The FDA approves 5 CAR-T therapies in a row, and 3 domestic R&D models are in progress

CAR-T cell therapy is one of the most innovative gene therapies.
This therapy is mainly used for the treatment of blood cancers.
The patient's T cells are extracted and modified into CAR-T cells to precisely attack cancer cells.
Now, as CAR-T cell therapy is successively approved globally, it is expected that this type of drug will be launched in China in the near future.

5 CAR-T cell therapies approved in the U.

S.

01Kymriah (tisagenlecleucel)

On August 30, 2017, the FDA approved the first gene therapy, Novartis’ Kymriah (tisagenlecleucel), for children and young adults with acute lymphoblastic leukemia (ALL).

The safety and effectiveness of Kymriah have been demonstrated in a multicenter clinical trial of 63 children and young adults with relapsed or refractory B-cell precursor ALL.
The total remission within three months of treatment The rate is 83%.

On May 1, 2018, Kymriah was approved for the second indication 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 Non-Hodgkin’s lymphoma forms—diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma and DLBCL due to follicular lymphoma (FL).

02Yescarta (axicabtagene ciloleucel)

On October 18, 2017, the second CAR T cell therapy came out.

Yescarta (axicabtagene ciloleucel) from Kite Pharma (acquired by Gilead) was approved by the FDA for the treatment of relapsed or refractory after two or more systemic treatments.

On March 5, 2021, Yescarta was approved by the FDA for adult patients with relapsed or refractory follicular lymphoma (FL) who have undergone two or more systemic treatments.
This approval makes Yescarta the first approved for use in CAR T cell therapy for patients with indolent follicular lymphoma.

03Tecartus (brexucabtagene Autoleucel)

On July 24, 2020, Kite Pharma's second CAR-T cell therapy Tecartus (brexucabtagene Autoleucel) was approved by the FDA for the treatment of adult patients with relapsed/refractory mantle cell lymphoma (MCL).

04Breyanzi (lisocabtagene maraleucel)

On February 5, 2021, Breyanzi (lisocabtagene maraleucel) of Juno Therapeutics, a subsidiary of Bristol-Myers Squibb, was approved by the FDA 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 DLBCL caused by indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma and grade 3B follicular lymphoma.

05Abecma (idecabtagene vicleucel)

On March 26, 2021, Bristol-Myers Squibb and bluebird bio announced that the FDA has approved Abecma (idecabtagene vicleucel; ide-cel) as the first B-cell maturation antigen (BCMA) CAR-T cell therapy for four treatments Adult patients with relapsed or refractory multiple myeloma after or above pre-treatment (including immunomodulators, proteasome inhibitors and anti-CD38 monoclonal antibodies).

Abecma is the first CAR-T cell therapy targeting BCMA approved by the FDA.
BCMA is a protein commonly expressed on multiple myeloma cancer cells, and it is an important potential target for this aggressive blood cancer.
The other four CAR-T cell therapies all target the antigen CD19, which is an antigen protein expressed on the surface of a variety of blood tumor cells, including B-cell lymphoma and leukemia cells.

Domestic CAR-T cell therapy development

In my country, although no CAR-T cell therapy has been approved for marketing yet, judging from the regional distribution of the number of CAR-T cell therapy clinical trials registered on ClinicalTrials.

gov, China has surpassed Europe and the United States to become the CAR-T cell therapy in the world today.
The country with the largest number of T cell therapy clinical studies is expected to usher in a variety of CAR-T cell therapies on the market in the near future.

The development of domestic CAR-T cell therapy is mainly through three modes: cooperative introduction and development, independent development by foreign companies and independent development by domestic companies.

01Cooperative introduction and development

The world's leading CAR-T cell therapy biotechnology company has established a joint venture with domestic companies to complement each other's advantages.

Technology introduction and cooperative development have become a shortcut to quickly enter the Chinese market.

Yescarta (Yi Ji Li Lun Sai injection, code FKC876) was developed by Fosun Kite Biotechnology Co.
, Ltd.
(FOSUN Kite), a joint venture established by Shanghai Fosun Pharmaceutical Group and Kite Pharma.
From the introduction of Yescarta by Fosun Kate Biotechnology Co.
, Ltd.
in April 2017, to the official acceptance of the FKC876 new drug listing application by the National Medical Products Administration (NMPA) in February 2020, it took less than 3 years.
This product is the first CAR-T cell therapy product promoted by Fosun Kate for commercialization in China, and it is also the first CAR-T cell therapy product officially accepted by the National Medical Products Administration.
FKC876 has been included in the priority review in March 2020 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after second-line or above systemic treatment, including diffuse large B-cell lymphoma (DLBCL) non-specific type , Primary mediastinal B-cell lymphoma (PMBCL) high-grade B-cell lymphoma and DLBCL transformed from follicular lymphoma.

In 2016, WuXi AppTec and Juno Therapeutics, a leading American CAR-T pharmaceutical company, established a joint venture company WuXi Juno to jointly develop and produce CAR-T and TCR (T cell antigen receptor) therapies.
WuXi's leading flagship product JWCAR029 (relma-cel, Ruijilunsai injection) is an anti-CD19 CAR-T cell therapy for the third-line treatment of relapsed or refractory B-cell lymphoma.
Ruijilunsai injection (ie JWCAR029) is a CAR-T product independently developed by WuXi Juno based on Juno's lisocabtagene maraleucel (liso-cel, JCAR017).
In June 2020, the National Medical Products Administration of China accepted and reviewed WuXi Junuo's new drug application for the use of relma-cel as a third-line therapy for diffuse large B-cell lymphoma (DLBCL), and granted priority review for new drug applications in September 2020 qualifications.
It is reported that the difference between JCAR017 and JWCAR029 is only that the former produces CD4 and CD8 separately and then mixes them in a ratio of 1:1, while the latter produces CD4 and CD8 T cells at the same time.

02Independent development by domestic enterprises

In August 2020, the LCAR-B38M (cilta-cel) independently developed by Nanjing Legend became the first CAR-T cell therapy variety to be included in the breakthrough therapeutic drug program in China.

LCAR-B38M is a CAR-T cell therapy targeting B-cell maturation antigen (BCMA); in December 2017, Johnson & Johnson’s Janssen Pharmaceuticals signed a global exclusive license and cooperation agreement with Nanjing Legend for joint development cilta-cel and commercialize it.
On December 21, 2020, Janssen announced that it has begun rolling submission to the FDA for its research drug B-ciltacabgene autoleucel (cilta-cel) for the treatment of relapsed and/or refractory multiple myeloma in adults with a biological product marketing application (BLA) , And completed the submission recently, waiting for FDA approval.

On December 23, 2020, the CNCT19 cell injection (anti-CD19 CAR-T cell therapy) of Heyuan Biotechnology (Tianjin) Co.
, Ltd.
was approved to be included in the breakthrough therapy in my country, and the indication is relapsed or refractory acute lymphocytes.
leukemia.
The project is carrying out Phase II clinical trial research in China.

In addition, according to the Insight database information, many domestic biotechnology companies are developing CAR-T cell therapy, and are conducting research on multiple indications, and have even begun to enter the field of solid tumors.

03 Independent development by foreign companies

As a major leader in the field of CAR-T cell therapy, Novartis has chosen to independently develop the world's first approved CAR-T cell therapy Tisagenlecleucel (CTL-019) in China.

On August 12, 2019, Novartis submitted a clinical trial application for CTL019 in my country, which has been accepted by CDE.
At present, the trial of Tisagenlecleucel in the treatment of aggressive B-cell non-Hodgkin's lymphoma in adult patients is undergoing phase III clinical trials in China.

Extended reading: The dilemma of clinical application

As a revolutionary technology, the widespread application of CAR-T cell therapy is still facing numerous difficulties.

01
logistical problems

The working principle of CAR-T cell therapy is to first remove the patient's blood through an intravenous infusion line.

Then the white blood cells, including T cells, are removed, and the blood is reinjected into the patient's body through another intravenous infusion line.
After removal, the T cells are separated and sent to the laboratory where they are genetically modified by adding specific chimeric antigen receptors (CAR).
It usually takes several weeks to complete the preparation of a large number of T cells required for treatment.

The unique nature of each CAR-T cell therapy will cause many manufacturing and logistics problems, and Novartis is one of the companies facing major difficulties.
In August 2017, Novartis Kymriah was approved by the FDA, but as of the end of 2019, the company had only shipped these therapies to approximately 1,800 patients with blood cancer.
Although the number of patients seems to be small, considering that each product must be personalized according to the patient's own immune cells, this is also an impressive milestone.
This process usually takes an average of 21 days for the company to complete.
Because the patients in need of treatment are often in serious conditions, the time is extremely urgent.

However, due to specifications or manufacturing issues, about 10% of Novartis cannot supply medicines at all.

In addition, one of the FDA's requirements for Kymriah is that the product contains at least 80% viable T cells, which has changed from the 70% threshold set in clinical trials and is also higher than other countries that have approved treatments.
This is because the FDA believes that less than 80% may cause safety hazards.
This rule makes Novartis extremely frustrated.

02Price
issue

It is undeniable that CAR-T cell therapy is an improvement on the previous methods of treating blood cancers.
Prior to FDA approval, diseases like lymphoma could only be treated with a combination of chemotherapy regimens.
According to various information, CAR-T cell therapy can provide long-term and lasting relief for about 60% of patients.

Novartis’s Kymriah clinical trial showed that the remission rate of leukemia patients who did not respond to standard treatment reached 83%.
Gilead’s Yescarta can also make the remission rate of aggressive B-cell non-Hodgkin’s lymphoma reach 72%.

However, due to the personalized and complex bioengineering process of CAR-T cell therapy, the development cost is expected to be very expensive.
According to the company's product pricing in the United States, Novartis Kymriah costs US$475,000 for the treatment of leukemia; Yescarta costs US$373,000 for the treatment of lymphoma; and Breyanzi costs US$428,363 for the treatment of lymphoma.
The newly listed Abecma treatment of multiple myeloma is also expensive, at US$419,500.

And whether this huge treatment price is really cost-effective is still controversial.

03Solid
tumor indications to be overcome

Although CAR-T therapy has been considered to be able to successfully treat blood cancers, as far as the treatment of other types of cancers such as solid tumors is concerned, no substantial progress has been made.

CAR-T therapy in blood cancer is effective because they are malignant tumors of B cells that can be completely eliminated, but solid tumors do not have B cell equivalents.
It is difficult for CAR-T cells to enter solid tumors when injected intravenously.
More complicated is that each different type of organ has a different immune microenvironment, which makes it a challenge to test CAR-T in different types of cancer patients.

Nevertheless, including research institutions and biotechnology companies, CAR-T treatment of solid tumors is conducting various studies.

CAR-T cell therapy may change the treatment of cancer, and its limited use in the treatment of blood cancer is successful, but its cost may limit the popularity of this treatment.

For pharmaceutical companies, the market promotion of products after the launch also faces challenges.
For example, three years after the approval of two products in the field in 2017, the sales in 2020 will be: Yescarta of Gilead received US$563 million in global sales.
Revenue, while Novartis’ Kymriah received $474 million in revenue.
Compared with other therapies in the oncology field (such as small molecules and monoclonal antibodies, etc.
), these sales figures may be considered mediocre.