Legend Biotech's BCMA CAR-T Therapy Carvykti Receives FDA Approval with $465,000 Price Tag

On February 28 Eastern Time, the U.S. FDA officially approved Legend Biotech's BCMA-targeted chimeric antigen receptor T-cell (CAR-T) product Ciltacabtagene autoleucel (cilta-cel, trade name Carvykti). As the second BCMA CAR-T, Carvykti is priced at $465,000.

Cilta-cel is a CAR-T therapy developed by Legend Biotech that targets BCMA for the treatment of adult relapsed and/or refractory multiple myeloma (R/RMM). It includes a 4-1BB co-stimulatory domain and two BCMA-targeting single-domain antibodies.

This time, Legend Biotech's cilta-cel has been officially approved for marketing in the U.S., becoming the first successful example of a CAR-T product independently developed in China to achieve an overseas breakthrough.

Cilta-cel: The "Front-runner" of Legend Biotech's CAR-T Therapy

Cilta-cel is the product that made Legend Biotech famous, and it has also been quite "charming" in terms of regulatory developments:

In 2018, the therapy received the first CAR-T clinical trial application (IND) approval from the China National Medical Products Administration and IND approval from the U.S. FDA;

In 2019, cilta-cel received the European Medicines Agency's Priority Medicines (PRIME) designation and was granted Breakthrough Therapy Designation by the U.S. FDA.

In December 2020, a Biologics License Application (BLA) for cilta-cel was submitted to the U.S. FDA;

In May 2021, the marketing application for cilta-cel was accepted for priority review, with a Prescription Drug User Fee Act (PDUFA) date of November 29, 2021.

In November 2021, Legend Biotech announced that the FDA had extended the PDUFA goal date for cilta-cel by three months to February 28, 2022. (The FDA extended the review period this time but did not request the company to submit new clinical data, indicating that the delay in approval is unrelated to the cilta-cel trial data.)

It is reported that the submission of the Biologics License Application (BLA) for cilta-cel was primarily based on the results of the pivotal Phase Ib/II CARTITUDE-1 study, which evaluated the efficacy and safety of ciltacel in patients with relapsed and/or refractory multiple myeloma. Among the 97 subjects enrolled, 99% had progressed on their last line of therapy, and 88% had previously received at least three prior lines of therapy.

The results showed that, at a median follow-up of 12.4 months, the ORR reviewed by an independent committee was 97%, including 67% sCR (stringent complete response), 26% VGPR (very good partial response), and 4% PR. The incidence rate of ≥Grade 3 cytokine release syndrome (CRS) was 5%, and the incidence rate of ≥Grade 3 neurotoxicity was 10%.

In addition to the previously prominent clinical data, at the 40th Annual J.P. Morgan Healthcare Conference not long ago, Dr. Ying Huang, CEO and CFO of Legend Biotech, announced the latest data from the cilta-cel clinical trial: After a median 24-month long-term follow-up, the primary endpoint overall response rate (ORR) reached 97.9%, VGPR was 94.9%, with 82.5% of patients achieving sCR. At 2 years, 60.5% of patients were alive and progression-free. Among 61 evaluable patients for MRD, 92% achieved 10-5 MRD negativity.

Besides the cilta-cel that has reached the finish line of regulatory success, Legend Biotech is developing single-target, dual-target, and triple-target CAR-T products targeting multiple promising antigens in the hematological malignancies field, including BCMA, CD4, CD20, CD33/CLL-1, CD19/CD20/CD22, etc. Among them, the autologous CD4-targeted CAR-T therapy LB1901 has passed the FDA’s IND application and has initiated Phase I clinical trials in the United States for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). This makes it one of the fastest progressing products in Legend Biotech's pipeline.

Notably, earlier this month, Legend Biotech received an email from the FDA stating that the Phase I clinical trial of its LB1901 had been suspended. The reason for the suspension was not mentioned by either the FDA or Legend Biotech. However, it is understood that the clinical trial was not halted by the FDA but rather due to issues experienced by the patient involved.

In the field of solid tumors, Legend Biotech has developed multiple products to address gastric cancer, liver cancer, small cell lung cancer, non-small cell lung cancer, and ovarian cancer. Among them, LB1908 targeting Claudin18.2 and LB1902 targeting MSLN have both entered Phase I clinical trials.

In addition, Legend Biotech also owns a Chimeric Antigen Receptor Natural Killer Cell (CAR-NK) platform.

CAR-T Market Has Broad Prospects, First BCMA-Targeted Product Faces Competition

CAR-T (Chimeric Antigen Receptor T-Cell Immunotherapy) cell therapy has been proven to be a powerful weapon against blood cancers. This therapy is a novel precision targeted treatment for tumors, which works by genetically reprogramming the patient’s natural infection-fighting and cancer-killing immune T cells in vitro. These reprogrammed T cells, after being cultured and modified outside the body, are reinfused into the patient's body where they can recognize antigen markers on cancer cells. Subsequently, these CAR-T cells are expanded using cell culture techniques and then reinfused into the patient's body to attack the cancer.

As of now, the U.S. FDA has approved six CAR-T cell therapies for marketing, four of which target CD19 and two target BCMA.

In terms of the market, according to Frost & Sullivan data, the global CAR-T cell therapy market grew from US$10 million in 2017 to US$700 million in 2019 and US$1.1 billion in 2020. It is expected to accelerate growth in the coming years, reaching US$6.6 billion by 2024, and further expanding to US$21.8 billion by 2030.

According to the 2021 performance announcements recently released by major pharmaceutical companies:

The earliest marketed Kymriah from Novartis achieved sales of $587 million in 2021, representing a year-over-year increase of 24%.

Gilead's two products followed: Yescarta achieved sales of $690 million in 2021, increasing by 23% from last year; Tecartus also realized revenue of $170 million in its first full fiscal year.

Breyanzi, launched by Bristol-Myers Squibb last year, had a disappointing first-year performance with only $87 million in sales. In contrast, Abecma, which was approved a month later and was the world's only BCMA-targeted CAR-T therapy at the time, achieved first-year sales of $164 million, nearly double Breyanzi’s total annual sales.

As the second CAR-T therapy targeting BCMA to be approved globally, cilta-cel's most direct competitor comes from the same track — Abecma by Bristol-Myers Squibb. The sales of this product serve as a certain reference value for cilta-cel, although its first-year sales may not be as satisfactory compared to earlier CAR-T products.

However, according to previous clinical data, the median OS of patients previously treated with three classes of therapies and then treated with Abecma was 24.8 months, with an ORR of 73% and 33% of patients achieving CR. As mentioned above, the clinical data of Legend Biotech's cilta-cel showed an ORR of 98%, with 80% of patients achieving sCR, while also demonstrating a certain differentiated safety advantage.

This suggests that cilta-cel might have a slight edge in future sales.

It is reported that even before cilta-cel took shape, Legend Biotech had already gained the favor of major multinational corporations (MNCs). In December 2017, Legend Biotech entered into a global collaboration and license agreement with Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. According to the cooperation agreement, within Greater China, Legend Biotech and Janssen share costs and profits in a 7:3 ratio; in other regions globally, the two companies split costs and profits equally.

Currently, Legend Biotech has received a prepayment of $350 million and milestone payments of $250 million.

Chinese Companies Are Not Willing to Fall Behind, Competition for CAR-T Targets Is About to Unfold

In China, the National Medical Products Administration (NMPA) has currently approved two CAR-T products for marketing, both targeting CD19. These two products are Fosun Kite's Axicabtagene Ciloleucel Injection and Wuxi Juno's Relmacabtagene Autoleucel Injection. It is reported that both products were introduced through collaborations; Axicabtagene Ciloleucel Injection was introduced by Fosun Kite from Kite Pharma, and Relmacabtagene Autoleucel Injection was introduced by Wuxi Juno from Juno Therapeutics.

Notably, on February 27, WuXi AppTec announced that the second indication for its CAR-T product, Relmacabtagene Autoleucel Injection, has been accepted by the National Medical Products Administration (NMPA) for the treatment of patients with relapsed or refractory (r/r) follicular lymphoma (FL).

In addition, other companies in China, such as Hoyo Biotech, CARsgen Therapeutics, and Yimiao Zhongshen, are also actively participating, with products that have entered the clinical stage. Their research and development targets mainly focus on CD19, followed by BCMA, and there are also dual-target products.

Editor: Liuli

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