Dr. Li Zonghai
Founder, Chairman of the Board of Directors, Chief Executive Officer and Chief Scientific Officer of Keji Pharmaceuticals
Wen | Fang Wei
In the second half of 2021, a new tumor immunotherapy, CAR-T cell therapy, suddenly "caught fire". A lymphoma patient received this treatment at Shanghai Ruijin Hospital, and with only one dose (one injection), the cancer cells were "cleared", the symptoms were completely alleviated and he was quickly discharged. Car-T therapy, introduced by the United States, was once called "miracle drug" by the media.
This treatment is magical for blood tumors such as leukemia and multiple myeloma. In 2012, CAR-T became famous in world war I in the United States for successfully "curing" a little girl with acute lymphoblastic leukemia, and was named the world's top ten scientific and technological breakthroughs by Science the following year. Now, the little girl has survived cancer-free for 9 years.
The so-called CAR-T therapy can be simply understood as guiding the T cells that exert immune effects in the human body to attack tumor cells through the "command vehicle" of CAR (chimeric antigen receptor). To make this therapy work better, it is necessary to first propose T cells from the patient, activate them and then "load" them back into the infusion, expanding the "army" of T cells while trying to avoid accidentally injuring normal cells.
However, the CAR-T therapies that are currently on the market are all products for the treatment of blood tumors. There is no CAR-T for solid tumors such as stomach cancer and liver cancer in the world. The reason is that the development of solid tumor CAR-T is more difficult: CAR-T cells are injected into the human body through blood, which makes it easier to find cancer cells scattered in the blood to defeat each; even if the solid tumor is found, the cancer cells are more "grouped" and the defense system is stronger, making car-T more difficult to play a role.
Today, China's innovative pharmaceutical companies are expected to be the first to break through this problem. On March 22, 2022, Keji Pharmaceutical (2171. HK) announced its first post-IPO annual results report, revealing that CT041, a research product for the treatment of stomach and pancreatic cancer, is scheduled to be listed in the United States and China in 2024.
CT041 has completed the first patient enrollment in a confirmatory Phase II clinical trial at Peking University Cancer Hospital, which is also the earliest solid tumor CAR-T product released in the world to enter this stage. Previously, CT041 has been recognized by the EU EMA "Priority Drug" (PRIME) and the US FDA "Advanced Regenerative Medicine Therapy" (RMAT). This means that the development of the drug will receive more support from regulatory agencies, which can accelerate the review process and benefit patients early.
Chinese drug developers are finally on track to make a true "first-in-class" CAR-T product. More importantly, more than 1 million new stomach cancer patients worldwide each year (including nearly 500,000 new cases in China), as well as pancreatic cancer patients who are unfortunate enough to suffer from the so-called "cancer king", may benefit from this. Behind this is a huge market that is expected to achieve sales of nearly 10 billion or more by 2030.
Challenge solid tumors and find breakthroughs
Koji Pharmaceuticals focuses on innovative CAR-T cell therapies for the treatment of hematologic malignancies and solid tumors
The start of 2022 for China's innovative drugs is not wonderful. Needless to say, the stock market fell sharply, and the anti-cancer drugs developed by an innovative drug company were frustrated in listing in the United States. For global practitioners, whether it can be recognized by the US FDA is the "touchstone" of the value of new drug research and development, and it is also an important criterion for judging the possible market space in the future.
"The price of drugs in the United States is particularly high, the market is particularly large, even if it only takes a small market share, the revenue and profit contribution to Chinese companies will be greater." A secondary market pharmaceutical analyst said that selling drugs for 100,000 to 300,000 yuan in China can sell for 100,000 to 300,000 US dollars in the United States. In fact, the price of the listed CAR-T in the United States ranges from $373,000 to $475,000. At present, only two innovative drugs in China have passed FDA approval, and one of them has accounted for half of global sales within two years of listing.
Coji Pharmaceutical's solid tumor CAR-T product CT041 has been awarded RMAT qualification by the FDA and can enjoy all relevant preferential policies of "breakthrough therapy" and "fast-track review". Companies can communicate more closely with the FDA, which is conducive to accelerating the approval of listings.
"For regulators, the purpose of the policy is to promote the development of innovative products to meet the unmet medical needs as soon as possible, so their principles I think are very clear and transparent, as long as we go down this road, we have the opportunity to be recognized accordingly." Li Zonghai, founder of Keji Pharmaceutical, revealed that when two products, including CT041, applied for clinical research in the United States, they were quickly approved within a month. "In fact, when we submitted the relevant qualifications, we did not communicate in advance. The main thing is to do the preliminary work solidly, rely on our own product performance and declaration quality, of course, in accordance with the FDA's guiding principles. ”
The so-called "performance" refers to the real clinical efficacy and product quality. Coji Pharmaceutical disclosed the data of some investigators initiating the trial at the 2021 European Society of Oncology, and the objective response rate reached 61.1% in 18 patients with gastric cancer/esophageal-gastric junction adenocarcinoma who had previously received at least 2-line treatment failure and received a certain dose of CT041 cell therapy.
The so-called objective response rate, in cancer treatment, refers to the proportion of patients whose tumors shrink by a certain proportion and remain for a considerable period of time, which is an important criterion for judging the efficacy. As a reference for CAR-T efficacy, in patients with gastric cancer who have failed treatment with at least 2-line therapy, the objective response rate of chemotherapy drugs or anti-angiogenic polykinase inhibitors is about 4% to 8%, and the objective response rate of anti-PD-1 monoclonal antibody is about 11%.
For pancreatic cancer, which is known as the "cancer king", CT041 has also begun to show efficacy in some patients. Previously, patients who failed first-line treatment had difficulty finding further treatment. There are reports that pancreatic cancer patients have a five-year survival rate of less than 5%, which is only one-tenth of stomach cancer.
"Solid tumors are the future of tumor treatment and hard bones that CAR-T can chew on." A primary market investor analyzed that the CAR-T products currently listed in China and the United States are cut from more successful blood tumors, but compared with physical tumors, this market is "an order of magnitude worse than the naked eye." ”
Today, not only Coji, but also well-known investment institutions such as Hillhouse, Eli Lilly Asia Fund, Zhengxin Valley, AND CDH VGC have bet on real money and silver on the solid tumor CAR-T.
"When we first started doing it, many investors still had doubts about the solid tumor CAR-T, and even a few well-known scientists in the United States said in public that it was difficult to succeed in this field. Now our clinical data proves to be promising. Li Zonghai, a pioneer who has focused on CAR-T research and development since 2010, sighed, "This time and another time." ”
Li Zonghai's original idea of the choice was simple, "Surely all patients want to be cured, not just treated and extended by three months or five months." I conducted a study on liver cancer in collaboration with Professor Zhai Bo of Renji Hospital in 2015, and there were 2 patients who survived for a long time from 2015 to the most recent follow-up, and these results led us to believe that CAR-T has a promising cure for solid tumors, but we still need a lot of research and data to support this view. ”
Competitive efficacy and good safety provide new options for patients with blood tumors
Coji Pharmaceutical has established end-to-end independent manufacturing capabilities for clinical and commercial use in all phases of CAR-T manufacturing
The already marketed hematology tumor CAR-T has also verified the "miraculous" efficacy, and its volume is also growing rapidly with the prolonged disease-free survival of patients, and it has created billions of dollars in sales in the first three quarters of 2021.
At present, CAR-T products are mainly listed in China and the United States, and about 90% are occupied by Novartis and Gilead, two multinational pharmaceutical companies. Take Gilead's CD19 product, Yescarta, which was approved in October 2017 and generated sales of $264 million in 2018, rising to $563 million the following year and $695 million in 2021.
The industry doesn't think such sales figures are eye-catching, after all, among all kinds of blood tumors, lenalidomide, a drug with multiple myeloma as the main indication, has annual sales of $12.8 billion. But for the previous CAR-T products, there are still many challenges in order to achieve exponential sales growth.
Li Zonghai believes that a simple comparison with lenalidomide is not appropriate. Lenalidomide can be used for early-line therapy and has been approved for several indications. CAR-T is currently approved for treatment at the end of a hematological tumor. "The population treated at the end of the line is much smaller. If we can advance to early treatment, then the market should be much larger. ”
"Even at the end, the market is expanding and maturing." Li Zonghai said that CAR-T is a new therapy after all, from the management process and other levels are constantly improving, the supply chain also needs to continue to expand, in order to cover more countries and regions. In addition, hospitalization in the United States is expensive, and if the cost of hospitalization other than CAR-T caused by toxic side effects can be reduced, it can also make more patients accessible.
Coji also has multiple pipelines in hematological tumors, including the core product CT053, a whole-human anti-TARGET BCMA CAR-T cell, which has completed a key Phase 2 clinical trial enrollment in China and is preparing to submit a new drug listing application (NDA) in the near future. The product is also undergoing key Phase 2 clinical trials in the United States.
Keji Pharmaceutical has 12 product candidates, 9 of which are for solid tumors
There have been media reports that American inpatients spend more than $4,000 a day in hospitals, the most expensive of which is $12,500. "Based on the high cost of hospitalization in the United States, considering our previous data, which is generally safer and there are no treatment-related deaths, we have now started to try outpatient treatment in the United States." If outpatient treatment is successful, the cost of treatment will be significantly reduced. Li Zonghai said.
At present, there are already two BCMA target CAR-T varieties listed in the United States, and CT053 will face two competitors if listed in the United States. In this regard, Li Zonghai's view is that "a target of CAR-T can accommodate 3-4 varieties of enterprises, especially for indications like multiple myeloma, which is relatively high in Europe and the United States." For example, THE CAR-T of the CD19 target, which currently has 4 products on the market in the United States and a fourth variety on the market in 2021, is currently rising in sales." He believes that the reduction in the total cost of treatment brought about by competitive efficacy and good safety will win market space for it.
Global R & D echelon layout, the construction of factories to recruit people to "prepare" for commercialization
Coji Pharmaceutical is committed to exploring and developing innovative technology platforms to produce better cell therapy products for cancer patients around the world
For the upcoming CT053, Keji Pharmaceutical is already preparing to build a commercialization team, planning to cover the hematology departments of key tertiary hospitals in first-tier cities and some second-tier cities across the country that can implement CAR-T cell therapy, and expand the coverage of CT041 and other solid tumor candidate products to oncology.
"Our goal is to establish a centralized collaborative system for standardized clinical management of CAR-T cell therapy by collaborating with major local research and clinical centers to achieve full-process management of patient treatment." The planning in the annual report has been laid out as early as the clinical trial, and the researchers cooperated by Keji Pharmaceutical have covered dozens of related departments in China, such as Peking University Cancer Hospital, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Renji Hospital, Xinhua Hospital, Fudan University Affiliated Cancer Hospital and Zhongshan Hospital, Tongji University Affiliated Oriental Hospital, Tongji Hospital, etc.
In order to meet the global production needs, Cozi Pharmaceutical has established factories in Shanghai, China and Durham, North Carolina, USA and put into clinical production operations. Among them, the Shanghai plant can support CAR-T treatment for up to 2,000 patients per year, compared with 700 in the United States.
At present, Coji has a complete production capacity from plasmids, carriers to CAR-T. In addition, given the large indication of early-term treatment of solid tumors, the company also has plans to continue to expand its production capacity in China and the United States to meet the needs of more patients. This is particularly important for the commercialization of CAR-T.
There are more than 100,000 new cases of multiple myeloma worldwide, while the total number of new cases of gastric cancer and pancreatic cancer exceeds 1.5 million. "If we continue to treat early, it will be possible to meet the needs of more patients and maximize the value of these products." At present, there have been a number of companies in the layout of the early line of blood tumor treatment attempts. As the leader of solid tumor CAR-T, we also have an unshirkable responsibility to go to the early line of treatment to see if how many patients can be cured. Li Zonghai said.
As we all know, innovative drug research and development investment is huge, so it needs to be as long as possible to show its value. Then, intellectual property protection has become an important guarantee for extending the life cycle of products. In fact, Coji has built a moat for intellectual property for itself: as of December 31, 2021, Coji Pharmaceutical has more than 300 patents, of which more than 60 are licensed worldwide (including China, the United States, Europe and Japan). This means that if products such as CT041 can be successfully launched, they will be in a competitive advantage for a long period of time and can greatly extend the life cycle of the product. In developed countries, innovative drugs generally do not only do not have price wars, but also often adjust the market for reasons such as inflation, which is also conducive to protecting the market value of these innovative drugs.
In the light capital market environment, investors have become particularly "harsh" on unprofitable pharmaceutical companies. A medical FA (financial advisor) executive who has long dealt with major investment institutions found that "the previous 'first-in-class' looked at the top three or the top five, and now even if you are the first, it depends on how many people are behind you, how much they are behind, and whether their business capabilities are stronger or weaker than yours." And long-term technical barriers must require continuous investment in research and development, the formation of their own research and development system and echelon, relying on a "miracle drug" is certainly not enough.
Li Zonghai believes that the competition for innovative drugs in the United States is generally relatively orderly, and generally speaking, there will be no more than 5 similar drugs. If CAR-T treatment can be pushed from the end to the early stage as Li Zonghai expects, Keji Pharmaceutical may really be able to create a "miracle drug" to cure cancer, not only blood tumors that have been verified by multinational pharmaceutical companies, but also stomach cancer, liver cancer, pancreatic cancer and other cancers with the highest incidence in China.
In fact, in addition to the two important candidates of CT053 and CT041, there are at least 9 CAR-T products for liver cancer and other cancers in the R&D echelon of Keji Pharmaceutical. In addition, Cody has also developed innovative technology platforms with independent intellectual property rights, such as CycloCAR (used to minimize therapeutic safety issues such as cytokine storms), THANK-uCAR (allogeneic CAR-T technology, which is conducive to greatly reducing the cost of patient treatment), LADAR (improving CAR-T cell targeting and target availability). Li Zonghai believes that the development space in the field of CAR-T cells is very large, and there are still many difficulties and pain points that need to be solved, and through the development of these innovative technology platforms to solve these difficult pain points, it not only provides technical support for better meeting the needs of patients, but also provides technical support for the long-term international development of Keji.
In 2021, the success of two products for the treatment of relapsed/refractory multiple myeloma and B-cell non-Hodgkin lymphoma, CT053 and CT032, makes the unprofitable pharmaceutical company hope to self-hematopoiesize in advance. According to Keji Pharmaceuticals, down payments and subsequent milestone payments for the development and commercialization of the two products in the Korean market total up to $50 million, plus royalties based on up to double-digit percentages of net sales generated in South Korea. Li Zonghai said that innovative drugs are essentially for the service of all mankind, "in some markets that we do not have the ability to reach in a short period of time, we should cooperate to maximize the value of these drugs." This external license is only the starting point of Codji, which will continue to cooperate with biomedical companies at home and abroad to develop together to better meet the needs of patients. ”
This may be the reason why capital giants such as Hillhouse and Eli Lilly Asia Fund bet on Keji Pharmaceutical.
Coji's plant in Jinshan, Shanghai, is The first commercial production plant in China to obtain a license to produce CAR-T cell drugs