Zhishan Weixin's Novel Target Gene Therapy for Hemophilia B Receives CDE's Implicit Approval for Clinical Trials

On August 30, 2022, the official website of the Center for Drug Evaluation (CDE) under China’s National Medical Products Administration (NMPA) announced that the Investigational New Drug (IND) application for ZS801 Injection, a gene therapy product independently developed by Sichuan Real&Best Biotech Co., Ltd. (R&B Bio), had received implicit approval from the CDE. As the first domestic gene therapy targeting an original indication for Hemophilia B, ZS801 Injection is poised to commence related clinical trials, marking a new breakthrough in China’s field of recombinant adeno-associated virus (rAAV) vector-based gene therapies. Meanwhile, Sichuan Province’s biopharmaceutical industry has secured the first rAAV gene therapy clinical trial approval in Western China, successfully advancing into the first tier of China’s gene therapy industry.

Sichuan Real&Best Biotech Co., Ltd. (R&B Bio), established in June 2018 and located in the Chengdu Tianfu International Bio-Town, is a leading Chinese gene therapy company dedicated to the research and development and disruptive manufacturing of rAAV-based gene medicines. The company boasts a professional team composed of distinguished scientists and entrepreneurs with extensive experience in gene therapy drug design, preclinical research, CMC development, GMP manufacturing, clinical trials, and operational management. Dr. Dong Biao, the founder, has been engaged in rAAV research for over a decade and has achieved breakthroughs in both gene therapy drug design and large-scale production.

The company holds multiple globally leading patents and technologies in the design of efficient gene expression cassettes and vector optimization. Its gene therapy portfolio covers a range of clinical indications, including hematologic disorders, central nervous system diseases, and metabolic disorders, with several pipeline candidates poised to become best-in-class gene therapies. Among these, the development program for hemophilia A is progressing smoothly, following closely behind its hemophilia B counterpart. The company has completed three batches of clinical-grade material production and is currently conducting toxicology and safety assessments, with a Pre-IND application expected to be submitted this October.

The company also possesses a globally leading novel poxvirus-adenovirus rAAV production system. This system overcomes the bottlenecks associated with large-scale rAAV manufacturing, significantly reducing production costs. This revolutionary new production platform is poised to substantially lower the cost of gene therapies, thereby further enhancing their accessibility.

ZS801 is a recombinant adeno-associated virus (rAAV) gene therapy indicated for the treatment of hemophilia B. In accordance with the Provisions for Drug Registration, this product is classified as a Class 1 therapeutic biological product. Compared with traditional enzyme replacement therapy, it holds the promise of achieving a “one-shot cure.”

ZS801 Injection is an rAAV gene therapy drug with independent intellectual property rights owned by R&B Bio. The drug design of ZS801 adopts core sequences and high-efficiency gene expression cassettes with fully independent intellectual property rights owned by R&B Bio, wherein the core sequence is an original drug target independently developed by R&B Bio in collaboration with renowned domestic medical institutions, demonstrating efficacy comparable to foreign counterparts. Meanwhile, R&B Bio employs its self-developed serum-free suspension culture and chromatography processes for GMP-compliant drug production, with both manufacturing processes and product quality standards reaching industry-leading levels. Furthermore, the AAV vector serotype selected by R&B Bio exhibits very low pre-existing neutralizing antibodies in patients, enabling coverage of a broader population of Chinese patients compared to similar products.

Currently, the ZS801 project is conducting clinical trials at the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences. Early analysis results indicate that the first enrolled subject with hemophilia B, who was initially ineligible for gene therapy due to the presence of neutralizing antibodies against other rAAV serotypes, has benefited from R&B Bio’s vector serotype development strategy. Seven weeks after receiving a low dose of ZS801, the patient’s disease severity decreased from severe (<1% clotting activity) to mild (5–40% clotting activity), preliminarily demonstrating the drug’s safety and efficacy.

Hemophilia B is a bleeding disorder caused by a deficiency of coagulation factor IX due to gene mutations. It is X-linked and predominantly affects males. Without treatment, patients may experience progressive joint deformity, loss of labor and daily living capabilities, and even life-threatening uncontrolled bleeding. In developed countries in Europe and America, the traditional approach to treating hemophilia is prophylactic therapy, which requires intravenous infusion of clotting factors 2–3 times per week. This regimen is burdensome for patients and extremely costly, with annual expenses ranging from $200,000 to $300,000. Furthermore, frequent infusions of clotting factors can lead to venous sclerosis, compromising future treatment options.