mainly in China outside the United States, especially by Chinese pharmaceutical enterprises.
Subsequently, Richard pazdur made it clear that relying on the clinical data of only one country to complete the approval of new drugs runs counter to the principle of the United States in trying to increase the diversity of patients in clinical trials.
Lai Yankun pointed out to times finance that if global multi center clinical trials are to be conducted, the clinical cost will increase significantly. “At present, the clinical cost in China is not low, but it is still much lower than that in the United States, about 60% of that in the United States. If you want to do clinical work in the United States, you should also consider the transportation cost of experimental drugs and the recruitment cost of local personnel. The R & D cost will be much higher.” Lai Yankun said.
Although the FDA’s attitude towards the approval of innovative new drugs in China has taken a big turn, Lai Yankun said that there is no need to be too pessimistic about the future situation of China’s innovative drugs going to sea.
“Just like our covid-19 vaccine, with more and more data on protection rate and safety, we have finally been recognized by many countries.” Lai Yankun said to times finance and economics.
