Economic Observer Network reporter Qu Yixian After a long period of downturn, China’s innovative medicine industry has received a shot in the arm. On March 1st, 2022, CAR-T therapy of legendary creatures was officially approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed/refractory multiple myeloma (r/r MM). This is the first domestic CAR-T cell therapy approved by FDA.
The approved CAR-T therapy is called Cilta-cel, which targets BCMA and is the second CAR-T therapy targeting BCMA in the American market. On the topic of domestic innovative drug "going out to sea", it is a sample-as early as 2017, it signed a global exclusive license and cooperation agreement with Johnson＆Johnson to jointly develop and commercialize this product.
Huang Ying, CEO and CFO of Legendary Bio, revealed that the price of Cedarchiorense in the United States is $465,000. This pricing strategy is because the pricing range of several CAR-T products that have been listed in the American market is $400,000-$470,000, and the price of the first CAR-T product with the same target is $419,500. "The premium of about 11% is a very reasonable premium, based on our differences in clinical efficacy."
According to the agreement signed at that time, in Greater China, Johnson & Johnson and Legend Bio will share the costs and benefits in a ratio of 3: 7; In other parts of the world, the agreed ratio is 5: 5.
Huang Ying said that in response to the commercialization of Cedakio Orense in the United States, Legendary Biology has recruited its own sales team in the past 6-9 months, responsible for 75-80% of large hospitals and clinics in the United States; Johnson & Johnson has a relatively large tumor sales team serving the community, and will recommend Cedactylosin to 5,500 hematology oncology specialists in the United States, hoping that these specialists can introduce patients to large local diagnosis and treatment centers and hospitals for treatment with Cedactylosin. At the same time, Johnson & Johnson will also set up a relatively small and specialized product team to promote this product to large hospitals and diagnosis and treatment centers.
Behind the first CAR-T
Sida Chiolense has attracted much attention in the research and development stage.
ASCO, the American Society of Clinical Oncology, is a great event in the medical field every year, and many heavy new drugs choose to publish the latest research data on ASCO. On the last day of ASCO in 2017, the legendary creature announced the early data of the self-developed CAR-T product LCAR-B38M (R&D code of Sida Giorense) to the pharmaceutical industry peers and experts around the world.
According to the report of Zhao Wanhong, the research organizer and deputy director of the Department of Hematology, the Second Affiliated Hospital of Xi ‘an Jiaotong University, among the 35 patients with recurrent multiple myeloma who were treated by CART, 33 (94%) got clinical remission 2 months after treatment, and the objective remission rate was 100%.
In addition, among the 19 patients who received treatment at the earliest time, 14 patients achieved strict complete remission, 1 patient achieved partial remission, and 4 patients achieved excellent partial remission. The earliest patients who received treatment have lived for more than one year, and they have reached the living state of healthy people.
It’s not imitation, nor improvement, but the exploration and innovation of a China enterprise in the "no man’s land", so when the data of Xidajiaolun match came out, everyone was surprised.
Fan Xiaohu, chief scientific officer of Legendary Biology, recalled that at that time, "it attracted global attention and (Legendary Biology) became the dark horse of China", and many people in the industry gave him feedback, and many start-ups after 2017 were encouraged.
Followed by a number of international pharmaceutical companies seeking business cooperation, after repeated communication and back tone, Legend finally joined hands with Johnson & Johnson.
In December, 2017, Legendary Bio signed an exclusive global license and cooperation agreement with Johnson & Johnson to jointly develop and commercialize Cedarchiorense. Johnson & Johnson paid Legendary Bio a down payment of $350 million and subsequent milestone payments.
By today’s standards, the down payment of $350 million is not high, but at that time, it was the best condition for China pharmaceutical companies to record the largest amount of down payment for foreign patent authorization and cooperation.
Regarding the cooperation between the two parties, Huang Ying said that Legend’s cooperation with Johnson & Johnson has strengthened the legendary creature’s ability in the process of R&D and registration of Sida Chiolense. From early R&D to late R&D, including clinical, commercial production, GMP production, compliance registration and other processes, the legendary creature’s team actively participated in the whole process, and also cultivated their own ability in the process of learning from Johnson & Johnson.
However, this cooperation model also has shortcomings, "the whole cycle is very long and the investment is very, very large", because Legend’s investment in the American market is as 50-50 as Johnson & Johnson’s, which is a relatively large financial burden for legendary creatures of innovative pharmaceutical companies.
multiple myeloma
Cedactylorense is a chimeric antigen receptor (CAR) T-cell immunotherapy with two single-domain antibodies targeting B-cell mature antigen (BCMA), which is administered by one-time infusion.
Cedactylorense has been approved by FDA to treat patients with relapsed or refractory multiple myeloma, who have received four or more treatments in the past, including proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies.
Multiple myeloma is considered as an incurable hematological tumor, and it is a malignant disease caused by excessive proliferation of plasma cells in bone marrow. Most patients relapse after initial treatment, and the prognosis is not good after receiving the main drugs such as immunomodulator, proteasome inhibitor and anti-CD38 antibody.
According to the American Cancer Society, in 2022, more than 34,000 people in the United States will be diagnosed with multiple myeloma, and more than 12,000 people will die.
Sundar Jagannath, a professor of hematology oncology at Mount Sinai Medical College and a principal investigator of CARTITUTE-1, said that the treatment process of most patients with multiple myeloma is a cycle of continuous remission and recurrence, and only a few patients get deep remission after last-line treatment. "That’s why I am very excited about the results of CARTITUDE-1 study, which shows that Sidakiorense can provide deep and lasting remission and long-term no treatment even after multi-line treatment.
The approval of Sida Chiolense is not based on the data reported in ASCO in the United States in 2017, but on the key data of a CARTITUDE-1 study. CARTITUDE-1 is an ongoing phase 1b/2, open-label, one-arm, multi-center study, with 100% patients from the United States.
In CARTITUDE-1 study, 97 patients with R/R MM experienced deep and lasting remission, with an overall remission rate (ORR) of 98% and a strict complete response (sCR) of 78%. During the median follow-up of 18 months, the median remission duration (DOR) was 21.8 months.
The incidence of multiple myeloma in China is 2-3 patients per 100,000 people. Although it is lower than that of Caucasian and African people, there are considerable unmet clinical needs because of its large base.
Regarding the listing of this product in China, according to the latest communication between Legend Bio and National Medical Products Administration Drug Evaluation Center (CDE), some patients need to be re-enrolled in clinical trials. Huang Ying said that she would keep in touch with CDE during this period.
Enlightenment of "going out to sea"
The research and development cost of innovative drugs is extremely high, and with the implementation of policies such as domestic centralized procurement and medical insurance negotiation, it is almost impossible to recover the research and development cost in a short period of time after the innovative drugs are listed. Under the circumstance that the cost cannot be covered by a single market, it has become an industry consensus to "go out to sea" and develop the international market.
Compared with biopharmaceuticals, the R&D and production of CAR-T are more complicated. The "Going to Sea" of Sidaji Orense is another innovative drug listed in the United States after Zebutini of Baekje Shenzhou.
But before that, in February, Cinda Bio’s PD-1 product Cindilizumab had just been defeated in the United States. In view of the passing of cindilizumab, FDA experts mainly pay attention to three issues: first, whether the control group selected in clinical trials is reasonable; Second, the clinical trial is only done in China population, is it applicable to American patients? Thirdly, it mainly studies whether the design of the terminal is reasonable.
In Huang Ying’s view, since China joined ICH, the regulatory standards of National Medical Products Administration, China are basically the same as those of FDA, focusing on efficacy and product safety evaluation. "There is not much difference between FDA and CDE standards. There may be slight differences in the number of patients enrolled, the length of follow-up, GMP, production process, quality control and other issues, but for a new drug, efficacy and safety are the gold standards."
However, Huang Ying also believes that for enterprises, there are also places that need special attention, such as whether the experimental population can represent the situation of American patients in the real world when doing clinical trials. In the United States, the Asian population is about 5%. It is difficult to apply for approval with the data of 100% Asian population or Chinese.
One more thing, does the control group designed in clinical trials use placebo or the best treatment standard already available in the market? "CDE has also issued guidelines. Even if you do clinical trials in China in the future, you can’t just use placebos, but you need to use the best standard drugs in the industry as the control standard." Huang Ying said.
Fan Xiaohu, on the other hand, thinks that biomedical enterprises in China should not worry about policy vacillation and payment all day long, or whether the door of the FDA in the United States will be closed. "These don’t need to be overly worried and interpreted, but (what is needed) do their own thing well and do scientific and technological innovation well."