Onasemnogene abeparvovec

– Data from pivotal dose level demonstrates long-term, sustained reductions in CSF levels of HS D2S6, a key biomarker of brain disease in MPS II – 80% of patients who received the pivotal dose discontinued intravenous enzyme replacement therapy or remained treatment-naïve – Submission of a rolling BLA using the accelerated approval pathway on track for Q3 2024 ROCKVILLE, MD, USA I September 3, 2024 I REGENXBIO Inc. (Nasdaq: RGNX ) today announced positive results from the Phase I/II/III CAMPSIITE ® trial of RGX-121 for the treatment of patients with Mucopolysaccharidosis Type II (MPS II), also known as Hunter syndrome. The results were presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2024. The totality of evidence from the CAMPSIITE trial continues to support RGX-121 as the potential first gene therapy and one-time treatment for MPS II. In the United States, RGX-121 is also on track to be the first treatment that addresses the neurocognitive decline associated with MPS II, with the potential to be the first-line treatment for patients with neuronopathic disease. “As we quickly approach the BLA filing for RGX-121, we are very pleased with the data presented at SSIEM demonstrating encouraging evidence of systemic activity and long-term reductions of CSF D2S6,” said Steve Pakola, M.D., Chief Medical Officer of REGENXBIO. “The data continue to support that by restoring the gene missing in boys with Hunter syndrome, RGX-121 changes the course of disease and has the potential to significantly improve both vital brain function and the systemic manifestations of this devastating disease.” Data Summary In new, long-term data from the Phase I/II/III CAMPSIITE ® trial, patients receiving RGX-121 at the pivotal dose level demonstrated an 85% median reduction of cerebrospinal fluid (CSF) levels of heparan sulfate (HS) D2S6, a key biomarker of brain disease activity, approaching normal levels and sustained for up to two years. Topline results presented earlier this year from the CAMPSIITE trial demonstrated that the pivotal phase of the trial met its primary endpoint with statistical significance. Pivotal results were consistent with data from the dose-finding phase of CAMPSIITE, in which the majority of patients were shown to be exceeding expectations in neurodevelopmental function compared to natural history data up to four years. In the dose-finding part of the trial, investigators chose to discontinue standard-of-care intravenous enzyme replacement therapy (ERT) or to remain ERT-naïve for a majority of patients. At the pivotal dose level (dose level 3), 80% of patients were ERT-free at last time point, up to more than 18 months post-dosing. At dose level 2, 71% of patients were ERT-free at last time point, up to almost three years. As of January 5, 2024, RGX-121 continues to be well tolerated in 25 patients dosed across all phases of the CAMPSIITE trial. “A potential one-time treatment that can allow these boys to exceed the natural history of this disease in their neurocognitive development, as well as the ability to remain off enzyme replacement therapy for multiple years represents a meaningful option for patients and their families,” said Roberto Giugliani, M.D., Ph.D., Professor, Department of Genetics, UFRGS, Medical Genetics Service, HCPA, Porto Alegre, Brazil. “I continue to be very encouraged by the data supporting RGX-121 and look forward to the seeing this program advance towards potential approval for this community.” REGENXBIO is on track to initiate a rolling Biologics License Application (BLA) submission using the accelerated approval pathway in the third quarter of 2024 using CSF D2S6 as a surrogate endpoint reasonable likely to predict clinical benefit. Approval of the planned BLA could result in receipt of a Priority Review Voucher in 2025. Data presented is available on the “Publications” section of the REGENXBIO website at WWW.REGENXBIO.COM . About the CAMPSIITE ® Trial CAMPSIITE is a Phase I/II/III multicenter, open-label trial for boys aged four months up to five years with neuronopathic MPS II. The primary endpoint of the trial is measurement of CSF GAGs. Accurate and sensitive measurements of CSF GAGs, such as HS D2S6, have the potential to be considered a surrogate endpoint that is reasonably likely to predict clinical benefit in MPS II disease under the accelerated approval pathway, as buildup of GAGs in the CSF of MPS II patients correlates with clinical manifestations including neurodevelopmental deficits. The pivotal program is using commercial-scale cGMP material from REGENXBIO’s proprietary, high-yielding suspension-based manufacturing process, named NAVXpress™. In addition to measuring GAGs in the CSF, the trial will continue to collect neurodevelopmental data and caregiver-reported outcomes. About RGX-121 RGX-121 is a potential one-time AAV therapeutic for the treatment of boys with MPS II. RGX-121 expressed protein is structurally identical to normal I2S. RGX-21 Delivery of the IDS gene within cells in the CNS could provide a permanent source of secreted I2S beyond the blood-brain barrier, allowing for long-term cross correction of cells throughout the CNS. RGX-121 has received Orphan Drug Product, Rare Pediatric Disease, Fast Track and Regenerative Medicine Advanced Therapy designations from the U.S. Food and Drug Administration and advanced therapy medicinal products (ATMP) classification from the European Medicines Agency. About Mucopolysaccharidosis Type II (MPS II) MPS II, or Hunter Syndrome, is a rare, X-linked recessive disease caused by a deficiency in the lysosomal enzyme iduronate-2-sulfatase (I2S) leading to an accumulation of glycosaminoglycans (GAGs), including heparan sulfate (HS) in tissues which ultimately results in cell, tissue, and organ dysfunction, including in the central nervous system (CNS). MPS II is estimated to occur in 1 in 100,000 to 170,000 births. In severe forms of the disease, early developmental milestones may be met, but developmental delay is readily apparent by 18 to 24 months. Specific treatment to address the neurological manifestations of MPS II remains a significant unmet medical need. Key biomarkers of I2S enzymatic activity in MPS II patients include its substrate HS D2S6, which has been shown to correlate with neurocognitive manifestations of the disorder. ABOUT REGENXBIO Inc. REGENXBIO is a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy. Since its founding in 2009, REGENXBIO has pioneered the development of AAV Therapeutics, an innovative class of gene therapy medicines. REGENXBIO is advancing a pipeline of AAV Therapeutics for retinal and rare diseases, including ABBV-RGX-314 for the treatment of wet AMD and diabetic retinopathy, being developed in collaboration with AbbVie, RGX-202 for the treatment of Duchenne and RGX-121 for the treatment of MPS II. Thousands of patients have been treated with REGENXBIO’s AAV Therapeutic platform, including Novartis’ ZOLGENSMA for children with spinal muscular atrophy. Designed to be one-time treatments, AAV Therapeutics have the potential to change the way healthcare is delivered for millions of people. For more information, please visit www.regenxbio.com . SOURCE: REGENXBIO

本文作者：缇娜 上个月，辉瑞的血友病基因疗法 Durveqtix 获得欧盟委员会有条件批准，而在此之前，这款药已于今年 4 月获 FDA 批准上市。 EMA 官网截图 对于 B 型血友病患者来说，这种一次性基因治疗无疑是具有极大吸引力的——仅需一次，就能让绝大多数患者恢复正常生活。 但伴随着期待，质疑声也络绎不绝，原因很简单——价格太高了。 一支能买上海江景房，疗效究竟如何？ 根据辉瑞公开的信息，Durveqtix 预计每剂次价格为 350 万美元（约合人民币 2493 万元），追平了此前获批的另一款 B 型血友病基因治疗药物 Hemgenix。 目前，在全球已公开的「全球十大最贵药物」中[3]，Durveqtix 与 Hemgenix 并列第二，仅次于定价 425 万美元（约合人民币 3028 万元）的全球最贵药 Lenmeldy。 此前全球最贵药 Lenmeldy 获批官网公告 Durveqtix 凭什么这么贵？这要从这款药的机制说起。 Durveqtix 是一种使用腺相关病毒（AAV）载体制作的基因疗法，它在腺相关病毒 Rh74 变异株中导入了含有全长凝血因子 IX 的质粒，这些改造过的 AAV 进入人体，就会很快「感染」负责分泌凝血因子的肝细胞，从而增加体内凝血因子 IX 的合成，纠正 B 型血友病患者凝血因子 IX 不足的问题[1]。 在该药的 III 期临床研究中，共有 102 名患者接受了治疗[2]，其中 59 名患者完成了为期 6 个月的随访。经过单次治疗和数月的恢复期后，患者的年平均出血事件数相比采用凝血因子替代治疗时降低了 71%，使用凝血因子治疗的比例也大幅降低；临床试验中有 64% 的患者在治疗后从未发生出血事件。 在安全性方面，仅有 6 例患者在接受 Durveqtix 治疗后出现抗质粒抗体，重新恢复凝血因子治疗，不过，在接受皮质类固醇治疗后，大部分患者已再次停用凝血因子，Durveqtix 治疗依然有效。 基因疗法，为何屡次刷新「全球最贵」 实际上，Durveqtix 所引发的价格争议，在此前获批的不少细胞基因疗法中都曾出现过。在目前公开的「全球十大最贵药物」榜单中，细胞基因疗法包揽前五。 基因疗法这个领域，为何频出「百万美元宝贝」？ 首先，在现有商业化疗法中，基因疗法的研发成本名列前茅。基因治疗涉及在体外构建载体、动物试验评估载体效果、I 期临床研究评估载体效果和安全性、II/III 期研究充分评估疗效等环节，各种研发工具价格同样昂贵，这使得企业的试错成本极高。 以榜单排名第七、目前最畅销的基因疗法之一 Zolgensma 为例，该药的价格为每剂次 210 万美元（约合人民币 1495 万元），但根据研发药企诺华披露，其针对 Zolgensma 研发的总投入达到了 94 亿美元（约合人民币 669 亿元）[5]，而通常来说化学药物的研发成本大多为数亿美元。 图源：图虫创意 而这样高额投入在基因治疗领域并不少见。2023 年一篇论文对细胞疗法和基因疗法的研发成本进行了估算[6]，结果发现，一款细胞疗法/基因疗法药物的临床试验阶段平均耗费 19.43 亿美元（约合人民币 138 亿元），而适用人群可能只有几百甚至几十个患者。 因此，研发企业往往会对基因疗法进行更高定价，以平摊利润和研发利用。 其次，基因疗法多为「一次性治疗」，绝大多数患者在治疗后能起到明显的症状改善乃至于疾病痊愈，虽然单次基因治疗的价格昂贵，从长远的角度来看，基因疗法的花费可能比终生使用传统疗法还要便宜。 以 Durveqtix 为例[4]，虽然价格高达 350 万美元，但 B 型血友病患者每年在美国接受凝血因子治疗的费用可高达 110 万美元，如果基因疗法能让患者摆脱凝血因子治疗，那么这笔帐在治疗三年后就可以「回本」。 掌声与争议并存，有的药已悄然退市 定价有了，这些动辄上百万美元的疗法，究竟好卖吗？ 实际上，绝大多数细基因疗法的收入来源，不在于患者，而在于保险。 例如在一些国家，符合适应症的患者的基因治疗费用可以部分或全部由医保报销，药企也会在全球范围通过慈善机构开展赠药计划等。此外，部分药企还和保险公司达成了分期付款或按疗效付款的协议，在按疗效付款协议中，保险公司可以根据疗效来逐渐支付费用，且如果治疗失败，药企将部分或全部退还治疗费用。 而在销售结果上，「全球十大最贵药物」中排名第七的基因疗法 Zolgensma 就是一个较为理想的案例。 尽管研发成本极高，定价也并不便宜，但 Zolgensma 在一众罕见病中选择了较为常见的一条赛道——脊髓性肌萎缩。 同时，这款药在临床试验阶段展现出了相当不错的疗效：用药后 24 个月时 100% 患者可以脱离气管插管生存，75% 的患者可以不靠辅助坐至少 30 秒，这些效果在未治疗的患者中几乎不可能发生。[8] 种种光环加持下，Zolgensma 上市后第一季度销售额就达到了 1.6 亿美元，2021 年销售额高达 13.51 亿美元，2022 年销售额进一步上涨到 13.7 亿美元，甚至比同样治疗脊髓性肌萎缩的口服药物利司扑兰（2022 年销售额 11.73 亿美元）更高。 Zolgensma 已获国家药监局药品评审中心临床试验默示许可 但不是每一款基因疗法都有这样的「好运」。 如「全球十大最贵药物」排名第五第六的 Skysona 和 Zynteglo，公司年报显示，其 2023 年销量分别为 1670 万美元（约合人民币 1.19 亿元）和 1240 万美元（约合人民币 8828 万元）[10]。 目前，这两款疗法也因「企业战略问题」相继撤出欧洲市场。 再如排名第四、用于治疗杜氏肌营养不良的基因治疗产品 Elevidys，在获得 FDA 加速批准后，曾引起了包括 Nature[11]等各大医学媒体的对疗效的质疑。 多数报道认为，Elevidys 疗效轻微且适用患者非常少，因此很难盈利。不过，研发企业的坚持最终证明了 Elevidys 潜力——根据两项临床研究的结果，Elevidys 获得 FDA 批准大幅扩展适应症[12]，从原来的仅限于 4～5 岁具有行走能力的儿童，扩展为 4 岁及以上的儿童（无论是否有行走能力）。 目前，Elevidys 销售额在 2023 年也达到了 2 亿美元（约合人民币 14.2 亿元），在基因治疗产品中也称得上「热卖」。 整理自参考资料 3 截至目前，Durveqtix 获批后，「全球十大最贵药」榜单中，前 7 席已全部被细胞基因疗法包揽。在这个机遇与挑战并存的赛道上，榜单的再次更新，或许很快就能来到。 策划：z_popeye | 监制：carollero 题图来源：图虫创意 参考文献： [1]https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-beqveztm-fidanacogene-elaparvovec [2]https://genetherapy.isth.org/efficacy-and-safety-of-fidanacogene-elaparvovec-in-adults-with-moderately-severe-or-severe-hemophilia-b-results-from-the-phase-3-benegene-2-gene-therapy-trial [3]https://www.drugs.com/article/top-10-most-expensive-drugs.html [4]https://www.fiercepharma.com/pharma/pfizer-scores-fda-nod-hemophilia-b-gene-therapy-will-charge-35m-dose [5]https://www.spglobal.com/marketintelligence/en/news-insights/latest-news-headlines/r-d-report-card-zolgensma-maker-novartis-spending-reaches-9-4b-in-2019-60760144 [6]Sabatini MT, Chalmers M. The Cost of Biotech Innovation: Exploring Research and Development Costs of Cell and Gene Therapies. Pharmaceut Med. 2023;37(5):365-375. doi: 10.1007/s40290-023-00480-0 [7] Schlander M, Hernandez-Villafuerte K, Cheng CY, et al. How Much Does It Cost to Research and Develop a New Drug? A Systematic Review and Assessment. Pharmacoeconomics. 2021;39(11):1243-1269. doi: 10.1007/s40273-021-01065-y [8] https://www.zolgensma-hcp.com/clinical-experiences/start-trial-efficacy/ [9]https://www.biopharmadive.com/news/novartis-zolgensma-sales-slow-newborn-screening/634896/ [10]https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-fourth-quarter-and-2023-annual-results-and [11]Mullard A. FDA approves first gene therapy for Duchenne muscular dystrophy, despite internal objections. Nat Rev Drug Discov. 2023 Jun 23. doi: 10.1038/d41573-023-00103-y [12]https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy 丁香园是面向医疗从业者的专业平台，以「助力中国医生」为己任。在丁香园，可以和同行讨论病例 ，在线学习公开课，使用用药助手等临床决策工具，在丁香人才找可靠医疗岗位。