CAR-T therapy targets are diversified!

Keywords: Cidacchi Oronza; BCMA; CAR-T therapy

On May 27th, GenScript announced that its non-wholly-owned subsidiary Legend Bio BCMA targeted CAR-T therapy cilta-cel's biologics license application (BLA) was given priority review by the FDA Qualified for the treatment of patients with relapsed and/or refractory multiple myeloma
.

According to the Prescription Drug User Fees Act (PDUFA), the FDA will complete its review of the BLA by November 29, 2021

Cidaki Oronza (cilta-cel, LCAR-B38M/JNJ-4528) is a CAR-T therapy targeting B cell maturation antigen (BCMA) developed by Legend Bio.
In December 2017, Legend Bio and Janssen Reach global cooperation and licensing agreements
.

In terms of transaction amount, Yang Sen paid the first installment of US$350 million and subsequent milestone payments to GenScript, setting a record of the largest down payment for foreign patent authorization by Chinese pharmaceutical companies and the best conditions for cooperation at that time

Sidaki Orenza has a novel structure and contains a 4-1BB costimulatory domain and two BCMA targeting single domain antibodies, aiming to increase its comprehensive ability to target cancer cells
.

Moreover, compared with other CAR-T products, the clinical dose of Cidacchi Orenthal is significantly smaller, with high safety and excellent efficacy

Prior to this, Cidacchi Oronza obtained the priority drug designation of the European Commission in April 2019, the breakthrough therapy designation in the United States in December 2019, and the breakthrough therapy designation in August 2020 in China
.

Moreover, the U.

In December 2020, Xi’an Janssen and Legendary Biotechnology announced that they have begun rolling submission to the FDA for the BLA of Cidacchio Lunza for the treatment of relapsed/refractory multiple myeloma adult patients
.

The submission of the BLA is based on the results of the pivotal Phase Ib/II study CARTITUDE-1, which evaluates the effectiveness and safety of Cedacchio Lentose in patients with relapsed and/or refractory multiple myeloma

The results of the study showed that at a median follow-up of 12.
4 months, the ORR reviewed by the independent committee was 97%, including 67% sCR (strict complete response), 26% VGPR (very good partial response), and 4% PR
.

In terms of safety, the incidence of cytokine syndrome (CRS) of grade ≥3 in the study was 5%, and the incidence of neurotoxicity of grade ≥3 was 10%

In addition, Legend Bio will also announce a preliminary data on the clinical research cohort A codenamed CARTITUDE-2 on Cidacchi Oron at the 2021 ASCO annual meeting
.

The CARTITUDE-2 study is a multi-cohort phase II clinical study, which aims to evaluate the safety and effectiveness of Cedacchio Lunza for MM patients in different clinical environments, and to explore the suitability of outpatient administration

As of February 2021, the median follow-up time was 5.
8 months.
A total of 20 patients were treated with Cidacchio Lunza, and one patient was treated in an outpatient clinic
.

The median number of subjects previously received treatment was 2-line, 12 cases received ≤3-line therapy, 8 cases received 3-line therapy, and all patients received PI (proteasome inhibitor) and IMiD (immunomodulator) With dexamethasone treatment, 95% had received alkylating agents and 65% had received daratumumab treatment

The results of the study showed that the patient’s ORR was 95%, of which 75% achieved sCR/CR and 85% achieved VGPR; the median time to first remission was 1.
0 month, the median time to best remission was 1.
9 months, and the median duration of remission Not yet reached
.
All 4 MRD-evaluable patients reached MRD-negative levels at the time of data cut-off
.

In terms of safety , the incidence of hematology-related adverse reactions (AEs) in the CARTITUDE-2 study ≥20% include: neutropenia, thrombocytopenia, anemia, lymphopenia, leukopenia; CRS (cytokine release syndrome) The incidence rate was 85%, with grade 3/4 accounting for 10%; the incidence of CAR-T cell neurotoxicity was 20%, all with grade 1/2
.

In Europe, Janssen submitted to the EMA in April this year a marketing application (MAA) for the treatment of relapsed and/or refractory multiple myeloma with Cidacchio.
In May, the EMA formally accepted the MAA
.
In China, Cidacchi Oronza is in the phase II clinical research phase, and it is expected to submit a listing application in the second half of this year
.

       Legend Bio is a global clinical-stage biopharmaceutical company dedicated to the discovery and development of new cell therapies for oncology and other indications.
It was listed on NASDAQ in June 2020, becoming the first domestic CART therapy to be marketed.
Company
.
According to the company's official website, Legend Bio also has a number of CAR-T therapies under development, including research autologous chimeric antigen receptor T cells (CAR-T) for the treatment of adult relapsed or refractory T-cell lymphoma (TCL) The therapy has been approved by the FDA's New Drug Clinical Trial (IND) application in December 2020, becoming the second IND application approved by Legend Bio in the United States
.
Moreover, Legend Bio is also advancing a number of clinical programs initiated by researchers, including diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML), gastric cancer, pancreatic cancer, and non-Hodgkin’s lymphoma (NHL).
) Allogeneic treatment
.

       The number of CAR-T therapies approved globally increases to 5

       CAR-T therapy is a new type of cell therapy that uses repaired immune cells to attack and destroy malignant tumors.
It is one of the most eye-catching innovative therapies in the field of tumor, especially hematoma treatment in recent years
.
According to statistics, 5 CAR-T therapies have been approved globally
.

       From an enterprise perspective , Gilead and BMS each have two seats, among which Yescarta and Tecartus owned by Gilead are obtained through Kite Pharma
.
From the time of the first batch of FDA, it is mainly concentrated in the past two years
.

       From the point of view of the target point of action , except for Abecma, the other 4 models all act on CD19, which also makes Abecma different from other CAR-T therapy indications
.
However, in China, no CAR-T therapy has yet been approved.
Among them, Fosun Kate introduced Yescarta® (Axicabtagene Ciloleucel) from Kite Pharma and the progress of WuXi Geno’s Regi-Olenza.
Faster, currently in the listing application stage
.

       Kymriah is the world’s first CAR-T therapy approved by the FDA in August 2017 for the treatment of children and young adults (age to 25 years old) with acute lymphoblastic leukemia (ALL).
The drug was again approved by the FDA in May 2018.
Approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (previously received two or more systemic treatments), including the most common form of non-Hodgkin’s lymphoma-diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma and DLBCL due to follicular lymphoma (FL)
.
In April 2020, the drug was granted regenerative medicine advanced therapy (RMAT) qualification for the treatment of relapsed or refractory follicular lymphoma (R/R FL) by the FDA, and it is expected to submit a marketing application for this indication this year
.

       Yescarta is the second CAR-T therapy approved worldwide.
It was approved by the FDA in October 2017 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more systemic treatments, including diffuse large B DLBCL caused by primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and follicular lymphoma
.
In March 2021, Yescarta was again approved by the FDA for use in adult patients with relapsed or refractory follicular lymphoma (FL) after two or more systemic treatments.
This approval makes this drug the first approved drug for indolence CAR T cell therapy for patients with follicular lymphoma
.

       Tecartus is the third CAR-T therapy approved worldwide.
It was accelerated by the FDA in July 2020 for the treatment of relapsed or refractory sets that had previously received 2 or more systemic therapies (including a BTK inhibitor).
Adult patients with cellular lymphoma (R/R MCL) have become the first and only CAR-T therapy approved for the treatment of R/R MCL
.
In April of this year, Gilead submitted to the FDA a supplementary biological product license application (sBLA) for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)
.

       Breyanzi was developed by Juno Therapeutics.
Xinji acquired Juno for $9 billion in 2018 and acquired Breyanzi.
In 2019, Xinji was acquired by BMS for $74 billion, and the product changed ownership again
.
The drug was approved by the FDA in February 2021 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more systemic treatments, including diffuse large B-cell lymphoma (DLBCL) (including indolent) DLBCL caused by lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and grade 3B follicular lymphoma
.
In addition to relapsed or refractory large B-cell lymphoma, the drug is also approved in Japan for the treatment of relapsed or refractory follicular lymphoma (R/R FL)
.

       Abecma is the only BCMA targeted CAR-T therapy currently approved.
It was approved by the FDA in March 2021 for the treatment of four or more pre-therapies (including immunomodulators, proteasome inhibitors and anti-CD38 monoclonal antibodies) ) Adult patients with relapsed or refractory multiple myeloma (MM)
.

Among the four CD19-targeted CAR-T therapies, except for Tecartus, the other three are approved for the treatment of DLBCL.
Among them, Breyanzi is different from the other two CAR-T therapies.
This product adds purified CD4+ and CD8+ cells.
, Safety has been significantly improved, and the incidence of cytokine release syndrome has been significantly reduced
.

       According to the financial reports of various companies, the scale of the global CAR-T market has continued to expand in recent years.
Among them, Yescarta has the highest sales, exceeding US$500 million in 2020
.
Kymriah followed, with sales in 2020 reaching 474 million U.
S.
dollars, while Tecartus’s sales in the first year of listing reached 44 million U.
S.
dollars
.
According to the Frost & Sullivan report, the global CAR-T therapy market is expected to reach US$6.
6 billion in 2024 and US$21.
8 billion in 2030.
From this point of view, the global CAR-T market is not yet saturated, and it is bound to roll up in the future.
More intense competition
.

       Diversified targets for CAR-T therapy under development

       In addition to the 5 CAR-T therapies approved above, there are currently many CAR-T therapies under development, such as the BCMA targeted bb2127 jointly developed by BMS/Bluebird Bio, and the CT103A targeted by Reindeer Medical/Cinda Bio BCMA ( IBI326), ALLO-715 targeted by Allogene Therapeutics BCMA, CT041 targeted by Claudin 18.
2 and CT053 targeted by BCMA, and MB-106 targeted by Mustang Bio CD20
.

       From the point of view of targets, CAR-T therapy targets will become more and more diversified in the future, and BCMA is another very competitive CAR-T therapy target after CD19, of which Claudin 18.
2 is a four-time target.
Transmembrane proteins, with complex structures, are highly specifically expressed in cancer cells in many patients with gastric cancer and pancreatic cancer, which also makes the indications of CAR-T therapy transfer from hematological tumors to solid tumors
.

       In addition, some companies have now developed dual-targeting CAR-T therapies, such as Hengrun Dasheng's anti-human CD19-CD22 T cell injection, and Genxi Bio-BMCA/CD19 dual-targeting GC012F
.

       Among the above-mentioned CAR-T therapies under development, Tessa Therapeutics' CD30-directed auto-chimeric antigen receptor T cell (CD30 CAR-T) therapy was awarded the FDA Regenerative Medicine Advanced Therapy (RMAT) qualification for the treatment of R/R cHL in 2020.
In 2021, he was awarded the priority drug qualification (PRIME) for the treatment of relapsed or refractory classic Hodgkin lymphoma (R/R cHL) by EMA
.

       Precision/Servier’s PBCAR0191 is a universal allogeneic CD19 targeted CAR-T cell therapy, derived from qualified donor T cells, after gene editing to remove the expression of endogenous T cell receptor (TCR), It is prepared by inserting CAR into the same site.
In August 2020, it was granted fast track qualification for the treatment of advanced B-cell precursor acute lymphoblastic leukemia (B-ALL) by the FDA
.
Allogene Therapeutics' ALLO-715 is currently being developed for the treatment of R/R MM patients, and was granted Regenerative Medicine Advanced Therapy (RMAT) qualification by the FDA in April 2021
.

       In addition, it is worth mentioning that the preparation of CAR-T therapy has gradually begun to change
.

       The CAR-T products currently on the market all over the world are autologous therapies, and their preparation requires modification of each cancer patient’s own T cells and reinfusion into the patient’s body after expansion.
They are tailor-made patient-specific drugs.

.
However, some patients have impaired their immune system due to pre-treatment, and their T cells cannot be used to prepare CAR-T
.
At the same time, in view of the very high production costs of CAR-T products for autologous therapy, many research institutions and pharmaceutical companies at home and abroad are promoting the development of allogeneic or universal CAR-T therapies.
These therapies can be derived from healthy donor cells or other A large number of ready-made cell sources are produced, engineered to express the required CAR, and then used in multiple patients
.

       In view of the market potential of CAR-T therapy, global pharmaceutical companies are also very active in BD transactions around CAR-T therapy authorization, cooperation, and acquisition, such as Gilead’s acquisition of Kite Pharma, Xinji’s acquisition of Juno Therapeutics, and Mustang Bio’s acquisition from Fred Hutch authorized MB-106, the British record as far as obtaining CNCT19 project authorization from biological sources together, WuXi Juno cooperation and the establishment of a clear drug giant Novo companies
.

       Editor in charge: Sanqi