Source of this article: Times Finance Author: Li Aohua
Dr. Ying Huang, CEO of Legendary Biologics. Image source: Courtesy of interviewee
Every year on May 10, American girl Emily Whitehead posts a photo on social platforms to celebrate her healthy year again. She is the world's first child with acute lymphoblastic leukemia (ALL) to receive CAR-T cell therapy, and this year marks her 11th year of cancer-free survival.
Emily's success story in fighting cancer has become the best endorsement of CAR-T cell therapy "one shot to remove cancer cells".
Since 2008, when the Fred Hutchison Cancer Institute first used CAR-T cells to treat B-cell lymphoma, proving the safety of this method, CAR-T cell therapy has been developed in just 15 years. In the past 15 years, CAR-T cell therapy has developed strongly, and it has repeatedly made major breakthroughs in clinical applications, and has become the brightest star in the field of cell and gene therapy (CGT).
In 2017, Swiss pharmaceutical giant Novartis Kymriah received approval from the US Food and Drug Administration (FDA) as the world's first CAR-T cell therapy. Up to now, a total of 9 CAR-T cell therapies have been approved worldwide. Among them, Cilta-cel, independently developed by Legendary Bio (LEGN.US), has attracted much attention because of the halo of "China's first cell therapy product approved by the US FDA".
Although CAR-T cell therapy has significant advantages and broad application prospects, its commercialization still faces great challenges, and so far, a real "bombshell" has not been born in the global field of CAR-T cell therapy. Due to large R&D investment, high production costs, limited production capacity, and limited indication range, the cost of CAR-T cell therapy treatment remains high, and its accessibility and affordability are still the biggest factors restricting development.
Under multiple pressures, whether the legendary bio, which has made repeated breakthroughs in clinical research and successfully achieved the approval of the first product Cedarchicel for marketing abroad, can create another "legend" in commercialization has become the focus of market attention.
On the breakthrough of CAR-T commercialization, Times Finance exclusively interviewed Dr. Huang Ying, CEO of Legendary Biotechnology. During the interview, "differentiation" and "innovation" were the keywords that Huang Ying kept mentioning. In his view, the ultimate core of a drug is efficacy, that is, whether it is really beneficial to patients. For patients with advanced cancer, their only appeal is to prolong survival, and at this point, so far, Cedarchicel has demonstrated best-in-class clinical data, which is the greatest advantage of Legend Bio and a prerequisite for successful commercialization.
"FIC (First-in-class) and BIC (Best-in-class) have always been the tenets of legendary bio-research and development. Although the risk is high and the cycle is long, we are still willing to take risks, willing to spend time and energy to do something that others have not done, hoping to make differentiated products. Because without differentiation, the product is not competitive in the market. Huang Ying said.
An adventure from zero to one
In the history of the development of CAR-T cell therapy in China, Legendary Creature is an inescapable name. It was developed by GenScript Biotechnology (01548. HK), Legendary Bio was almost described as "nothing" at the beginning of its establishment in 2014 - no start-up capital, no intellectual property rights, even experimental equipment and office space were provided by GenScript Rui, and only a research and development team of less than 10 people.
For legendary creatures, the venture to choose a new target BCMA to cut into the CAR-T track is the beginning of all glory, and the real moat comes from the moment of daring to take risks.
The bigger the wind and waves, the more expensive the fish. Although making new targets greatly increases the risk of clinical failure, it is clear from the results that this risky decision is the right one.
At the 2017 American Society of Clinical Oncology (ASCO) annual meeting, Legend Bio's CAR-T product Cedarchiolensep was shocked as soon as it was unveiled. The early clinical data released at that time showed an objective response rate of nearly 100%, and such excellent data immediately attracted the attention of the world, and the multinational pharmaceutical giant Johnson & Johnson (JNJ.US) immediately threw an olive branch to Legendary Bio.
In December 2017, Legend Biologics partnered with Janssen Corporation, a subsidiary of Johnson & Johnson, to jointly develop and commercialize Cedarchi Cel. Huang Ying told Times Finance that through the cooperation with Johnson & Johnson Janssen, Legend Bio's clinical development, GMP (Good Manufacturing Practice) production and supervision, and the ability to apply for registration have been strengthened.
"It's a win-win partnership. Before this, we may have strong early research and development capabilities, but there are still shortcomings in late development, clinical trials, production, registration, etc. In this process, Janssen has helped us a lot. Huang Ying said.
Image source: Tuworm Creative
Since then, Legendary Creature has gradually become a benchmark player in domestic CAR-T cell therapy. With the blessing of Johnson & Johnson, Cedakicel has been granted orphan drug designation, breakthrough therapy designation and priority review by the US FDA, and in August 2020, it became the first "breakthrough therapy variety" awarded by the Center for Drug Evaluation (CDE) of the National Medical Products Administration of China.
At the end of February 2022, cedarchicel passed the US FDA approval for marketing, becoming a milestone event for China's innovative drugs to "go overseas". Subsequently, it obtained conditional marketing authorization from the EU in May and was approved for marketing in Japan in September, rapidly advancing commercialization.
According to financial report data, Cedarkiorma's sales in 2022 will be about 134 million US dollars (equivalent to about 924 million yuan), and the sales in the first quarter of 2023 will be 72 million US dollars (equivalent to about 500 million yuan). Based on this calculation, in the past year since listing, the actual sales of Cedarchicel reached 206 million US dollars (equivalent to about 1.424 billion yuan).
Now, this adventure is about to reach a new milestone.
In January 2023, information from the Center for Drug Evaluation of the State Food and Drug Administration showed that cedarchicel was included in the priority review and approval process. During ASCO in June, Legend Biologics announced the latest Phase 3 clinical study data of cedarchicel. Results showed that, at a median follow-up of 16 months, cedarchicel reduced the risk of disease progression or death by 74% in adult patients with lenalidomide-resistant multiple osteoma who had previously received 1- to 3 lines of therapy compared with standard regimens (SOCs).
This data means that cedarchicel is expected to become a BIC product in the field of multiple myeloma (MM) treatment, bringing new therapeutic hope to MM patients.
Self-production of virus vectors to break through production capacity limitations
The full name of CAR-T is Chimeric Antigen Receptor T-Cell Immunotherapy, that is, chimeric antigen receptor T cell immunotherapy, which refers to the extraction of T cells from patients, in vitro using genetic engineering technology, a virus containing a chimeric antigen receptor that recognizes tumors and activates T cells is transferred into T cells through vectors, transformed into CAR-T cells, and then re-infused back into patients after expansion. Efficiently and quickly identify and accurately kill diseased cells, so as to achieve the purpose of treating diseases and restoring patients to health.
From the therapeutic principle of CAR-T cell therapy, it is not difficult to see that autologous CAR-T cell therapy is a highly personalized customized therapy, because each product comes from the patient's own T cells, its development, production and use is very complex, in the manufacturing and delivery requirements precision and speed, need to invest a lot of resources, in line with the conditions of good manufacturing practice (GMP) to achieve continuous standardized production, each batch requires strict quality testing. Therefore, in the face of the extensive clinical needs of patients, how to break through the limitations of personalized customization and achieve large-scale mass production is a threshold for cell therapy products that urgently need to break through.
Huang Ying frankly told Times Finance that due to the inability to scale production, in the past year, Cedarchi Cel was in short supply in overseas markets. He analyzed that one of the important reasons for the CAR-T production capacity dilemma is the shortage of lentiviral vectors.
In CAR-T therapy, lentiviral vectors mainly play the role of introducing CAR constructs into patient T cells. Viral vectors are the mainstream vectors for cell and gene therapy clinical trials, and data show that more than two-thirds of clinical trials have chosen viruses as vectors. With the explosion of cell and gene therapy in recent years, a large number of therapies have entered the clinical or commercial stage, and the market demand for lentiviral vectors has also increased, resulting in frequent supply shortages.
Huang noted that most pharmaceutical companies do not manufacture vectors in-house, but rely on third-party suppliers, such as Lonza in Switzerland, Thermo Fisher in the United States, and WuXi AppTec (603259. SH, 02359.HK), etc. However, in the past two or three years, the manufacture of new crown vaccines has occupied a lot of production capacity, which is one of the many reasons for the shortage of lentiviral vectors.
In addition, the US FDA has strict supervision on the production of CAR-T products, and increasing production capacity is a gradual process.
In order to solve the problem of supply of lentiviral vectors, Legend Bio and Johnson & Johnson decided to produce viral vectors themselves. In October 2022, Legend Biologics and Johnson & Johnson announced that they would invest an additional USD 500 million in their plant in New Jersey, USA. The plant, along with another Belgian plant, is expected to have capacity to meet production demand with peak sales of more than $5 billion.
In April 2023, Legend Biologics announced that it signed an agreement with Johnson & Johnson and Novartis on technology transfer, manufacturing and clinical supply services for CAR-T products to continue to increase CAR-T production. Under the agreement, Legend Biologics and Johnson & Johnson will initiate the necessary technology transfer activities with Novartis to enable Novartis to execute the Cedarchicel production process.
"We've done a lot of work over the past year and expect a big improvement in the second half of the year. We decided not to use third-party viral vectors, but all lentiviral vectors produced by Johnson & Johnson, and believe that in the near future, the supply problem of viral vectors can be completely solved. Huang Ying said to Times Finance.
Explore diversified payment + cost reduction and efficiency increase, and improve drug accessibility
The highly customized characteristics determine that self-generated CAR-T products cannot be produced on a large scale, and another challenge brought about by the fact that it is difficult to reduce costs by expanding production. Coupled with the large investment in R&D and the difficulty of controlling manufacturing costs, the price of such products remains high, and the payment problem has never been effectively solved.
At present, cedarcel is priced at $465,000 per needle in the United States, and the rest of the CAR-T cell therapies that have been approved for marketing are priced at more than 2 million yuan per needle in the U.S. market. The two CAR-T products that have been listed in the mainland are priced at more than 1.2 million yuan per needle and are not included in the national medical insurance. This price is an insurmountable obstacle for the average patient.
In the case that medical insurance payment cannot be covered in the short term, CAR-T products urgently need to expand innovative payment models. At present, in addition to medical insurance, pharmaceutical companies and people from all walks of life are also actively exploring more diversified payment methods, including commercial insurance, special assistance, patient organization assistance, etc., to increase the accessibility of patients to obtain drugs.
Huang Ying pointed out that solving the payment problem of CAR-T requires the joint efforts of many parties such as the production side, hospitals, commercial insurance and national medical insurance. "It is hoped that the domestic commercial insurance market can mature and provide payment space for anti-cancer drugs with slightly higher prices but good clinical effects." At the same time, we are also strengthening cooperation with governments of different countries on local insurance and commercial insurance, exploring the possibility of reducing patient payment to benefit more patients. Huang Ying said to Times Finance.
The high price of millions of yuan has reduced patients' access to innovative drugs, and also raised questions about the commercialization prospects of products. This is undoubtedly a huge challenge, and cost reduction and efficiency increase are one of the means to deal with it.
"The main cost reduction methods of CAR-T include finding alternative raw materials, increasing the degree of automation of the production process, and researching allogeneic universal CAR-T cell therapies. These measures take time to accumulate and develop before the price of the product can ultimately be reduced. Huang Ying concluded.
Image source: Tuworm Creative
The raw materials of CAR-T products include cell culture media, viral vectors, lipids, etc., most of these raw materials currently need to be imported from the United States or Europe, if the domestic replacement of raw materials and production equipment can be realized, it can reduce costs to a certain extent. Secondly, the labor and transportation costs of CAR-T products are high, which can reduce labor costs by improving the degree of automation of the production process.
In addition to relying on simply reducing the cost of labor and raw materials, the most important path to cost reduction and efficiency improvement is still technological innovation. The allogeneic universal CAR-T technology developed on the basis of the current self-logous CAR-T products is one of them.
The production process of allogeneic universal CAR-T products is similar to that of autologous CAR-T products, except that the donor of T cells changes from a patient to a screened healthy donor. After the production of autologous CAR-T products, it can only be lost back to the patients themselves, and the heterogeneous universal CAR-T products can prepare hundreds or even thousands of CAR-T drugs at one time, freeze and store them for use, and can be lost back to hundreds of patients, and the production cost is greatly reduced.
Huang Ying told Times Finance that at present, a large part of the research and development resources of Legendary Bio are tilted towards allogeneic universal CAR-T cell therapy. It is understood that Legend Bio has a total of 3 general-purpose cell therapies in the research and development stage, of which 2 targeted BCMA therapy for multiple myeloma and 1 targeted CLL1/CD33 therapy for acute myeloid leukemia have entered the phase 1 clinical stage.
Expand the population and advance to more frontline and solid tumors
In general, first-line drugs are preferred for clinical treatment, and alternative treatments such as second-line and third-line drugs are selected sequentially after the treatment effect is difficult to maintain or poor (there is disease progression). Currently, Legendary Creatures are actively promoting cedarcel for frontline treatment.
Based on excellent data from the Phase 3 clinical study of cedarchicel, Legend Biologics has submitted applications to the U.S. FDA and the European Medicines Agency (EMA) to expand the indication of cedarcel for the treatment of adult patients with lenalidomide-resistant multiple myeloma who have received at least one prior treatment, including a proteasome inhibitor and an immunomodulator.
Once approved, the drug will be further expanded to the adapted population, which will undoubtedly increase the sales revenue of the drug.
In addition, although CAR-T cell therapy has made breakthroughs in the treatment of hematological tumors, from the published cases of CAR-T treatment of solid tumors, most of them are still in the early clinical stage, with small sample sizes and limited clinical efficacy. Solid tumors account for about 90% of all tumors, and the unmet medical need is huge.
At present, Legend Bio is conducting clinical studies on solid tumors such as gastric cancer, esophageal cancer, pancreatic cancer, and hepatocellular carcinoma, which is still in the phase 1 clinical trial stage.
"Cell immunotherapy is still a very new track, CAR-T from an academic research topic in the laboratory to today's commercialization stage, but more than 10 years. There is still a lot to explore in this field, such as studying different kinds of NK cells, gamma delta-T cells, autologous cells and allogeneic cells. Huang Ying added to Times Finance, "In addition, there is a continuous expansion of the scope of indications and pushing to more advanced treatments, CAR-T cell therapy is currently mainly used to treat hematological tumors, we hope to overcome solid tumors in the future, and at the same time push cell therapy to an earlier treatment stage, so that more patients around the world can benefit from innovative therapies." ”
Although the overall investment pace of medical and health care has slowed down and many investment institutions have held coins on the sidelines, with record-breaking clinical data and forward-looking R&D layout, Legendary Biotech has stood out in the capital market and has successively won the favor of top investment institutions.
In April this year, data from the phase III CARTITUDE-4 clinical trial of cedarcel showed that cedarcel was much more effective than expected in patients with multiple myeloma, reducing the risk of disease progression or death by 74%. This news instantly ignited the mood of the capital market, and the stock price of Legendary Bio immediately soared, and the total market value quickly exceeded the 10 billion dollar mark. Since then, Legend Bio's stock price has climbed steadily and climbed to an all-time high of $75.45 per share on June 22. At the close of U.S. stocks on July 3, local time, Legendary Biotech closed at $68.86 per share, with a total market value of more than $12 billion.
Legendary creatures also raised more than $700 million in just two months. On April 19, Legendary Bio received an investment of US$200 million from RA Capital, a well-known overseas venture capital; On May 2, Hillhouse Capital purchased $12.7 million of shares in Legendary Bio; On May 6, Legend Biologics entered into a subscription agreement with T. Rowe Price, under which investors will purchase $350 million of the company's shares at a price of $64 per American depositary share, and on May 19, Hillhouse Capital reinvested and purchased $22.2 million of the company's shares.
In the case of the successful completion of a new round of financing, what new legends will legendary creatures create? The story after that is worth looking forward to.