On February 4, the breakthrough therapy application disclosure information from the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) showed that Johnson & Johnson's AAV5-hRKp.RPGR intravitreal injection solution is proposed to be included in the breakthrough therapy designation. This drug is an adeno-associated virus (AAV) vector-based gene therapy for treating patients diagnosed with X-linked retinitis pigmentosa associated with pathogenic RPGR variants.
On the golden track of ophthalmic AVV gene therapy, more than 20 companies in China are already making strategic plans. Among them, several investigational new drugs have entered the clinical trial stage, bringing new hope for the treatment of hereditary eye diseases.
High Clinical Demand for Ophthalmic Gene Therapy
AAV5-hRKp.RPGR Intravitreal Injection Solution aims to deliver functional copies of the RPGR gene to the subretinal space to improve and maintain visual function. In 2020, the 6-month data from the Phase I/II trial of AAV5-hRKp.RPGR Intravitreal Injection Solution was released: interim results showed that low and medium doses were well tolerated and indicated significant improvement in vision.
Data shows that in 2019, Johnson & Johnson signed a collaboration with MeiraGTx to develop gene therapies for inherited eye diseases, including the AAV5-hRKp.RPGR intravitreal injection solution and two other gene therapy drugs for achromatopsia. By the end of 2023, MeiraGTx announced that Johnson & Johnson acquired the development rights of the drug for up to $415 million. MeiraGTx will receive a $130 million upfront payment and near-term milestone payments, as well as up to $285 million in additional funds following the first commercial sales of the drug in the United States and the European Union, and the transfer of manufacturing technology.
In December 2017, Luxturna, the world's first ophthalmic gene therapy, was approved for marketing in the United States, sparking a wave of enthusiasm for ophthalmic gene therapies. Compared with other organs, the eye is relatively small in volume, requiring only a low dose of medication to achieve therapeutic effects. Additionally, it has advantages such as immune privilege and low systemic risk, making it a key area that pharmaceutical companies have prioritized. Currently, the indications for ophthalmic gene therapy mainly include hereditary retinal diseases associated with single-gene mutations, such as retinitis pigmentosa, choroideremia, Leber's hereditary optic neuropathy (LHON), Leber congenital amaurosis (LCA), Stargardt disease, achromatopsia (ACHM), X-linked retinoschisis (XLRS), and age-related macular degeneration (AMD). Due to the significant impact of these diseases on patients' ability to live independently and perform daily activities, there is a substantial clinical demand for treatment.
Many gene mutations responsible for hereditary eye diseases have been precisely identified, offering numerous target options for the development of gene therapies. Research on gene therapy for ocular conditions has consistently remained at the forefront. Ophthalmic AAV gene therapy is the golden track within AAV gene therapy, accounting for one-quarter of AAV gene therapy clinical trials. Due to its low immunogenicity and site-specific integration capability, the adeno-associated virus is considered to have good safety and is one of the most promising gene delivery systems, further strengthening the momentum of development in the AAV gene therapy field.
A Large Number of Innovative Pharmaceutical Companies in China Enter the Track
In the field of ophthalmic AVV gene therapy, numerous innovative pharmaceutical companies in China are actively making advances, including Neurophth, Innostellar Biotherapeutics, Shanghai Jiayin Biotechnology Ltd., Tianze Yuntai, Kanghong Pharmaceuticals, CHIGENOVO, Huada Gene, Anlong Biotechnology, Jinweike Biotechnology, Bendao Gene, Skyline THERAPEUTICS, Fangtuo Biotechnology, Dingxin Gene, Lingyi Biotechnology, Jimo Biotechnology, Xingmu Biotechnology, Mujing Biotechnology, Niulunjie Biotechnology, LeadNova Pharmaceuticals, Aoweiluxin, Nanjing Beisiao, Ruifeng Biotechnology, and InnovoGene. Many of their investigational drugs have already entered clinical trials.
Neurophth is China's first gene therapy company focused on ophthalmic diseases. In March 2021, NR082 (R&D code NFS-01), China’s first clinical-stage in vivo AAV gene therapy drug for ophthalmic diseases developed by Neurophth, was approved by the National Medical Products Administration to conduct drug registration clinical trials for Leber's Hereditary Optic Neuropathy caused by ND4 mitochondrial gene mutations.
NR082 is the first in vivo AAV gene therapy drug for ophthalmology to receive clinical trial approval in China. It obtained orphan drug designation from the U.S. FDA in September 2020 and was approved for clinical trials in the United States in 2022. In July 2022, the drug was included in the breakthrough therapy category by the National Medical Products Administration, putting it on the "fast track" for market entry. On February 22, 2023, Neurophth announced that NR082 had completed patient enrollment and dosing for a Phase III clinical trial in China, which is aimed at treating Leber's hereditary optic neuropathy caused by ND4 mutations. In addition to this drug, Neurophth has more than ten ongoing projects targeting various ophthalmic diseases such as optic nerve damage and vascular retinopathy.
In January 2022, LX101 Injection, submitted by Innostellar Biotherapeutics' subsidiary Innostellar Biotherapeutics Co., Ltd., was accepted by the National Medical Products Administration (NMPA) for clinical trial to treat Leber Congenital Amaurosis. This marks the first gene therapy in China to submit a clinical trial application for this indication, which was approved for clinical trial on April 19, 2022. LX101 is a gene therapy independently developed by Innostellar Biotherapeutics using rAAV as a vector. In previous investigator-initiated clinical studies, LX101 demonstrated good safety and has shown efficacy in improving vision in several patients. On April 19, 2022, Innostellar Biotherapeutics Co., Ltd. further announced that the clinical trial application for LX101 had been approved by the Center for Drug Evaluation (CDE) to treat patients with inherited retinal degeneration associated with biallelic RPE65 mutations.
On January 19, 2023, Jiayin Biotech announced that the U.S. Food and Drug Administration (FDA) had approved the Investigational New Drug (IND) application for its novel gene therapy EXG102-031 injection to treat wet age-related macular degeneration. In March of the same year, the clinical trial application for this indication was accepted by the National Medical Products Administration in China. EXG102-031 injection requires only a single administration to achieve long-term expression in the body and effectively treat abnormal blood vessel formation and leakage in the retina.
In January this year, Jinweike Biotechnology disclosed that its self-developed JWK006 injection for Stargardt disease type 1 (fundus flavimaculatus) completed the first dosing of a subject at the Ophthalmology Department of West China Hospital, Sichuan University. This also marks the world's first AAV gene therapy clinical trial for Stargardt disease type 1. The drug, co-developed by Jinweike Biotechnology and Professor Lu Fang's team from the Ophthalmology Department of West China Hospital, Sichuan University, is an AAV gene therapy product. Utilizing a self-developed dual AAV vector technology, it can efficiently restore the expression of full-length ABCA4 protein in retinal cells, thereby improving the structure and function of patients' retinas.
CHIGENOVO's ZVS101e Injection is a gene replacement therapy developed in collaboration with Peking University Third Hospital. It is also the first gene therapy for BCD (a specific type of retinitis pigmentosa) to enter clinical trials both in and outside China. The drug will be applicable to all BCD patients carrying mutations in the CYP4V2 gene. In May 2021, the clinical trial targeting BCD indications was initiated, marking the world’s first clinical trial for BCD using gene therapy. The Phase I/II registrational multicenter clinical study of ZVS101e for the treatment of BCD completed the enrollment of its first patient on February 20, 2023.
The clinical trial application for Skyline Therapeutics' ophthalmic AAV gene therapy drug SKG0106 intravitreal injection solution was approved by the National Medical Products Administration in October 2023 for the treatment of neovascular age-related macular degeneration. SKG0106 received FDA approval in June 2023 to initiate a global Phase I/IIa clinical trial for the treatment of neovascular age-related macular degeneration, and the global clinical trial has already been launched.
In addition to the aforementioned companies, the research and development of new drugs by other companies are also advancing continuously. In recent years, an increasing number of ophthalmic gene therapies have been approved for clinical trials. For patients, gene therapy will bring new hope for the treatment of ophthalmic diseases.
Reporter Wang Kala from The Beijing News
Proofread by Zhai Yongjun