China’s innovative drugs have made another success in “going global”. On November 13, local time in the United States, Legend Biotech (LEGN.US) announced that its wholly-owned subsidiary Legend Biotech Ireland Ltd. and Swiss pharmaceutical giant Novartis (NVS.US) have entered into an agreement on chimeric antigen receptor T cell (CAR-T) therapy that specifically targets DLL3. France has signed an exclusive global license agreement granting Novartis the global exclusive rights to develop, manufacture and commercialize cell therapies including autologous CAR-T therapy LB2102 (NCT05680922), and Novartis Antigens will use its T-Charge platform for its production.
Under the agreement, Legend will receive an upfront payment of US$100 million and is eligible to receive up to US$1.01 billion in clinical, regulatory and commercial milestone payments and tiered royalties, bringing the total transaction value to US$1.11 billion.
Under the license agreement, Legend will conduct Phase I clinical trials of LB2102 in the United States, and Novartis will conduct all other development of the licensed products.
The investigational new drug (IND) application for LB2102 has been approved by the U.S. Food and Drug Administration (FDA) in 2022 for the treatment of extensive-stage small cell lung cancer and large cell neuroendocrine cancer. In 2023, the US FDA granted this product "Orphan Drug" designation.
CAR-T is a new type of precision targeted therapy. It means that after T cells are extracted from the patient, genetic engineering technology is used in vitro to transfer a virus containing a chimeric antigen receptor that recognizes tumors and activates T cells into the T cells through a vector, transforming them into CAR-T cells. After amplification, they are reintroduced into the patient's body to efficiently and quickly identify and accurately kill diseased cells, thereby achieving the purpose of treating the disease and restoring the patient to health.
In 2008, the Fred Hutchison Oncology Institute first used CAR-T cells to treat B-cell lymphoma, proving the safety of this method. In just over ten years, this highly personalized and precise therapy has quickly become a star therapy in the world of cancer treatment.
In 2017, Novartis’ Kymriah became the first CAR-T cell therapy approved for marketing. Since then, the commercialization of CAR-T cell therapy has accelerated. As of now, there are as many as 10 CAR-T cell therapies approved worldwide. At the end of February 2022, Carvykti (cilta-cel), the first product of Legend Biotech and Johnson & Johnson (JNJ.US), was approved for marketing by the US FDA, becoming a milestone event for China's innovative drugs to "go overseas".
Frost & Sullivan predicts that in terms of sales value, the global CAR-T market has grown rapidly from US$10 million in 2017 to US$1.1 billion in 2020, and the global CAR-T cell therapy market sales value is expected to reach US$21.8 billion in 2030.
However, as competition intensifies, the CAR-T industry landscape is also quietly changing.
The sales trend of the earliest Kymriah on the market has declined. Financial report data shows that in 2022, Kymriah achieved revenue of US$536 million, a year-on-year decrease of 9%; in the first three quarters of 2023, Kymriah's sales revenue reached US$388 million, which was also a slight decline compared with US$397 million in the same period of 2022.
Currently, the CAR-T cell therapy with the highest sales in the world is Yescarta from Gilead (GILD.US), with sales in the first three quarters of this year reaching US$1.13 billion.
As a rising star on the CAR-T track, Carvykti's sales are also rapidly increasing. According to data disclosed by partner Johnson & Johnson, Carvykti’s cumulative sales in the first three quarters of this year reached US$341 million.
In order to gain the upper hand again in the next stage of industry rankings, Novartis is stepping up its efforts to deepen the research and development layout of CAR-T. The introduction of CAR-T cell therapy targeting DLL3 is not the first time Legend Biotech has cooperated with Novartis.
In April 2023, Legend Biotech announced that it had signed agreements with Johnson & Johnson and Novartis on CAR-T product technology transfer, production and clinical supply services, and will continue to increase CAR-T production. According to the agreement, Legend Biotech and Johnson & Johnson will initiate necessary technology transfer activities with Novartis to enable Novartis to implement Carvykti's production process.
The above-mentioned T-charge platform is the cornerstone of Novartis’ next phase of layout in the CAR-T field.
At the 63rd American Society of Hematology (ASH) in 2021, the T-charge platform made its debut. Novartis also announced the early results of the Phase 1 clinical trials of two CAR-T cell therapies developed based on this platform, namely YTB323 (anti-CD19) and PHE885 (anti-BCMA).
Legend Biotech told Times Finance that the Novartis T-Charge platform is a next-generation CAR-T cell therapy production platform designed to maintain the stemness of T cells and promote the expansion of CAR-T cells in the body. The T-Charge platform is designed to reduce the need for prolonged culture in vitro, allowing T cells to have greater proliferative potential and reduce exhausted T cells.
The traditional CAR-T cell preparation cycle takes 2-4 weeks, but the T-Charge platform can complete the production of CAR-T cells in less than 2 days, which can undergo substantial proliferation after infusion into the patient. In addition, the infusion dose required for CAR-T cell products developed through the T-Charge platform is only 1/10~1/50 of existing CAR-T cell products.
After the cooperation with Novartis is reached, LB2102 will be the first time Novartis applies the T-Charge platform to a cell therapy candidate targeting solid tumors.
Currently, the approved indications for CAR-T cell therapy are mainly hematological tumors. A person engaged in the research and development of immune cell therapy once pointed out to Times Finance that solid tumors are highly dense, have complex microenvironments, and there are many types of solid tumors and high heterogeneity of target expression, which have brought challenges to the application of CAR-T in solid tumors.
DLL3 is a member of the Notch pathway ligand family, plays a key role in Notch signaling, and is highly expressed in small cell lung cancer. Yaorongyun data shows that there are currently 17 drugs under development targeting DLL3 globally, including mono/double antibodies, ADCs and CAR-T.
Small cell lung cancer accounts for about 15%-20% of lung cancers. It is characterized by rapid tumor growth, and only about 1/3 of patients are in the localized stage when diagnosed, and 2/3 of patients are in the extensive stage. The median survival time of patients with limited-stage small cell lung cancer is approximately 16 to 22 months, while that of patients with extensive-stage small cell lung cancer is only 10 months after treatment.
Dr. Guowei Fang, chief scientific officer and head of business development at Legend Biotech, said: "We believe that LB2102 has an innovative CAR design and armor mechanism that can increase its anti-tumor activity. Preclinical evidence suggests that autologous CAR-T may be a differentiated treatment option for patients with small cell lung cancer. The unique candidate design in LB2102, combined with the T-Charge platform, has the potential to bring transformative benefits to patients with small cell lung cancer."