Why did the legendary CAR-T succeed?

On February 28, local time, the FDA officially approved the launch of Legend Bio/Johnson & Johnson's BCMA CAR-T therapy Ciltacabtagene autoleucel (cilta-cel, Cidaki Orenza, trade name Carvykti), becoming the first FDA-approved drug in China , and the world's second CAR-T cell immunotherapy targeting BCMA
.
The approval of Cidaki Orenza also witnessed an important "milestone" for China's innovative drugs to go overseas
.
Why do legendary creatures "ride the wind and waves"? Under the background that Innovent Bio's PD-1 was blocked in the FDA's approval, whether Legend Bio's Sidaki Orenza can "go overseas" has attracted more attention
.
It is understood that Cidaki Orenza is a BCMA-targeting CAR-T independently developed by Legend Bio.
The therapy contains a 4-1BB co-stimulatory domain and two BCMA-targeting single-domain antibodies, aiming to increase its targeting Comprehensive capabilities of cancer cells for the treatment of adult relapsed/refractory multiple myeloma (MM)
.
It is reported that the submission of the marketing application (BLA) of Cedarquiorenza is mainly based on the results of the pivotal Phase Ib/II CARTITUDE-1 study, which evaluated the efficacy of Cedarquiorenza in relapsed and/or refractory multiple patients.
Efficacy and safety in myeloma patients
.
Of the 97 subjects recruited, 99% were refractory to last-line therapy, 88% of whom had received at least 3 prior lines of therapy
.
At a median follow-up of 12.
4 months, the independent committee-reviewed ORR was 97%, including 67% sCR (strict complete response), 26% VGPR (very good partial response) and 4% PR
.
Grade ≥3 cytokine syndrome (CRS) occurred in 5%, and grade ≥3 neurotoxicity occurred in 10%
.
From the perspective of industry insiders, it is almost difficult to pick out major faults when examining Legend Bio's Sidaki Orenza based on the core reasons why Innovent Bio's PD-1 was rejected by the FDA (→click to review).

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First of all, Legend Bio’s application for listing to the FDA is based on global multi-center clinical trial data, involving clinical research data from the United States, Japan, the European Union and other regions, which is more accurate than the single Chinese clinical data of Innovent Bio.
It is convincing; second, the primary endpoint of Legend Bio is set to ORR, which corresponds to the approved Abecma setting standard, in contrast, the control group of Innovent's sintilimab does not meet the US clinical practice standards; third Third, a number of PD-1/L1 products have been launched in the United States, and for the non-small cell lung cancer indications declared by sintilimab, the clinical treatment options are relatively abundant, and the needs are basically met, while there is only one BCMA CAR- T therapy
.
Therefore, there are optimistic expectations in the industry for the successful FDA approval of Cidaki Orenza
.
Against the background that Innovent Bio's PD-1 was blocked from overseas, Cidaki Orenza successfully landed in the US market, which also brought great confidence to domestic pharmaceutical practitioners and investors
.
Affected by this news, Legend Bio’s stock price rose 12% after the market, closing at $39.
59, with a market value of $6.
8 billion
.
According to relevant statistics, up to now, 16 new Chinese drugs have been trying to enter the US market, of which 8 have been accepted by the FDA
.
In addition to Innovent Bio, BeiGene, Junshi Bio, Kangfang Bio’s 4 PD-1 models, and the cell therapy Xidaki Orensai, including Chi-Med Bio, there are Chi-Med’s surufatinib, Yiyi The exploration of innovative drugs such as F-627 of Fan Medicine and the combination therapy of Tengsheng Biopharma's new crown neutralizing antibody ambavirumab/romisevirumab are all worthy of respect.
Accumulate valuable experience in high-quality development stage
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As one of the most innovative gene therapies at present, CAR-T cell immunotherapy has been attracting industry attention in recent years
.
Primarily used to treat blood cancers, the therapy takes a patient's T cells and modifies them into CAR-T cells to precisely attack cancer cells
.
With the rise in popularity of CAR-T, more and more companies have begun to enter the track.
Whether it is a multinational pharmaceutical company or a local pharmaceutical company, the enthusiasm for R&D in this field has only increased.

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As of April 16, 2021, there were 2,073 active cell therapy drug R&D pipelines in the world, an increase of 572 over the same period in 2020, a growth rate of 38%
.
Among different types of cell therapy, CAR-T continued to dominate, adding 299 new CAR-T drugs, a 35% increase over the same period in 2020
.
Most CAR-T therapies (80%) are in preclinical and clinical phase I stages
.
In addition, TCR-T cell therapy added 80 new drugs, followed by NK/NK-T cell therapy with an increase of 67
.
According to statistics, there are 355 ongoing CAR-T clinical trials in China in 2020, and Fosun Kite's Yescarta has become China's first CAR-T cell therapy product
.
In the selection of indications, the projects in China mainly focus on hematological indications, and the targets mainly focus on CD19 and BCMA; the targets in solid tumors mainly include GPC3 and Claudin18.
2
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Up to now, with the addition of Legend Bio's Sidaki Orenza, the U.
S.
FDA has approved 6 CAR-T cell therapies
.
They are: Novartis' Kymriah, Kite's Yescarta, Tecartus, Juno's Breyanzi, and Bristol-Myers Squibb (BMS) and Bluebird Bio's Abecma
.
The CAR-T therapy previously approved by the FDA has also been marketed in China.
Two CAR-T therapies have been launched in China: one is the 2021 National Medical Insurance Drug Catalog adjustment, which has passed the preliminary form review and application, but has not entered the negotiation.
One is the second domestically approved and listed first class 1 biological product, Ruikilenxe Injection
.
In addition to facing the increasingly competitive track, CAR-T developers also need to consider pricing
.
As the second BCMA-targeting CAR-T therapy approved for marketing in the world, Cedarquiorenza is the most direct competitor after its listing is BMS' Abecma.
It is understood that Legend Bio's BCMA CAR-T is priced at 46.
5 $419,500; BMS' BCMA CAR-T is priced at $419,500
.
The first mover is the advantage.
Kymriah, the earliest listed company, will have sales of US$587 million in 2021, a year-on-year increase of 24%; Yescarta, the second approved for listing, will have sales of US$690 million in 2021, a year-on-year increase of 23%; and 2021 The first-half sales revenue of Breyanzi and Abecma, which just went public in 2018, only reached US$87 million and US$170 million, respectively
.
It is worth noting that Cidaki Orenza is the first product that Legend Bio is about to commercialize
.
In Legend Bio's results announced on February 18, the company's sales and marketing expenses were approximately $95.
3 million to $106.
2 million, primarily due to increased costs related to the commercial readiness activities of Cedar Keorenza
.
This means that Legendary Bio is ready for the sale of Sidaki Orenza, but whether it can live up to expectations and commercialize its first product will leave time to answer
.
Innovation risk is high and competition is "multiple bases in the suburbs" Although Legend Bio has obtained FDA approval for its listing application in the United States with Sidaji Orenza, achieving a "zero breakthrough" in domestic cell therapy drugs, innovation itself contains greater risks.
On the one hand, There are uncertainties in product development and approval; on the other hand, competition is intensifying.
In the current CAR-T research and development boom, a large number of pharmaceutical companies are deploying, and the competition will be very fierce in a few years
.
On February 15, GenScript announced that its subsidiary Legend Bio received an email notification from the US FDA on the 11th, suspending the Phase I clinical trial of one of its CAR-T products
.
The product is a CAR-T therapy targeting malignant CD4+ T cells and will be used to treat adult patients with relapsed or refractory T-cell lymphoma
.
This is Legend Bio's second CAR-T product to go overseas
.
It is understood that in addition to Sidaki Orenza, the product with the fastest R&D progress of Legend Bio is LB1901, which has been advanced to clinical phase I in both China and the United States
.
This is a CD4 CAR-T product, and the main global competitor is iCell, an American gene therapy company
.
As early as December 2020, Legend Bio has obtained FDA authorization to carry out the clinical approval of the new drug LB1901, but it was not until September 2021 that the Phase I clinical trial was officially launched
.
The announcement shows that as of now, one patient has been injected in the clinical trial, but the peripheral blood CD4+ T cell count is low.
Legend Bio has suspended the clinical trial and notified the FDA according to the trial protocol
.
The patient had no drug-related serious adverse events (SAEs) and is currently being monitored according to the trial protocol
.
As we all know, the development of new drugs is a risk of life and death, and problems in the early clinical stage are more common
.
However, the CAR-T track is still crowded.
At present, there are many domestic companies or institutions deploying CAR-T cell therapy.
Among them, Legend Bio, Sibiman Bio, Keji Pharmaceutical, Gracell Bio,
etc.
CAR-T therapy layout of domestic companies It is worth noting that in the field of treatment, the indications of CAR-T therapy are concentrated in hematological tumors (mainly leukemia, lymphoma and myeloma, etc.
), but hematological tumors are among all human malignant tumors.
Only about 10%, and the remaining 90% are solid tumors, such as lung cancer, liver cancer, breast cancer,
etc.
If CAR-T can make breakthroughs in solid tumors, its commercial value will be further enhanced
.
Therefore, many companies are committed to differentiated layouts, such as deep cultivation in the field of solid tumors
.
In addition to conventional CAR-T therapy, TCR-T therapy has become a research and development hotspot due to its unique advantages in the field of solid tumor treatment
.
According to incomplete statistics, there are currently 53 drugs in the clinical stage at home and abroad, most of which are in the I/II stage and the early preclinical stage.
The indications include metastatic non-small cell lung cancer, hepatocellular carcinoma, and multiple myeloma.
, soft tissue sarcoma, head and neck cancer, melanoma, liposarcoma, cervical cancer,
etc.
Immunocore announced today that the U.
S.
Food and Drug Administration (FDA) has approved its innovative therapy, Kimmtrak, the first FDA-approved therapy for unresectable or metastatic uveal melanoma and the first regulatory-approved T cell receptor (TCR).
therapy
.
As the company with the first listed CAR-T cell therapy, Novartis has also invested a lot in TCR-T cell therapy
.
In addition to multiple rounds of investment in TScan, Novartis and TScan reached a collaboration of hundreds of millions of dollars in April 2020 to develop TCR-T cell therapies targeting up to 3 new targets
.
Domestic companies, such as Xiangxue Precision, take cellular immunotherapy as an entry point, and are committed to developing new methods of adoptive immunotherapy targeting specific T cells with China's independent intellectual property rights
.
At present, a full-coverage R&D platform has been established from TCR-T product R&D, preparation, quality control, product industrialization to clinical transformation, and there is a product pipeline covering most of the genotypes of the population
.
The antigen-specific high-affinity T cell receptor-transduced autologous T cell therapy (TAEST) developed by it, the first product TAEST16001 injection has been approved by the State Food and Drug Administration to enter the clinical trial of new drugs, and it is the first registration in China.
TCR-T cell drugs for clinical trials
.
In general, the CAR-T track is already very crowded, and the market competition will be more intense in the future.
The future commercialization capability will be a test for many companies
.