PCSK4

▎药明康德内容团队报道本周，全球细胞和基因疗法（CGT）领域迎来诸多进展。例如：多家细胞和基因疗法新锐完成早期融资，君赛生物、雅科生物等公布细胞疗法最新临床数据，信达生物、明慧基因、艺妙神州等细胞疗法申报临床等。本文将节选其中部分重要进展做简单介绍，仅供读者参阅。图片来源：123RF———✦新锐融资✦———ImmuneBridge宣布完成了超额认购的1200万美元的种子轮融资。该公司正在开发同种异体自然杀伤细胞（NK）免疫疗法，用于治疗血液恶性肿瘤和实体肿瘤。ImmuneBridge公司的特点在于，它所使用的脐带血样本具有遗传多样性，并且其专有的扩增技术使在实验室中长期培养这些干细胞成为了可能。这两大特点相结合将加速ImmuneBridge公司发现并转化更有效的细胞疗法。CTRL Therapeutics宣布获得1000万美元种子轮融资，用于推进下一代细胞治疗平台，以治疗实体肿瘤。CTRL公司使用一种新一代平台，从血液中提取循环肿瘤反应性淋巴细胞（cTRLs），有望解决现有细胞治疗技术的挑战。它基于肿瘤浸润淋巴细胞（TIL）疗法的优势，同时通过改善治疗细胞的免疫表型、质量和一致性，提高了疗效。这种方法可能通过避免具侵入性和昂贵的手术，使更多患者能接受此疗法，并同时提供较好的成本效益和简化制造过程。Function Oncology宣布已完成2800万美元的A轮融资。Function Oncology的功能基因组学平台利用CRISPR技术直接对患者的临床样本进行基因调控，对患者的肿瘤进行个体化、全面的分析，揭示无法通过传统基因组分析完全确定的药物靶点依赖性。通过超越传统的基因测序方法，测量基因功能，该公司旨在为癌症患者找到最佳治疗方案，并推动下一代靶向癌症治疗的发展。———✦新药进展✦———REGENXBIO宣布，一次性基因疗法RGX-202获得美国FDA授予快速通道资格，用于杜氏肌营养不良症（DMD）的治疗。DMD是一种致命的X连锁遗传性神经肌肉疾病，主要由编码抗肌萎缩蛋白的基因发生突变所引起，这种突变通常会导致抗肌萎缩蛋白的缺失或缺陷。RGX-202旨在提供一种新型微小肌萎缩蛋白的转基因，通过NAV AAV8载体和一种特征良好的肌肉特异性启动子（Spc5-12）在骨骼和心肌中进行基因的传递和靶向表达。Verismo Therapeutics开发的细胞疗法SynKIR-110获得FDA授予快速通道资格，用于治疗间皮瘤。此前，FDA已授予其治疗间皮瘤的孤儿药资格。SynKIR-110是一种基于杀伤性免疫球蛋白样受体（KIR）-CAR平台技术的CAR-T细胞疗法。这种KIR-CAR能够自然地与DAP12蛋白相互作用，向T细胞传递重要的信号，促进T细胞增殖和细胞因子分泌等。图片来源：123RF君赛生物宣布其天然TIL细胞新药GC101的剂量爬坡试验取得阶段性进展，在治疗多种类型晚期实体肿瘤中显示积极疗效，且未观察到剂量限制性毒性（DLT），安全耐受性良好。GC101是一款自体天然肿瘤浸润淋巴细胞注射液，也是一款无需清淋、无需IL-2注射的TIL细胞新药。雅科生物科技CD7 CAR T细胞临床结果在Journal of Hematology & Oncology上发表。20名参与者接受了CD7 CAR T细胞输注。经过中位随访27.0个月后，受试者总体反应率和完全缓解率分别为95％和85％；治疗后24个月的无进展生存率（PFS）和总生存率（OS）分别为36.8％和42.3％，中位PFS和OS分别为11.0个月和18.3个月。治疗后30天内报告的不良事件包括3-4级细胞因子释放综合征和1-2级移植物抗宿主病。赛诺菲（Sanofi）与Alnylam公司联合开发的siRNA疗法fitusiran用于治疗血友病的两项3期随机对照试验临床数据分别发表于《柳叶刀》和《柳叶刀-血液学》杂志。这两项研究结果显示，通过每月一次预防性注射fitusiran可将患者年出血率降低90%，与按需治疗相比，出血事件改善具有统计学显著性和临床意义，改善了患者的生活质量。君实生物与润佳医药共同研发的JS401在中国获批临床。这是一种靶向血管生成素样蛋白3（ANGPTL3）信使RNA的小干扰RNA（siRNA）药物，主要用于高脂血症等治疗。JS401经N-乙酰半乳糖胺（GalNac）被递送至肝细胞内，在肝细胞内特异性降解ANGPTL3 mRNA，并持续性抑制ANGPTL3蛋白的表达，从而发挥其降脂（甘油三酯及胆固醇）的作用。达博生物研发的基因治疗药物E10A联用抗PD-1单抗方案获得中国国家药监局（NMPA）批准进入2期临床试验，用于头颈部鳞癌等实体肿瘤的治疗。E10A是一种新型抗肿瘤基因治疗药物，它采用第二代重组腺病毒为载体，携带重组构建的人内皮抑素基因，在转染肿瘤细胞后可表达大量的人内皮抑素，进而特异性抑制血管内皮细胞增殖和肿瘤血管生成，阻断肿瘤组织血液供应。根据中国国家药监局药品审评中心（CDE）官网公示，多款CGT产品申报临床并获得受理。例如：信达生物靶向BCMA的CAR-T疗法IBI346；明慧基因抗CD30嵌合抗原受体自体T细胞注射液；至善唯新rAAV基因药物ZS802；艺妙神州IM83 CAR-T细胞注射液等。除了上述动态，本周细胞和基因疗法领域还有一些其它进展，限于篇幅，本文不再一一介绍。希望该领域迎来更多的新进展和突破，惠及更多患者。本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

RGX-202 is a potential one-time AAV Therapeutic for the treatment of Duchenne and includes an optimized transgene for a novel microdystrophin and REGENXBIO's proprietary NAV® AAV8 vector Commercial-scale cGMP material from the REGENXBIO Manufacturing Innovation Center to be used in the clinical trial AFFINITY DUCHENNE™ Phase I/II trial of RGX-202 is active and recruiting patients; anticipated to report initial trial data in the second half of 2023 REGENXBIO Inc. (Nasdaq: RGNX) today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for RGX-202, a potential one-time gene therapy for the treatment of Duchenne muscular dystrophy (Duchenne). Fast Track designation aims to facilitate the development and expedite the review of new therapeutics that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Therapies granted this designation are given the opportunity for more frequent interactions with the FDA and may qualify for priority review. The FDA has granted RGX-202 Orphan Drug Designation and Rare Pediatric Disease Designation. "Fast Track designation, along with our capabilities to conduct our clinical trials using commercial-scale cGMP material, will further support the efficient development of RGX-202 from clinic to commercial readiness," said Kenneth T. Mills, President, and Chief Executive Officer of REGENXBIO. "RGX-202 is a key part of our '5x25' strategy, and we look forward to continuing to work closely with the FDA and the Duchenne community as we advance a highly differentiated product candidate developed with the potential to make a meaningful difference for patients. We look forward to reporting initial data from our clinical trial of RGX-202 in the second half of this year." "We are pleased that the FDA has granted Fast Track designation for RGX-202," said Debra Miller, Founder and CEO of CureDuchenne. "Accelerating the development of medicines for Duchenne, especially potential one-time gene therapies like RGX-202, is critical for this community." RGX-202 Clinical Program In January, REGENXBIO announced that the Phase I/II AFFINITY DUCHENNE™ trial of RGX-202 for the treatment of Duchenne is now active and recruiting patients. AFFINITY DUCHENNE is a multicenter, open-label dose evaluation and dose expansion clinical study to evaluate the safety, tolerability and clinical efficacy of a one-time intravenous (IV) dose of RGX-202 in patients with Duchenne. Six ambulatory, pediatric patients (ages 4 to 11 years old) with Duchenne are expected to enroll in two cohorts with doses of 1x1014 genome copies (GC)/kg body weight (n=3) and 2x1014 GC/kg body weight (n=3). After an independent safety data review for each cohort, a dose expansion phase of the trial may allow for up to six additional patients to be enrolled at each dose level (for a total of up to nine patients in each dose cohort). Additionally, REGENXBIO is recruiting patients in the AFFINITY BEYOND™ trial, an observational screening study to evaluate the prevalence of AAV8 antibodies in patients with Duchenne up to 12 years of age. Information collected in this study may be used to identify potential participants for the AFFINITY DUCHENNE trial and potential future trials of RGX-202. REGENXBIO Gene Therapy Manufacturing REGENXBIO has manufactured additional clinical supply of RGX-202 in its in-house Manufacturing Innovation Center using the NAVXpress™ platform process. Located in REGENXBIO's headquarters in Rockville, MD, the Manufacturing Innovation Center is designed to meet global clinical and commercial regulatory standards, and includes two independent bulk drug substance production suites, a final drug product suite and integrated quality control labs. REGENXBIO is one of only a few gene therapy companies worldwide with a cGMP facility capable of production at scales up to 2,000 liters. About RGX-202 RGX-202 is designed to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-Terminal (CT) domain found in naturally occurring dystrophin. Presence of the CT domain has been shown in preclinical studies to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice. Additional design features, including codon optimization and reduction of CpG content, may potentially improve gene expression, increase translational efficiency and reduce immunogenicity. RGX-202 is designed to support the delivery and targeted expression of genes throughout skeletal and heart muscle using the NAV AAV8 vector, a vector used in numerous clinical trials, and a well-characterized muscle-specific promoter (Spc5-12). RGX-202 has been granted Fast Track, Orphan Drug and Rare Pediatric Disease designations by the FDA. About Duchenne Muscular Dystrophy Duchenne muscular dystrophy (Duchenne) is a rare genetic disorder, caused by mutations in the gene responsible for making dystrophin, a protein of central importance for muscle cell structure and function. Duchenne primarily affects males with approximately 1 in 3,500 to 1 in 5,000 males affected worldwide. The absence of functional dystrophin protein in individuals with Duchenne results in cell damage during muscle contraction, leading to cell death, inflammation, and fibrosis in muscle tissues. Initial symptoms of Duchenne include muscle weakness that is often noticeable at an early age, with diagnosis typically occurring by 5 years of age. Over time, individuals with Duchenne experience progressive muscle weakness and eventually lose the ability to walk. Respiratory and heart muscles are also affected, leading to difficulty breathing and the need for ventilator assistance, along with the development of cardiomyopathy. There is presently no cure for Duchenne. About REGENXBIO Inc. REGENXBIO is a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy. REGENXBIO's NAV Technology Platform, a proprietary adeno-associated virus (AAV) gene delivery platform, consists of exclusive rights to more than 100 novel AAV vectors, including AAV7, AAV8 and AAV9. REGENXBIO and its third-party NAV Technology Platform Licensees are applying the NAV Technology Platform in the development of a broad pipeline of candidates, including late-stage and commercial programs, in multiple therapeutic areas. REGENXBIO is committed to a "5x'25" strategy to progress five AAV Therapeutics from our internal pipeline and licensed programs into pivotal-stage or commercial products by 2025. SOURCE REGENXBIO Inc.

- Company has initiated Phase I/II AFFINITY DUCHENNE™ trial of RGX-202 - Company also enrolling newly active observational screening study, AFFINITY BEYOND, evaluating AAV8 antibody prevalence in boys with Duchenne - Commercial-scale cGMP material from the REGENXBIO Manufacturing Innovation Center to be used in the clinical trial - RGX-202 is a potential one-time AAV Therapeutic for the treatment of Duchenne and includes an optimized transgene for a novel microdystrophin and REGENXBIO's proprietary NAV® AAV8 vector ROCKVILLE, Md., Jan. 23, 2023 /PRNewswire/ -- REGENXBIO Inc. (Nasdaq: RGNX) today announced that the Phase I/II AFFINITY DUCHENNE™ trial of RGX-202 for the treatment of Duchenne muscular dystrophy (Duchenne) is now active and recruiting patients. RGX-202 is designed to deliver a transgene for a novel microdystrophin protein that includes the functional elements of the C-Terminal (CT) domain found in naturally occurring dystrophin. RGX-202 uses REGENXBIO's proprietary NAV® AAV8 vector. AFFINITY DUCHENNE is a multicenter, open-label dose evaluation and dose expansion clinical trial to evaluate the safety, tolerability and clinical efficacy of a one-time intravenous (IV) dose of RGX-202 in patients with Duchenne. Additionally, REGENXBIO is recruiting patients in the AFFINITY BEYOND™ trial, an observational screening study. The primary objective is to evaluate the prevalence of AAV8 antibodies in patients with Duchenne up to 12 years of age. Information collected in this study may be used to identify potential participants for the AFFINITY DUCHENNE trial and potential future trials of RGX-202. "I am pleased that we are now able to initiate the trial for RGX-202 and also begin enrollment activities in our AAV8 antibody screening study," said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. "The RGX-202 program is a key piece of our '5x'25' strategy to have five AAV Therapeutics either on the market or in late-stage development by 2025. We look forward to continuing to work closely with the Duchenne community as we advance a highly differentiated product candidate developed with the potential to improve muscle strength and motor function in boys with Duchenne." "Duchenne muscular dystrophy is a devastating disease and there are still unmet therapeutic needs," said Aravindhan Veerapandiyan, M.D., a principal investigator in the study and Director of the Comprehensive Neuromuscular Program, PPMD Certified Duchenne Care Center, and Co-Director of the Muscular Dystrophy Association Care Center at Arkansas Children's Hospital. "Gene therapies, like RGX-202, have the potential to impact the progressive nature of Duchenne." REGENXBIO has manufactured additional clinical supply of RGX-202 in its in-house Manufacturing Innovation Center using the NAVXpress™ process platform. Located in REGENXBIO's 132,000 square foot headquarters in Rockville, MD, the Manufacturing Innovation Center is designed to meet global clinical and commercial regulatory standards, and includes two independent bulk drug substance production suites, a final drug product suite and integrated quality control labs. REGENXBIO is one of only a few gene therapy companies worldwide with a cGMP facility capable of production at scales up to 2,000 liters. Additional information can be found on clinicaltrials.gov for AFFINITY DUCHENNE and AFFINITY BEYOND. AFFINITY DUCHENNE™ Trial Design In the dose evaluation phase of the trial, six ambulatory, pediatric patients (ages 4 to 11 years old) with Duchenne are expected to enroll in two cohorts with doses of 1x1014 genome copies (GC)/kg body weight (n=3) and 2x1014 GC/kg body weight (n=3). After an independent safety data review for each cohort, a dose expansion phase of the trial may allow for up to six additional patients to be enrolled at each dose level (for a total of up to nine patients in each dose cohort). The trial design also consists of thorough safety measures informed by the Duchenne community and engagement with key opinion leaders, including a comprehensive, short-term, prophylactic immunosuppression regimen to proactively mitigate potential complement-mediated immunologic responses, and inclusion criteria based on dystrophin gene mutation status, including DMD gene mutations in exons 18 and above. Trial endpoints include safety, immunogenicity assessments, pharmacodynamic and pharmacokinetic measures of RGX-202, including microdystrophin protein levels in muscle, and strength and functional assessments, including the North Star Ambulatory Assessment (NSAA) and timed function tests. Initial trial sites are located in the U.S., with additional sites in Canada and Europe expected to follow. AFFINITY BEYOND™ Observational Study AFFINITY BEYOND is an observational screening study. The primary objective is to evaluate the prevalence of anti-adeno-associated serotype 8 (AAV8) antibodies in participants with Duchenne muscular dystrophy. AAV gene therapies are delivered via viral vectors that are not known to cause disease in humans. For AAV gene therapies delivered systemically, it's important to screen patients for antibodies to the vector. This observational study is intended to help inform future clinical research in Duchenne. About RGX-202 RGX-202 is designed to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-Terminal (CT) domain found in naturally occurring dystrophin. Presence of the CT domain has been shown in preclinical studies to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice. Additional design features, including codon optimization and reduction of CpG content, may potentially improve gene expression, increase translational efficiency and reduce immunogenicity. RGX-202 is designed to support the delivery and targeted expression of genes throughout skeletal and heart muscle using the NAV AAV8 vector, a vector used in numerous clinical trials, and a well-characterized muscle-specific promoter (Spc5-12). About Duchenne Muscular Dystrophy Duchenne muscular dystrophy (Duchenne) is a rare genetic disorder, caused by mutations in the gene responsible for making dystrophin, a protein of central importance for muscle cell structure and function. Duchenne primarily affects males with approximately 1 in 3,500 to 1 in 5,000 males affected worldwide. The absence of functional dystrophin protein in individuals with Duchenne results in cell damage during muscle contraction, leading to cell death, inflammation, and fibrosis in muscle tissues. Initial symptoms of Duchenne include muscle weakness that is often noticeable at an early age, with diagnosis typically occurring by 5 years of age. Over time, individuals with Duchenne experience progressive muscle weakness and eventually lose the ability to walk. Respiratory and heart muscles are also affected, leading to difficulty breathing and the need for ventilator assistance, along with the development of cardiomyopathy. There is presently no cure for Duchenne. About REGENXBIO Inc. REGENXBIO is a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy. REGENXBIO's NAV Technology Platform, a proprietary adeno-associated virus (AAV) gene delivery platform, consists of exclusive rights to more than 100 novel AAV vectors, including AAV7, AAV8, AAV9 and AAVrh10. REGENXBIO and its third-party NAV Technology Platform Licensees are applying the NAV Technology Platform in the development of a broad pipeline of candidates, including late-stage and commercial programs, in multiple therapeutic areas. REGENXBIO is committed to a "5x'25" strategy to progress five AAV Therapeutics from our internal pipeline and licensed programs into pivotal-stage or commercial products by 2025. Forward-Looking Statements This press release includes "forward-looking statements," within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These statements express a belief, expectation or intention and are generally accompanied by words that convey projected future events or outcomes such as "believe," "may," "will," "estimate," "continue," "anticipate," "assume," "design," "intend," "expect," "could," "plan," "potential," "predict," "seek," "should," "would" or by variations of such words or by similar expressions. The forward-looking statements include statements relating to, among other things, REGENXBIO's future operations and clinical trials. REGENXBIO has based these forward-looking statements on its current expectations and assumptions and analyses made by REGENXBIO in light of its experience and its perception of historical trends, current conditions and expected future developments, as well as other factors REGENXBIO believes are appropriate under the circumstances. However, whether actual results and developments will conform with REGENXBIO's expectations and predictions is subject to a number of risks and uncertainties, including the timing of enrollment, commencement and completion and the success of clinical trials conducted by REGENXBIO, its licensees and its partners, the timing of commencement and completion and the success of preclinical studies conducted by REGENXBIO and its development partners, the timely development and launch of new products, the ability to obtain and maintain regulatory approval of product candidates, the ability to obtain and maintain intellectual property protection for product candidates and technology, trends and challenges in the business and markets in which REGENXBIO operates, the size and growth of potential markets for product candidates and the ability to serve those markets, the rate and degree of acceptance of product candidates, the impact of the COVID-19 pandemic or similar public health crises on REGENXBIO's business, and other factors, many of which are beyond the control of REGENXBIO. Refer to the "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of REGENXBIO's Annual Report on Form 10-K for the year ended December 31, 2021, and comparable "risk factors" sections of REGENXBIO's Quarterly Reports on Form 10-Q and other filings, which have been filed with the U.S. Securities and Exchange Commission (SEC) and are available on the SEC's website at . All of the forward-looking statements made in this press release are expressly qualified by the cautionary statements contained or referred to herein. The actual results or developments anticipated may not be realized or, even if substantially realized, they may not have the expected consequences to or effects on REGENXBIO or its businesses or operations. Such statements are not guarantees of future performance and actual results or developments may differ materially from those projected in the forward-looking statements. Readers are cautioned not to rely too heavily on the forward-looking statements contained in this press release. These forward-looking statements speak only as of the date of this press release. Except as required by law, REGENXBIO does not undertake any obligation, and specifically declines any obligation, to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. Contacts: Dana Cormack Corporate Communications dcormack@regenxbio.com Investors: Chris Brinzey, ICR Westwicke 339-970-2843 chris.brinzey@westwicke.com Company Codes: NASDAQ-NMS:RGNX