In-depth analysis of WuXi Junuo CAR-T therapy product Ruijilunsai injection for the first time globally

On September 6, 2021, Suzhou WuXi Junuo Biotechnology Co.
, Ltd.
announced its CD19-targeting autologous chimeric antigen receptor T (CAR-T) cellular immunotherapy product Benoda (Reiki Orenza Injection, The development code JWCAR029) was approved for marketing by the National Medical Products Administration (NMPA) of China for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) after second-line or above systemic treatment
.

This product is the first CAR-T product approved as a category 1 biological product in China and the sixth approved CAR-T product in the world
.

 Figure 1 Source: WuXi Biotech's official website Benoda is the first CAR-T product independently developed by China and approved as a Category 1 biological product.
It is also the only CAR-T product that has been awarded the "Major New Drug Development" special project, priority review and breakthrough at the same time.
CAR-T products have been approved for three awards of sex therapy drugs
.

Benoda’s approval is based on the results of a single-arm, multi-center, pivotal study (RELIANCE study), which aims to evaluate the relapsed or refractory large B-cell lymphoma in China (r/r LBCL) Effectiveness and safety in patients
.

The results of the RELIANCE study showed that Ruiji Orenxil exhibited a higher and sustained disease remission rate and lower CAR-T treatment-related toxicity
.

At the 62nd Annual Meeting of the American Society of Hematology (ASH), WuXi Genuo announced the key clinical research (RELIANCE trial) data of Regi-Olenza injection under the path of new drug research
.

The data of 58 patients with evaluable efficacy in the JWCAR029 pivotal study (RELIANCE trial) showed that the best objective response rate was 75.
9% (95% CI, 62.
8 ~ 86.
1), and the best complete response rate was 51.
7% (95%) CI, 38.
2 ~ 65.
1)
.

The median follow-up time was 8.
9 months, and the median OS was not reached.
The 6-month DOR, PFS and OS were 60.
0%, 54.
2% and 90.
8%, respectively
.

Among 59 patients who received treatment, 28 patients (47.
5%) developed cytokine release syndrome (CRS) of different grades
.

Two patients (3.
4%) and one patient (1.
7%) had Grade 3 and Grade 4 CRS, respectively
.

The median time to onset of CRS was 4.
5 days after infusion (range 1 to 5), and the median duration was 7.
0 days (range 1 to 18)
.

Twelve patients developed neurotoxicity, of which only 3 patients (5.
1%) were severe (all grade 3)
.

The median onset time of neurotoxicity was 8.
5 days after infusion, and the median duration was 12.
5 days (range 1 to 49)
.

Except for one patient who died on the 8th day after CAR-T cell reinfusion (death due to sepsis), the CRS of grade 4 was still not alleviated, and the CRS and neurotoxic symptoms of all other patients were resolved and disappeared
.

 Large B-cell lymphoma (LBCL) is a malignant lymphoma that contains large B-lymphoid cells with a nucleus that is larger than a normal macrophage nucleus or twice as large as a normal lymphocyte nucleus.
It is mainly a diffuse type and is the most common type in all countries and age groups.
A subtype of non-Hodgkin's lymphoma that accounts for more than one-third of newly diagnosed cases
.

Although traditional treatments such as chemotherapy, surgery, and hematopoietic stem cell transplantation have prolonged the survival time of some patients with hematological malignancies; R-CHOP, R-CHOEP, R-miniCHOP, DA-EPOCH-R are the current first-line treatment options.
The treatment of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) still has the problem of poor prognosis and high risk of death
.

The phenomenon of relapse, refractory and even drug resistance is still a huge challenge currently facing
.

The "2020 CSCO Lymphoma Diagnosis and Treatment Guidelines" has included CAR-T cell therapy as an alternative for relapsed or refractory diffuse large B-cell lymphoma
.

01 Global approval of CAR-T therapy Chimeric antigen receptor (CAR, Chimeric antigen receptor)-T cell immunotherapy is an adoptive cell immunotherapy for tumors.
The basic principle is to modify T lymphocytes by genetic engineering to express chimeric Antigen receptors kill tumor cells in a non-MHC (major histocompatibility complex) restrictive manner
.

As a tumor treatment method that has emerged in recent years, it has now become the fourth tumor treatment method after surgery, radiotherapy, and chemotherapy
.

The therapy has shown good targeting, lethality and durability in clinical trials, and has a significant therapeutic effect in the treatment of hematological tumors [1-2]
.

Figure 2 Schematic diagram of the 1-4 generation CAR-T cell structure [3] The structure of CAR mainly includes three parts: extracellular antigen binding region, transmembrane structure region and intracellular signal transduction region
.

The extracellular antigen binding region is composed of the variable region sequence (scFv) of the antibody, which is responsible for specifically identifying and binding to the antigen on the surface of tumor cells, and designing the extracellular antigen binding region of CAR by targeting specific antigens on the surface of different tumor cells The transmembrane region is responsible for connecting the extracellular antigen binding region and the intracellular signal transduction region.
It is composed of homologous or heterologous dimeric membrane proteins.
By changing the design of the transmembrane region, the expression level of CAR genes can be adjusted; intracellular The signal transduction region usually uses immunoreceptor tyrosine activation motifs, the most common being CD3ζ and immunoglobulin Fc receptor gamma chain [4]
.

(1) Kymriah (Tisagenlecleucel, CTL019): The world’s first CAR-T therapy product.
On August 30, 2017, the US FDA approved Novartis’ Kymriah to be marketed for the treatment of 25-year-olds with refractory conditions or two or more relapses.
The following B cell precursors are patients with acute lymphocytic leukemia (ALL)
.

This is the first CD19-targeted genetically modified autologous T cell immunotherapy (CAR-T therapy) approved in human history, which modifies the patient's own T cells to fight and kill cancer cells
.

On May 1, 2018, Novartis announced that Kymriah's second indication has been approved for marketing by the FDA for adult relapsed or refractory (r/r) large B-cell lymph nodes who have previously received two or more systemic treatments.
Treatment of tumor patients (r/r LBCL), including non-specific diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma and DLBCL caused by follicular lymphoma
.

The efficacy of Kymriah in children and young adults with r/r B-cell precursor ALL was evaluated in an open-label, multi-center, one-arm trial (ELIANA, NCT02228096)
.

The results of the test showed that of the 63 evaluable patients, CR/CRi reached 83% three months after injection of Kymriah, and all patients were MRD negative
.

An open-label, multi-center, one-arm trial (JULIET, NCT02445248) trial evaluated Kymriah recurrence after receiving ≥ 2 lines of chemotherapy (including rituximab and anthracyclines, or autologous hematopoietic stem cell transplantation (HSCT)) Or the effectiveness and safety in patients with refractory DLBCL
.

The test results showed that the total remission rate of r/r LBCL patients reached 50%, the complete remission rate was 32%, and 18% of patients had partial remission
.

The safety results showed that the most common adverse reactions (>20%) of Kymriah were cytokine release syndrome (79%), hypogammaglobulinemia (43%), unexplained infection (41%), fever (40%) ), loss of appetite (37%), headache (37%), encephalopathy (34%), hypotension (31%), bleeding episodes (31%), tachycardia (26%), nausea (26%), diarrhea (26%), vomiting (26%), viral infectious diseases (26%), hypoxia (24%), fatigue (25%), acute kidney injury (24%), edema (21%), cough (21 %) and delirium (21%)
.

 Novartis’ annual report shows that Kymriah’s sales in 2019 were only $278 million
.

Despite the severe impact of COVID-19 in 2020, it still achieved substantial growth, reaching US$474 million
.

 On September 27, 2018, Cellular Biomedicine Group Inc.
announced that it has reached a strategic licensing and cooperation agreement with Novartis to be responsible for the production and supply of CAR-T cell therapy drug Kymriah® (Tisagenlecleucel) in China.
), Novartis will become the exclusive holder of the marketing license
.

According to CDE, Kymriah has obtained the implied license for clinical trials (JXSL1900067, JXSL1900121, CXSL2000370, CXSL2000369) in China
.

The drug clinical trial registration and information disclosure platform showed that its phase III clinical trial (CTR20200561) for the treatment of adult relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (CTR20200561) has been recruited on June 15, 2020
.

(2) Yescarta (Axicabtagene ciloleucel, KTE-C19): the first CAR-T product for specific non-Hodgkin's lymphoma (NHL), the first CAR-T cell therapy product approved to be marketed for FL.
2017.
10 On the 18th, the CD19-targeted CAR-T therapy product "Yescarta" of Gilead’s Kite Pharma Inc.
was approved by the US FDA to be used for relapsed or refractory large B cells after receiving two or more system treatments.
Adult patients with lymphoma (r/r LBCL), including unspecified diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and follicular lymphoma The resulting DLBCL is the first CAR-T cell drug approved by the US FDA for specific non-Hodgkin's lymphoma (NHL)
.

On March 5, 2021, its application for extended indications for adult patients with relapsed/refractory follicular lymphoma (r/r FL) after receiving 2 or more systemic treatments received accelerated approval from the US FDA, becoming a global The first CAR-T cell therapy product approved to be marketed for r/rFL
.

According to the results of the ZUMA-5 single-arm, open-label, multi-center trial, when the median follow-up time of Yescarta reached 17.
5 months, the overall response rate (ORR) of 104 patients with evaluable indolent non-Hodgkin’s lymphoma reached 92%, the complete remission rate (CR) reached 76%, of which the ORR of patients with follicular lymphoma was 94%, the CR reached 80%, the median DOR, PFS, and OS had not yet been reached, and 64% of FL patients were still Keep in relief
.

Fosun Kite Biotechnology Co.
, Ltd.
introduced Yescarta (Axicabtagene ciloleucel) from Kite Pharma Inc.
, a subsidiary of Gilead, for technology transfer in China at the beginning of 2017, and was authorized to locally produce CD19-targeted autologous CAR-T cell therapy in China Product
.

Akirensai injection (Yikaida, Yescarta) is used to treat adult patients with relapsed or refractory large B-cell lymphoma (including diffuse large B-cell lymphoma, non-specific type, Primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and diffuse large B-cell lymphoma transformed from follicular lymphoma) have been approved for marketing by NMPA on June 22, 2021
.

On August 17, 2021, NMPA officially included the new indications of Akirensai injection into the breakthrough treatment drug program.
The proposed indication is the treatment of relapsed or refractory inert non-Hodgkin after receiving second-line or above systemic treatment.
Chikin lymphoma (r/r iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL)
.

 According to the annual report of Gilead, Yescarta achieved a sales performance of US$563 million in 2020, which is a 23.
46% increase compared with the sales performance of US$456 million in 2019
.

(3) Tecartus (Brexucabtagene autoleucel, KTE-X19): The world's first CAR-T cell therapy product for the treatment of adult relapsed or refractory mantle cell lymphoma (r/r MCL)
.

On July 24, 2020, the CD19-targeted CAR-T cell therapy Tecartus of Gilead’s Kite Pharma Inc.
was approved by the FDA for accelerated listing in the United States, becoming the world’s first and only one approved for the treatment of adult relapsed or refractory disease.
CAR-T cell therapy product for mantle cell lymphoma (r/r MCL)
.

A single-arm, open-label, multi-center clinical trial (ZUMA-2, NCT02601313) for previous anthracyclines or chemotherapy containing bendamustine, anti-CD20 antibodies and Bruton tyrosine kinase inhibitor (BTKi The efficacy and safety of a single injection of Tecartus in adult patients with relapsed or refractory mantle cell lymphoma (r/r MCL) with ibrutinib or acatinib were evaluated
.

The clinical results showed that the objective response rate (ORR) in effectively evaluated patients was 87%, the complete response rate was 62%, and the partial response rate was 25%
.

The safety test results show that the most common (≥ 10%) grade 3 or above adverse reactions of Tecartus are anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, and deficiency.
Oxygen, fever, hyponatremia, hypertension, unexplained infection, pneumonia, hypocalcemia and lymphopenia
.

According to Gilead Sciences Inc.
's 2020 annual report, Tecartus sales are $44 million
.

 (4) Breyanzi (Lisocabtagene maraleucel, JCAR017): lower toxicity February 5, 2021, CD19 targeted CAR-T therapy Breyanzi (Lisocabtagene maraleucel, R & D code JCAR017) developed by Juno Therapeutics, a subsidiary of Bristol-Myers Squibb (BMS) Approved by the US FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) after two or more systemic treatment lines, including unspecified diffuse large B-cell lymphoma Neoplasms (DLBCL) (including DLBCL derived from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, grade 3B follicular lymphoma
.

The therapy has been granted Orphan Drug, Breakthrough Therapy Designation and Regenerative Medicine Advanced Therapy Designation (RMAT) by the U.
S.
FDA
.

The uniqueness of this therapy is that Breyanzi is composed of purified CD8-positive and CD4-positive T cells in a specific ratio, which can better control the side effects of cell therapy
.

In an open-label, multi-center, single-arm trial (TRANSCEND, NCT02631044) in the evaluation of the efficacy of Breyanzi in adult patients with r/r LBCL, the overall response rate was 73%, and 54% of patients achieved complete remission (CR)
.

Adverse reaction results suggest that the most common non-laboratory adverse reactions of any grade (≥ 20%) in Breyanzi are fatigue, cytokine release syndrome (CRS), musculoskeletal pain, nausea, headache, encephalopathy, unexplained infection, and loss of appetite , Diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting and edema
.

 (5) Abecma (Idecabtagene vicleucel, bb2121): The world's first BCMA targeting CAR-T cell therapy March 26, 2021, B cell maturation antigen (BCMA) targeted by Celgene Corporation, a subsidiary of Bristol-Myers Squibb (BMS) The chimeric antigen receptor (CAR)-T cell immunotherapy Abecma was approved by the US FDA for the treatment of 4 or more therapies (including immunomodulators, proteasome inhibitors and anti-CD38 monoclonal antibodies).
) Adult patients with relapsed or refractory multiple myeloma (r/r MM)
.

Prior to this, Abecma was granted Orphan Drug and Breakthrough Drug Designation (BTD) by the FDA
.

A clinical trial of patients with relapsed or refractory multiple myeloma (r/r MM) after receiving at least 3 treatments (including immunomodulators, proteasome inhibitors and anti-CD38 monoclonal antibodies) (MM-001 Research) showed that among the 100 evaluable patients, the overall response rate (ORR) reached 72%, 28% of the patients achieved complete remission (CR), and the median time to first response was 1 month
.

Abecma safety data shows that adverse reactions of grade 3 or higher include cytokine release syndrome (9%), neurotoxicity (4%), hemophagocytic lymphohistiocytosis (1.
6%), infection (23%) and Long-term cytopenia (61%)
.

02 Other clinically researched CAR-TCiltacabtagene autoleucel (Cidacchi Oriente): Cidacchi Oriente is a chimeric antigen receptor targeting B cell maturation antigen (BCMA) developed by Nanjing Legend Biotechnology Co.
, Ltd.
Somatic T cell (CAR-T) therapy, which is used to treat relapsed and/or refractory multiple myeloma (r/r MM)
.

On December 18, 2017, China's NMPA included Cidacchi Oriente into the priority review list (CXSL1700201); in August 2020, Cidacchi Oriente's breakthrough drug qualification (BTD) was awarded
.

It is currently in Phase II clinical research in China
.

In the United States, it was granted Orphan Drug Designation by the U.
S.
FDA in February 2019; in December 2019, the FDA granted Cidacchi Orienta breakthrough drug designation
.

On December 22, 2020, Janssen Research & Development Llc and Nanjing Legend Biotech submitted a marketing application to the FDA for the treatment of multiple myeloma
.

The results of the CARTITUDE-1 (Phase 1b/2) study showed that the overall response rate (ORR) of the 18-month median follow-up of Cidacchi Oriente was 98%, and 80% of the patients achieved a strict complete remission (sCR).
)
.

The 18-month progression-free survival rate (PFS) was 66%, and the overall survival rate (OS) was 81%
.

03 Summary Since the US FDA approved the world's first CAR-T cell therapy on August 30, 2017, six CAR-T cell therapy products have been approved for use in various relapsed or refractory blood worldwide.
Tumor treatment
.

Although it started late in China, many companies have deployed CAR-T cell therapy and achieved excellent results
.

As an emerging innovative therapy in recent years, it has quickly entered a stage of rapid development from the initial stage
.

Compared with traditional innovative drugs, CAR-T cell therapy has high R&D costs and requires collection of patient T cells for personalized customization, resulting in high treatment prices for cellular immunotherapy
.

In addition, CAR-T cell immunotherapy also has certain risks, such as off-target effects, cytokine burst syndrome, and nervous system toxicity
.

But as an emerging cellular immunotherapy, the hope it brings to cancer patients is unquestionable
.

Among the 6 CAR-T cell therapy products approved for marketing, 5 products are aimed at the CD19 target and 1 is the BCMA target
.

CAR-T therapies under clinical research (phase I-III) are also mostly focused on CD19 targets, with a ratio of 5:1 to BCMA target therapy
.

In terms of indications, all CAR-T therapies approved for marketing are aimed at the treatment of non-solid tumors.
The study of CAR-T therapy for solid tumors is only in clinical phase II (4 cases), clinical phase I (4 cases), and clinical trials.
The early stage of research and development such as the previous (6 cases) is still far from the market
.

Therefore, new targets and new therapeutic areas (solid tumors) may be important directions for the future development of CAR-T cell therapy
.

It is hoped that in the near future, CAR-T therapy can bring good news to more cancer patients
.

 References [1] Rong Bin, Yuan Ye, Wu Chunqi, et al
.

Research progress of CAR-T cell immunotherapy[J]
.

Journal of Integrated Traditional Chinese and Western Medicine Cardiovascular Diseases, 2018: 6 (30), 8-12.
[2] Li Fang
.

The principle and latest research progress of CAR-T cell immunotherapy[J]
.

Modern Medicine and Health, 2010: 35 (23), 3648-3651.
[3] Zhang Jing, Bruce Lee, Huang Xiaofeng, et al
.

Application of chimeric antigen receptor T cells in blood and solid tumors[J]
.

Guangdong Medicine, 2018: 39, 253-257.
[4] Xiao Yijun, Zhou Gucheng
.

Overview of the principle and clinical application of CAR-T cell immunotherapy for tumors[J]
.

Biology Teaching, 2018: 43 (9), 4-5.
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