On July 30, the listing application for the CAR-T product, relma-cel, of WuXi Giant Nuo targeting CD19, has been completed on-site inspection and is waiting for approval. Following the launch of Fosun Kate's Yiji Lilunsai injection (CD19CAR-T) at the end of June, Ruiji Ruiji Orensai injection is expected to become the second CAR-T product approved for marketing in China.
CAR-T cell therapy, as a brand-new cancer treatment method, has attracted much attention from the market. Since 2017, five CAR-T cell therapies have been approved for the market worldwide, including four CAR-T cell therapies targeting CD19 and one cell therapy targeting BCMA. my country also ushered in its first at the end of June. A CAR-T cell therapy targeting CD19. From a target point of view, CAR-T therapies targeting CD19 are getting together. Whether CD19CAR-T is an excellent investment track is worth pondering.
(1) IPO sprint
Ruiji Orenza injection (JWCAR029, Relma-Cel) is an autologous CAR-T therapy with CD19 antigen as the target developed by WuXi Macronuo. WuXi Juno was jointly established by WuXi AppTec and Juno, aiming to become an integrated platform focusing on the development, manufacturing and commercialization of blood and solid tumors. In terms of structural design, Relma-Cel uses mouse-derived scFv. scFv is a smaller form of recombinant antibody, which not only retains the specificity of the original immunoglobulin to antigen, but also enhances tumor penetration, but mouse-derived scFv may There is a certain degree of immunogenicity. The costimulatory domain uses 4-1BB, which can promote mitochondrial production, enhance T cell respiration and fatty acid oxidation. In addition, compared with the CD28 costimulatory domain, CAR-T cell expansion using the 4-1BB costimulatory domain is milder , Security is expected to improve. In June 2020, WuXi Giant Nuo submitted to NMPA a marketing application for the indications for the treatment of diffuse large B-cell lymphoma (DLBCL) with Ruiji Orenxil injection. At the 2020 ASH Annual Meeting, WuXi Juno announced the key clinical research data of Ruiji Orenza injection in the treatment of DLBCL. Among the 58 evaluable patients, the objective response rate was 75.9%, the complete response rate was 51.7%, and the 6-month DoR, PFS, and OS were 60%, 54.2%, and 90.8%, respectively. In terms of adverse events, the CRS rate of grade 3 and above was 5.1%, and the NT toxicity was 5.1%. In general, whether from the perspective of clinical efficacy or safety, the performance of Ruijio Lun Sai injection is very excellent.
(2) The melee is imminent
Although it has been less than two months since the first CAR-T cell therapy in China was launched, CAR-T research and development is facing problems such as high homogeneity and clustering of targets. According to KPMG statistics, in 2020, the number of domestic CAR-T cell therapy clinical trials has reached 335, which has increased tenfold in five years. CAR-T cell therapy targeting CD19 is even more clustered, accounting for 40% of CAR-T cell therapy. From the perspective of research and development, although the clinical risk of CAR-T therapy targeting CD19 is relatively low, after all, several products have been successfully marketed for demonstration, but these products may face extremely fierce competition in the future commercialization stage. The first 3-5 products on the market took advantage of the first-mover advantage and quickly occupied the market. If the latecomers lacked the unique advantages of the product, they would often have to survive in the cracks, or split up part of the market share through fierce price wars. In other words, latecomers usually find it difficult to enjoy incremental dividends, and it is more a game of stock. In addition, the road to commercialization of CAR-T products is relatively slow, and the short-term contribution to the company's performance is very limited. As a leader in CAR-T products, Yescarta has only brought about 1.283 billion U.S. dollars in performance after three years of listing. The high price is only one of the reasons, and the bottleneck of production capacity is another important factor restricting the development of CAR-T, just like BMS The Chief Commercial Officer stated at the 2021 mid-term earnings call that the shortage of viral vectors for cell therapy has led to a supply gap in the company's CAR-T products. This problem has always plagued the global CAR-T cell therapy manufacturing industry. In addition to the competition between CAR-T products, CD3×CD19 double antibodies represented by Blincyto and CD19ADC represented by Zynlonta are potential competitors for CD19CAR-T therapy. Reindeer Medical, Legendary Biology, etc. have even deployed CD19×CD22 dual-target CAR-T therapy, which may have a huge impact on CD19CAR-T products in the future. After all, dual targets are more specific than single targets and are expected Significantly reduce disease progression and recurrence caused by single-target therapy.
(3) Prospects
In addition to the fierce competition that may be faced in the future, autologous CAR-T cell products have also exposed problems such as excessive preparation time and unsuitability for patients. From the perspective of the future development of the industry, allogeneic CAR-T cell products and dual-target CAR-T cell products are expected to alleviate these problems. Preparation time is too long: At present, the preparation of autologous CAR-T cells usually takes 2-4 weeks under a good GMP environment. In the past few years, Novartis’s Kymriah has never been sold as well as Gilead’s Yescarta. The core factor lies in the long production cycle and low production efficiency. In 2018, when Gilead controlled the preparation cycle of Yescarta within 2 weeks, Kymriah still needed 3-4 weeks of preparation time. Inapplicable to patients: Clinical studies have found that the failure rate of autologous CAR-T therapy is 5%-14%. The reasons for failure include viral infection, poor quality of autologous T cells, and failure of frontline autologous CAR-T therapy, such as Some cancer patients have a low lymphocyte base, and it is difficult to expand and produce self-modified T cells. In response to these urgent problems, allogeneic CAR-T cell therapy and dual-target CAR-T cell therapy are expected to break. Allogeneic CAR-T cells are off-the-shelf cell therapy, which is expected to greatly shorten the preparation cycle and is an important development direction for CAR-T therapy in the future. Genxi Biologics GC007g is an allogeneic CD19CAR-T product, and its indication is acute lymphocytic leukemia (ALL). The results of the phase I clinical trial showed that the ORR of GC007g in the treatment of ALL was 84.6% (13/14), and the MRD-CR was 76.9%. From the perspective of efficacy, GC007g also has potential advantages over autologous CAR-T therapy. However, allogeneic CAR-T therapy has a GvHD risk. For example, the GvHD risk of GC007g is 14.3%. In this regard, the TruUCAR platform of Genxi Biosciences reduces the risk of GvHD by knocking out TCR, and the THANK-uCAR platform of Keji Pharmaceuticals destroys the genomic sites of TCR and β2 microglobulin (B2M) to eliminate the expression of TCR or B2M. Dual-target CAR-T therapy is expected to reduce disease progression and recurrence caused by single-target therapy. It is clinically found that some patients develop disease progression or recurrence after receiving CD19CAR-T treatment, which may be due to the loss or decreased expression of CD19 target on the surface of tumor cells. Similar to CD19, CD22 is also specifically expressed on the surface of a variety of B cells. By using CD19 and CD22 to target CAR-T therapy, it can theoretically reduce the risk of tumor escape caused by the loss of a single target after treatment, and further reduce disease recurrence. Reindeer Medical’s CT120 is a fully human CAR-T therapy targeting both CD19 and CD22 targets. After CT120 binds to the CD19 and CD22 antigens on the target cell membrane, it releases granzyme/perforin to directly kill the target cells and release at the same time Cytokines stimulate the expansion of CAR-T cells to continue their anti-tumor effects. On July 29, 2021, CT120 received an implied license from a clinical trial to develop two indications including B-cell lymphocytic leukemia (B-ALL) and B-cell non-Hodgkin’s lymphoma (B-NHL).
(4) Summary
With WuXi Biotech's CAR-T product targeting CD19, relma-cel, has completed the on-site inspection of its production, the launch is just around the corner. However, the development of CD19CAR-T cell therapy currently has risks such as target clustering and serious homogeneity. In addition, the long preparation cycle of autologous CAR-T therapy and the unavailability of patients also hinder the rapid development of the industry. In the future, allogeneic CAR-T cell therapy and dual-target CAR-T therapy are expected to break the ground and provide better treatment options for patients with advanced tumors.
August 04, 2021
