On March 23, 2022 CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on innovative CAR T cell therapies for the treatment of hematologic malignancies and solid tumors, reported its 2021 Annual Results (Press release, Carsgen Therapeutics, MAR 23, 2022, View Source;products-and-technologies-301508801.html [SID1234610770]).
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Business Highlights
CARsgen pipeline
CT053: completed subject enrollment for pivotal Phase II trial in China, NDA submission expected in H1, 2022
CT053: initiated pivotal Phase 2 clinical trial in North America
CT041: initiated confirmatory Phase II clinical trial in China
CT041: was granted PRIME by the EMA, and granted RMAT by the FDA
New product candidates (e.g. CT0590, CT0180 and CT0181) advanced to clinical stage
Development of innovative technologies (e.g. LADAR)
RTP Manufacturing Facility, a cGMP manufacturing facility in the U.S., began operations
Dr. Zonghai Li, Founder, Chairman of the Board, Chief Executive Officer, and Chief Scientific Officer of CARsgen Therapeutics Holdings Limited, commented that, "This is the first Annual Results following CARsgen’s listing on the Hong Kong Stock Exchange on June 18, 2021. In the past year, CARsgen has made important progress, especially in pipeline development, technology innovation, CMC capacity expansion, business development, and strengthening our leadership team. Driven by the vision of Making Cancer Curable, we will continue to advance our product pipeline, develop innovative technologies, and consolidate our global strategy. We believe that we can bring innovative and differentiated cell therapy to cancer patients around the world as soon as possible, creating value for investors and the public."
1. Rapid progress of pipeline products
CT053
CT053 is an autologous CAR T-cell product candidate against BCMA being developed for the treatment of relapsed/refractory multiple myeloma (R/R MM). It incorporates a CAR construct engineered by CARsgen that features a fully human BCMA-specific single-chain variable fragment with lower immunogenicity and increased stability, which reduces the self-activation of CAR T-cells in the absence of tumor associated targets.
CARsgen has completed subject enrollment in the pivotal Phase II trial in China (LUMMICAR STUDY 1). In addition, CARsgen has started the pivotal Phase 2 clinical trial in North America (LUMMICAR STUDY 2) and treated the first subject in the pivotal Phase 2 trial in August 2021. As communicated with the U.S. FDA, the company is adding outpatient administration of CT053 into its U.S. clinical investigations.
CARsgen plans to make regulatory submissions for marketing approval to the NMPA in the first half of 2022 and plans to submit the BLA to the U.S. FDA in 2023. The company also plans to conduct additional clinical trials to develop CT053 as an earlier line of treatment for multiple myeloma.
Additional data update from the Phase I/II study in China (LUMMICAR STUDY 1) and an integrated analysis in participants with R/R MM by high-risk factors have been available as posters at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") Annual Meeting in December 2021.
CT041
CT041 is an autologous CAR T-cell product candidate against the protein Claudin18.2 (CLDN18.2) and has the potential to be first-in-class globally. CT041 targets the treatment of CLDN18.2 positive solid tumors with a primary focus on gastric/gastroesophageal junction cancer (GC/GEJ) and pancreatic cancer (PC). In addition to the investigator-initiated trials, CARsgen has initiated a Phase Ib clinical trial for advanced GC/GEJ and PC and a confirmatory Phase II clinical trial for advanced GC/GEJ in China, and initiated a Phase 1b clinical trial for advanced gastric or pancreatic adenocarcinoma in North America.
In North America, CARsgen has initiated the Phase 1b trial of CT041-ST-02 and has treated the first subject in July 2021.
In 2020 and 2021, CT041 received Orphan Drug designation from the U.S. FDA for the treatment of GC/GEJ and Orphan Medicinal Product designation from the EMA for the treatment of advanced gastric cancer. In November 2021, CT041 was granted PRIME eligibility by the EMA for the treatment of advanced gastric cancer. In January 2022, CT041 was granted Regenerative Medicine Advanced Therapy (RMAT) Designation for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma with CLDN18.2 positive tumors.
CARsgen plans to submit an NDA to the NMPA in China in the first half of 2024 and also plans to initiate a Phase 2 clinical trial in the second half of 2022 in North America and to submit the BLA to the U.S. FDA in 2024.
CT041 has demonstrated promising therapeutic efficacy and safety in the ongoing investigator-initiated trial. The updates on the investigator-initiated trial of CT041 have been presented at the European Society for Medical Oncology Congress 2021 ("ESMO Congress 2021").
CT011
CT011 is an autologous CAR T-cell product candidate with proof-of-concept clinical data for the treatment of hepatocellular carcinoma (HCC) and has the potential to be the first-in class globally. The company has completed enrollment of a Phase I trial in China.
CT032
CT032 is an autologous CAR T-cell product candidate against CD19 being developed for the treatment of B cell Non-Hodgkin’s lymphoma (NHL). The company is conducting a Phase I/II clinical trial in China.
AB011
AB011 is a humanized monoclonal antibody product candidate against CLDN18.2 being developed for the treatment of CLDN18.2 positive solid tumors. During the second quarter 2021, CARsgen received supplemental application approval by CDE regarding the addition of a chemotherapy combination cohort with AB011 in Phase Ib, and the company has subsequently initiated the combination cohort of AB011 with chemotherapy. The company completed Phase I monotherapy cohort enrollment and initiated combination with chemotherapy.
The company plans to consult with the NMPA in the second half of 2022 and to initiate the subsequent Phase II clinical trial.
CT0180
CT0180 is an autologous T cell product engineered to express a fusion protein of GPC3-targeted antibody fused T cell receptor (aTCR). Preclinical studies have shown that CT0180 could effectively recognize and kill GPC3-positive hepatocellular carcinoma cells and significantly inhibit HCC tumor growth in mouse xenograft models with reduced cytokine release compared to GPC3-CAR T-cells in vitro and in vivo, which improve the safety and applicability of adoptive cell therapies.
CT0181
CT0181 is an autologous T cell product engineered with GPC3-targeted antibody fused T cell receptor co-expressing IL-7 cytokine. Preclinical studies have shown that CT0181 displays superior antitumor efficacy, T cell persistence, and immunological memory in solid tumors xenografts with low cytokine release compared to GPC3-CAR T-cells.
KJ-C2111 (CT0590)
CT0590 is an allogeneic CAR T-cell product candidate deploying THANK-uCAR technology that targets BCMA. CARsgen is developing CT0590 for the treatment of relapsed/refractory multiple myeloma (R/R MM). The company has initiated IIT trial to evaluate the efficacy and safety of CT0590 for the treatment of R/R MM.
In addition, there are other IND-enabling or pre-clinical stage product candidates: KJ-C1807 (CT048), KJ-C2112, KJ-C2113 and KJ-C2114.
2. Continuous Discovery and Technology Development
Despite the approved CAR T-cell products for the treatment of terminal line hematologic malignancies, there are still significant challenges. CARsgen strives to explore and develop innovative technology platforms to address these challenges to generate better cell therapy products to global cancer patients. The main focus includes:
Increasing efficacy against solid tumors: developing innovative technologies, such as CycloCAR technology, to enhance efficacies of CAR T-cell against solid tumors. CycloCAR is a next generation CAR T technology, which co-expresses cytokine IL-7 and chemokine CCL21 and potentially has greater clinical efficacy and reduced requirement for lymphodepletion conditioning.
Enhancing safety profile: developing innovative technologies to minimize safety concerns including CRS/neurotoxicity/on-target off-tumor toxicities.
Expanding patient accessibility: advancing differentiated allogeneic THANK-uCAR technology to reduce costs and increase affordability. THANK-uCAR technology has the potential to overcome inefficient expansion and persistence associated with existing universal CAR T-cells.
Improving target availability: exploring innovative technologies that can potentially enhance drug target availability and specificity of CAR T-cell therapy. CARsgen has developed Local Action Driven by Artificial Receptor (LADAR) technology, in which the intracellular transcription of the gene of interest is controlled by a chimeric regulatory antigen receptor. Through the LADAR artificial receptor, the intracellular activity is only triggered when the extracellular domain is activated upon binding to specific antigen, making it possible to precisely control when and where immune cells act against cancer cells.
These technologies are currently being developed in-house with global rights and can be used alone or combined to upgrade CARsgen’s existing product candidates as well as to generate future innovative pipeline product candidates.
As of December 31, 2021, CARsgen had more than 300 patents of which more than 60 patents had been issued globally including China, the United States, Europe, and Japan.
3. Manufacturing Capacity Expansion
CARsgen has established in-house end-to-end clinical and commercial manufacturing capabilities for all three stages of CAR T manufacturing, including production of plasmids, lentiviral vectors, and CAR T-cells. With the clinical manufacturing facility in Xuhui, Shanghai and commercial GMP manufacturing facility in Jinshan, Shanghai, CARsgen has been manufacturing CAR T-cells in house to support clinical trials in China and manufacturing the lentiviral vectors in house to support clinical trials globally.
The company has been expanding manufacturing capacity in China and the U.S. to support both the clinical trials and the subsequent commercialization of pipeline products. The company has opened its CGMP manufacturing facility located at the Research Triangle Park (RTP) in Durham, North Carolina ("The RTP Manufacturing Facility"). The RTP Manufacturing Facility, with a total gross floor area of approximately 3,300 sq.m, will provide additional manufacturing capacity of autologous CAR T-cell products for 700 patients annually, and it will support the company’s ongoing clinical studies and early commercial launch in North America and Europe.
4. External License Agreement
CAFA Therapeutics, a subsidiary of CARsgen Therapeutics, has entered into a licensing agreement with HK inno.N Corporation (KOSDAQ: 195940) to develop and commercialize CT032 and CT053, for the potential treatment of various cancers in the Republic of Korea, with an upfront and additional milestone payments totaling up to USD50 million plus up to double-digit percentage royalties on net sales. The collaboration with HK inno.N showcases CARsgen’s commitment to establishing more external partnerships with leading pharmaceutical companies to maximize the application of its technology platform and the value of its product pipeline to benefit more cancer patients globally.