2024年5月10日
2024年5月9日，上海天泽云泰生物医药有限公司（以下简称“天泽云泰”）在巴尔的摩举行的第27届美国基因与细胞治疗学会（ASGCT）年会上以口头报告的形式全球首次公布了治疗结晶样视网膜变性（BCD）的基因治疗产品VGR-R01的临床I/II期最新数据，充分展示了VGR-R01的优异疗效和安全性优势。
VGR-R01是全球首个获得临床批件的针对BCD的治疗产品。临床数据显示，视网膜下注射VGR-R01能够显著改善患者视力或增强昏暗环境下的功能性视力，达到矫正视力损害或保护残余视觉功能的积极效果，有望让BCD不再无药可治。
报告细节
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详细数据
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视力改善：截至2024年3月，该研究中低、中、高剂量组患者分别随访6-9个月时，目标眼BCVA与基线相比分别改善了0.267、0.422和0.547 logMAR（相当于分别提高13、21和27个ETDRS字母）。66.7%（8/12）的受试者目标眼BCVA有显著改善，即降低≥0.3 logMAR（相当于提高15个ETDRS字母）。其中4例受试者（中剂量组和高剂量组各2例）基线时无法看清视力表上的字母，即BCVA是指数（CF, 1.9 logMAR）或手动（HM, 2.3 logMAR），均在术后显著提高（最多能识别40个字母）。
功能性视力改善：低、中、高剂量组中目标眼MLMT评分平均变化约1-2分。41.7%（5/12）的受试者有显著改善（提高≥2分），提示在昏暗环境下功能视力有显著获益。
安全性数据显示：VGR-R01具有良好的耐受性和安全性。无剂量限制性毒性和与药物相关的SAE发生；4例受试者有眼部炎症，经研究者评估可能与VGR-R01相关，严重程度均为1-2级，治疗后未影响BCVA的改善。
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口头汇报节选
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关于结晶样视网膜变性
结晶样视网膜变性（Bietti crystalline dystrophy，BCD）又称Bietti结晶样视网膜病变，是一种常染色体隐性遗传的进展性视网膜变性疾病。BCD致病基因是位于4q35的CYP4V2，编码一种与脂肪代谢相关的蛋白酶。在世界范围内BCD均有分布，但在中国、日本和韩国人群中更为普遍。大多数BCD患者于20-40岁发病，出现夜盲和视力下降等症状，在50-60岁发展为法定盲人。基于临床特征和基因检测鉴定CYP4V2中的双等位基因致病变异，BCD可被确诊，然而仍缺乏有效的临床治疗手段。
关于VGR-R01
VGR-R01是针对CYP4V2基因突变导致的BCD患者的基因治疗产品。CYP4V2蛋白为P450酶家族成员，在视网膜色素上皮细胞（RPE）中高度表达，具有脂肪酸羟化酶活性，与脂肪代谢相关。VGR-R01的作用原理是一种基因替代疗法。
VGR-R01通过视网膜下腔注射给药后，AAV衣壳蛋白介导RPE细胞的转导，将VGR-R01基因表达盒递送至细胞核。VGR-R01表达盒以游离DNA的形式存在，在RPE细胞表达CYP4V2蛋白，以重建细胞的脂肪酸羟化酶活性。VGR-R01通过纠正患者视网膜内的脂肪酸代谢障碍，以期达到预防或改善RPE细胞、感光细胞及脉络膜的结构和/或功能损伤，并实现纠正视力损伤、保护残存视功能、或延缓视力恶化的临床效果。
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图 VGR-R01作用机制图示
关于天泽云泰
天泽云泰2020年3月注册成立于中国上海，致力于将前沿的基因及细胞治疗技术，转化为临床可及的治疗方法，以期造福更多患者。
天泽云泰拥有具有自主知识产权的ViVec®AAV载体筛选平台、ViLNP®脂质纳米粒技术平台、ViCas®CRISPR基因编辑技术平台和ViHiYi®AAV高产技术平台，通过基因替代、基因调控和基因编辑等策略，开发治疗中枢神经系统疾病、代谢及血液系统疾病、眼科疾病等领域的创新基因治疗药物，拥有包括多个潜在First-in-class产品的多元化管线。
目前，天泽云泰已经获得多家知名基金的多轮投资，分别在张江高科技园区、北京巢生实验室、临港新片区和外高桥自贸区建成面积2,500平米的基因治疗研发运营中心、基因编辑技术研发中心、3,000平米的基因治疗中试生产车间和5,500平方米GMP商业化生产车间。
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Vitalgen ASGCT announces the latest Phase I/II clinical data for VGR-R01 in the treatment of BCD
On May 9, 2024, Shanghai Vitalgen BioPharma Co., Ltd. (hereinafter referred to as “Vitalgen”) will globally publish the updated data on the phase I/II clinical trial of gene therapy product VGR-R01 in patients with Bietti crystalline dystrophy (BCD) in oral presentation form for the first time in the 27th Annual Meeting of American Society for Gene & Cell Therapy (ASGCT) to be held in Baltimore, fully demonstrating its excellent efficacy and safety advantages.
VGR-R01 is the world's first therapeutic product for BCD to receive clinical approve. Clinical data demonstrate that subretinal injection of VGR-R01 can lead to clinically significant improvement in visual acuity or enhancing functional vision in low-light environments, achieving the clinical effect of correcting visual impairment or protecting residual visual function, and is expected to render BCD no longer untreatable.
Presentation Details
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Detailed Data
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Improvement in visual acuity: As of March, 2024, in the low-, medium-, and high-dose groups of the study, the BCVA of the target eyes was improved by 0.267, 0.422, and 0.547 logMAR compared to baseline (equivalent to an increase of 13, 21, and 27 ETDRS letters) at the 9-month and 6-month follow-up, respectively. Moreover, 66.7% (8/12) of subjects showed a significant improvement in BCVA of the target eyes, i.e., a decrease of ≥ 0.3 log MAR (equivalent to an increase of 15 ETDRS letters). Among them, the baseline BCVA of 4 subjects (2 each in the medium- and high-dose groups) was either counting fingers (CF, 1.9 log MAR) or hand motion (HM, 2.3 log MAR) in the remaining, which showed significant improvements, i.e. equivalent to an increase of up to 40 letters, after VGR-R01 administration.
Improvement in functional visual acuity: The mean change in MLMT score of the target eyes increased by approximately 1~2 points in the low-, medium-, and high-dose groups. 41.7% (5/12) of subjects had a significant improvement, i.e., an increase of ≥ 2 points, suggesting the benefits of functional visual acuity in dim environments.
The safety data showed that VGR-R01 is generally well-tolerated and safe. There were no dose-limiting toxicities or drug-related SAEs; 4 subjects had eye inflammation that was assessed by the investigator to be possibly related to VGR-R01, with severity ranging from grade 1 to 2, which were all inconsequential to the visual acuity after treatment.
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Excerpt of oral presentation
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About BCD
Bietti crystalline dystrophy (BCD), also known as Bietti crystalline retinopathy, is an autosomal recessive, progressive retinal degenerative disease. The pathogenic gene for BCD is CYP4V2 located at 4q35, which encodes a protease involved in lipid metabolism. BCD is found worldwide, but more prevalent in Chinese, Japanese and Korean populations. Most patients with BCD develop symptoms such as night blindness and decreased visual acuity in their 20s and 40s, and develop legal blindness in their 50s and 60s. BCD can be diagnosed based on clinical characteristics and genetic testing to identify the biallelic pathogenic variation in CYP4V2, but there is still no effective clinical treatment option available.
About VGR-R01
VGR-R01 is a gene therapy product for patients with BCD caused by CYP4V2 gene mutation. CYP4V2 protein is a member of the P450 enzyme family. It is highly expressed in retinal pigment epithelium (RPE), with fatty acid hydroxylase activity, and is related to lipid metabolism. Mechanism of action of VGR-R01 is gene replacement.
After VGR-R01 is administered via subretinal injection, AAV capsid protein mediates transduction of RPE cells, delivering the VGR-R01 gene expression cassette to the nucleus. The VGR-R01 expression cassette exists as free DNA and expresses CYP4V2 protein in RPE cells to reconstitute the fatty acid hydroxylase activity of the cells. VGR-R01 aims to prevent or improve the structural and/or functional damage of RPE cells, photoreceptor cells and choroid by correcting the fatty acid metabolism disorder in the retina of patients, so as to correct visual impairment, protect residual visual function, or delay vision deterioration.
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Figure Mechanism of action of VGR-R01
About Vitalgen
Since its establishment in March 2020, Shanghai Vitalgen BioPharma Co., Ltd. (Vitalgen) has been dedicated to translating state-of-the-art discoveries and technologies in cell and gene therapy into clinically effective treatments for patients with unmet medical needs.
By leveraging our proprietary ViVec® AAV capsids, ViLNP® lipid nanoparticles, ViCas® novel CRISPR/Cas editing tools and ViHiYi® high yield/high fidelity AAV production system, we are dedicated to the development of innovative gene therapies for neurodegenerative diseases, metabolic and hematological diseases, as well as ophthalmic diseases. This will be achieved through strategies such as gene replacement, gene regulation, and gene editing. Our pipeline encompasses a diverse array of potential First-in-class products.
Vitalgen has received multiple rounds of investment from well-known funds. We have established a 2,500 square meter gene therapy R&D and operation center, a gene editing technology R&D center, a 3,000 square meter gene therapy pilot production workshop, and a 5,500 square meter GMP commercial production workshop in Zhangjiang High-tech Park, Beijing Nest Laboratory, Lingang New Area, and Waigaoqiao Free Trade Zone.
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