Spinal Muscular Atrophy

药价是医药行业永恒的话题，而且越来越永恒地纠缠不清。药价辩论的双方，一边是付款者，以公共医疗健康保险计划和雇主保险计划，以及参保人为代表，他们是付款方；另一边是制药公司，他们代表收款方。站在中间的，是那些把控中间环节的代表，诸如左右通吃的PBM（药品福利管理者）。Bloomberg最近的一篇文章（图1）针对的是大热的减肥药物Wegovy的价格问题，他们的切入点很特别：生产成本。图1. Bloomberg文章截图生产成本是制药公司和CDMO的商业机密内容，外人基本上无从置喙，但也可以见微知著地估计一个大概。Bloomber援引JAMA Network Open的论文（图2），表明每月1000美元左右的四剂的GLP-1受体激动剂多肽Semaglutide，其每月剂量的生产成本在0.89-4.73美元之间。图2. JAMA文章截图对此，佛蒙特州参议员，美国参议院健康、教育、劳工和养老金 (HELP) 委员会主席Bernie Sanders在他的推特上发文，再度表明声讨制药公司制定过高药物价格的行为。Sanders就是前不久以强硬手腕要求默沙东、强生和BMS的首席执行官参加听证会的那位参议院。Sanders在他的推文中直言不讳地向诺和诺德发出灵魂质问，“除了贪婪”之外，还有什么理由可以将美元生产成本不足5美元的Ozempic标价近1000美元，而在德国人们只需为此支付59美元？并且强调，诺和诺德必须大幅度降低Ozempic在美价格（图3）。图3. Bernie Sanders推文截图药品生产成本往往属于保密内容，只有制药公司和CDMO清楚，外人几乎无法得到准确信息。但众所周知的是，drug product的成本（包括活性药物中间体）在很多情况下只占据药品标价的极小一部分，就像JAMA Network Open发表的论文中描述的那样，这个结论一点都不让人吃惊。有研究发现，Ozempic生产过程中的最大成本可能并不来自于semaglutide，而是用于注射的一次性注射笔。这支注射笔每月使用一支，成本大约在2.83美元左右。相比之下，Ozempic 中的活性药物的生产成本约为每月30美分（1 mg剂量而言）。Semaglutide的每公斤成本据称超过7万美元，相当于1 mg 7美分，一周注射一次的话相当于一个月注射4.29次（以30天计），那么一个月的成本大约就是30美分。Ozempic的其他成本包括他成本包括每支笔的灌装成本（每月剂量估计为 20 美分）和其他化学成分，包括excipient（估计每月剂量为 15 美分）。药品价格和生产成本之间是否具有关联性？如果我们接受Ozempic每月剂量的生产成本不超过5美元的这个事实，那么是否可以理直气壮地以此作为凭据挑战其在美国将近1000美元的标价？恐怕不能。在为其产品的高价格辩护的过程中，制药公司根本就没有将生产成本作为依据。药物（新药）标价与生产成本之间原本就没有显著性的关联，这是业内基本都接受的共识。以前工作中接触的一款药物，据称其API成本只占据了价格的1%。如果拿Ozempic来对比，后者1000美元的每月价格对应的API成本只有0.3美元，也就是0.03%的比例，1%已经算是较高的情况了。药品标价与生产成本无显著性关联的一个最好说明就是前不久刚刚经历临床失败的ALS药物Relyvrio。这款Amylyx Pharmaceuticals开发的肌萎缩侧索硬化症（俗称渐冻症）药物2022年9月获得了FDA的加速批准。这款药物包含两个简单的活性成分：苯丁酸钠sodium phenylbutyrate和牛磺酸二醇taurursodiol。在获得加速批准之后，Amylyx的III期验证性研究表明了Relyvrio的无效性。在主要终点上的得分与对照组比较的p值为0.67，远高于设定的显著性水平α （0.05）。这表明 Relyvrio从统计学的角度来看与安慰剂没有显著性区别。除了主要临床终点之外，Relyvrio上市后研究的次要终点，即患者报告的生活质量、呼吸功能或生存率的改善也都没有实现。就是这样一款接近安慰剂的药物，它的活性成分生产成本有多高？单看苯丁酸钠sodium phenylbutyrate和牛磺酸二醇taurursodiol这两款简单小分子的化学结构，即便没有详细信息，人们心中对其生产成本也应该有一杆秤。Taurursodiol是一种廉价的营养补充剂，属于牛磺酸类似物，通常被用作消化助剂和肝脏支持，有时作为营养补充剂出现。而苯丁酸钠看上去更像是一个合成其它复杂化合物的原材料。那么Relyvrio的标价几何呢？每年16.3万美元。2023年销售3.81 亿美元，获得 4900 万美元的利润。药物价格与研发成本之间存在关联吗？制药公司从来不会用生产成本作为依据维护药物的高价格，但很多制药公司会选择研发成本作为高药价的背书，包括同类药物中“壮志未酬”未能撞线的先驱者所产生的研发成本。那么药物价格和研发成本之间存在显著关联吗？JAMA Netw Open上发表的另一篇文献研究了药价与研发成本之间是否存在关联。研究者选取了2009 年至 2018 年FDA 批准的60种新药价格与研发投资之间的关系作为研究对象。结果发现，新药上市时的标价（R2 = 0.0005，p值=0.87）或上市后 1 年后的净价格（R2 = 0.007，p值 = 0.73) 与药物研发成本之间不存在相关性。线性回归模型（linear regression model）显示，研发投资与药物标价之间没有关联。这项研究的结果表明，研发投资并不能解释样本中 60 种药物的标价。如果制药公司继续利用“研发投资”作为论据来支持高药价的合理性，他们应该提供出更多的数据来作证这一论点。即便对于超罕见病的疗法，其高昂价格也不应该从研发成本的角度解释，而是从潜在的市场规模和药物价值出发。唯一能够解释药物价格的，是它们的价值。这听上去似乎有些像废话，但price和value是两个不同的概念。什么是价值呢？简单地说，就是体现在购买者为产品支付价格的意愿。例如刚获批的Orchard早发性异染性脑白质营养不良基因疗法Lenmeldy，其425万美元的价格超过了美国非营利组织临床与经济评论研究所建议的230 万美元至 390 万美元的区间，对此Orchard Therapeutics 在其声明中表示，Lenmeldy的价格“反映了其临床、经济和社会价值”。又如2019 年获批的脊髓性肌萎缩症基因疗法Zolgensma。诺华为每剂Zolgensma指定了210万美元的价格，并允许分期付款（5年）的方式支付费用，这使得Zolgensma的费用与第一款脊髓性肌萎缩症药物的成本Spinraza可比。诺华还认为，一次性治疗带来的变革性效益和长期价值为Zolgensma的高价提供了背书。也就是说，Spinraza疗法穷患者一生所产生的费用，与一次性的Zolgensma疗法相当，这就是用价值解释价格的案例之一。又如Bluebird Bio 针对β地中海贫血的基因疗法Zynteglo刚被开发出来时，Bluebird 将单次治疗的价格定为 150 万欧元（180 万美元），但市场表现欠佳，于是Bluebird将这款基因疗法退出了欧洲市场，转而专注于美国，同时将治疗成本上调到每剂280万美元。Bluebird Bio认为，Zynteglo的治疗可以帮助患者节省大量成本，因为此前针对地中海贫血的定期输血疗法或者干细胞移植，同样会造成高额的成本，因此参照这些疗法，Bluebird Bio对他们指定的280万美元的基因疗法给予了背书。以上都是基因疗法的案例，我们再举一个小分子疗法，就是刚刚获得FDA批准的第一款代谢功能障碍相关脂肪型肝炎（MASH）疗法，Madrigal的小分子口服制剂Rezdiffra（有效成分resmetirom）。其研发成本数据不得而知，但根据其结构来看，它的制造成本不应该高于产能非常有限的GLP-1多肽。然而ICER （临床与经济评估研究所）去年五月曾经估算过，如果resmetirom的价格定在每年在 3.96万美元到 5.01万美元之间，那么它就属于具有成本效益的药物。最终这款小分子药物的年标价被定在4.74万美元左右上，远高于semagltuide和tirzaptide。小分子药物中也不乏超过100万美元的天价药物。例如102万美元的Ipsen的进行性骨化性纤维发育不良（FOP）疗法Sohonos（Palovarotene）以及Eiger BioPharmaceuticals 100万美元的Hutchinson-Gilford 早衰综合症疗法Zokinvy（Lonafarnib）。如果说价格和研发成本和生产成本有什么关联的话，那么开发商为产品制定的价格，必须能确保他们收回研发成本和生产成本。但在覆盖这些成本的基础之上，究竟应该设定怎样的溢出值，这就是一个非常复杂的问题了，涉及到市场规模、同行竞争、中间环节的“盘剥”（回扣与折扣），专利时间和市场独占期的长短等众多因素了。例如诺和诺德曾经表示过，他们的semaglutide产品销售收入中，有75%用于回扣与折扣。无论这个“藉口”找的是否到位，这些“不透明”因素无疑使得价格成为了开发商最为倚重的工具。价格与成本之间并不存在人们头脑中的绝对关联，就连经济思想先驱亚当∙斯密早在18 世纪的著作《国富论》中都有阐述。这位苏格兰哲学家和经济学家指出，“生产成本与市场上实际购买商品价格无关。当买家来到市场时，他从不询问生产成本，以及卖方在生产商品时花费了多少费用。”因此说，开发商搬出高昂的研发成本来解释高药价，是站不住脚的，但似乎又攻不破。你说药物的价格远高于研发成本（如果你有研发成本的数据的话），他会说，那还有很多相关联的研发没有走到终点，因此它们的成本也要揉入这款产品之中。你又找出那些项目的投入，证明价格还是高。他会说，我这款产品就剩几年的市场独占期了，之后不仅要面临仿制药，FDA还要有可能在上市后九年（小分子药物）开启价格谈判，我的利润肯定会受影响。你说即便如此，药价和销售额也足够覆盖这些成功并产生利润了。他会说，那这中间还有大量回扣和折扣，卖药的钱只有一部分落入了开发商的腰包。你问，那折扣和回扣有多少？他会说，折扣付款人知道，回扣PMB不让说，这都是商业机密。辩论结束。药价当然必须覆盖开发和生产成本，没有人会做赔本而买卖。但标价多少，就不是成本决定的了。价格实际上是购买者支付意愿的函数，而不是产品投资的函数。举个例子，如果在一个寒风凛冽的冬天出现了供暖供电中断，那么此时煤炭的价格还与它的成本有关吗？或者说CBD的房价是否合理，有人要去质疑它的地皮价格和建造成本吗？这里并不是说制药公司等同于奸商，只是为了说明他们对于产品的定价与其研发成本之间并无关联性。这也在一定程度上解释了上文提到的Relyvrio为什么敢于标出16.3万美元的价格。这个看不见的力量实际上也在一定程度上对FDA的监管决策产生了影响。Relyvrio的II期研究CENTAUR给出了不令人乐观的结果。FDA 的第一个顾问小组于 2022 年 3 月以 6 比 4 的投票拒绝批准该药物，而第二个小组在六个月后却改弦更张，投票支持加速批准，但仍然对 Relyvrio 的功效保留了怀疑。据报道，FDA在审批Relyvrio的进程中得到了一份有 5 万人签名的请愿书。患者权益倡导者的意见显然对FDA的决定起到了一定作用。ALS（渐冻症） 是一种罕见的、破坏性的进行性疾病，影响运动神经元功能，通常在症状出现后两到三年内致命。美国只有约 3万名 ALS 患者，但最终却搞到了一张五万人签名的请愿书。很难说FDA在做出加速批准Relyvrio时是否有投鼠忌器的掣肘。从这个角度不难看出ALS 患者为这款药物支付的意愿，尽管彼时Amylyx可能尚未对Relyvrio标出16.3万美元的“天价”。为什么ALS无效的16.3万药物没有引发轩然大波，而GLP-1减肥药的价格却成为众矢之的？背后的原因比较复杂，但还是离不开价值这一核心。作为一种罕见疾病，ALS面临着巨大的疗法未满足现状。行业领域内但凡出现一丝微小的进步力量，都会被视作希望，因此价格在其潜在的价值面前就有些不那么重要了。反观肥胖症，尽管越来越多的人已经将其视为一种疾病，但仍然有很多人怀疑其作为药物的价值（并非功效），尤其是考虑到这种药物可能需要终生服用，将会对公共健康保险计划和雇主保险计划带来沉重的负担，它的价格问题就成为了不可回避的论战焦点。这也解释了美国联邦政府选择十款药物作为IRA法案下的价格谈判的原因。它们都是为Medicare造成了极大经济负担的药物，因此它们的价格必然成为联邦政府终点关注的对象。结 语Concluding Remark购买者应不应该为研发投入支付金钱？这件事情很难说清楚。就像那副价格昂贵的“拐”一样，背后可能的确有很多只“甩丢的鞋”，但是买拐的是否应该为鞋埋单？这可能就是仁者见仁智者见智的话题了。不过对于制药行业来说，确定的因素是，只有他们存在下去并且有意愿为各种疾病和适应症开发新的更好疗法，人类的健康才能得到更大的保障。Reference：Barber, M. J. Estimated Sustainable Cost-Based Prices for Diabetes Medicines. JAMA Netw Open. 2024;7(3):e243474. doi:10.1001/jamanetworkopen.2024.3474Wouters, O, J. et al. Association of Research and Development Investments With Treatment Costs for New Drugs Approved From 2009 to 2018. JAMA Netw Open. 2022;5(9):e2218623. doi:10.1001/jamanetworkopen.2022.18623.Smith, A. Stock Watch: Acadia And Amylyx Trial Failures Were No Shock. Scrip. 26. 03. 2024.Carroll, J. Do big R&D budgets justify US premium drug prices? No way, analysts scoff. Endpoints News. 08. 03. 2017.Cohen, J. Pharmaceutical Industry Ought To Justify Drug Prices On Value, Not R&D Costs. Forbes. 01. 06. 2023.Ozempic, Novo’s $1,000 Diabetes Shot, Can Be Made for Under $5 a Month. Bloomberg. 27. 03. 2024从 “皇帝新衣”撤市和历史首封特殊CRL看FDA加速批准单抗统治下的倔强，小分子阿尔茨海默病疗法Ferring首席科学家杨翼博士：肥胖症疫苗离我们还有多远？点击阅读原文，了解更多！

A single ABBV-RGX-314 gene therapy treatment has the potential to become a new standard-of-care option among anti-VEGF treatments by sustaining vision health long term and overcoming the clinical challenges of managing wet AMD due to the treatment burden of chronic anti-VEGF injections Patients who received therapeutic doses resulted in stable or improved vision and retinal anatomy up to 2 years Additional long-term follow-up data has demonstrated durable treatment effect, with stable or improved vision, up to 4 years Enrollment is on track in pivotal trials of ABBV-RGX-314 in wet AMD that are expected to support global regulatory submissions in late 2025 through the first half of 2026 ROCKVILLE, Md., March 28, 2024 /PRNewswire/ -- REGENXBIO Inc. (Nasdaq: RGNX) today announced the publication of results from the Phase I/IIa trial evaluating the safety and tolerability of a single dose of subretinal ABBV-RGX-314 for the treatment of wet age-related macular degeneration (wet AMD). Two-year data were published in The Lancet in a paper titled "Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study." These positive study results informed the ongoing pivotal trials of ABBV-RGX-314, a potential one-time gene therapy, for the treatment of wet AMD. "We have started 2024 with strong, positive new data from the ABBV-RGX-314 program, and we believe that there is multi-billion-dollar potential for ABBV-RGX-314 to become a first-in-class gene therapy for wet AMD and the standard of care to treat and prevent progression of diabetic retinopathy," said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. "To have these Phase I/IIa data published in The Lancet highlights the groundbreaking work of our scientists and investigators, and further validates the clinically transformative nature of ABBV-RGX-314 as a potential one-time gene therapy for wet AMD that may help patients maintain or improve their vision." The findings highlighted in The Lancet demonstrated that a single administration of ABBV-RGX-314 was generally well tolerated. Stable or improved visual acuity and retinal thickness was observed with few or no supplemental anti-VEGF injections in most patients at two years. Patients who received therapeutic doses demonstrated sustained levels of ABBV-RGX-314 protein and stable or improved vision and retinal anatomy with few, to no, supplemental anti-VEGF injections in most participants up to two years. REGENXBIO has also reported additional positive interim data from a long-term follow-up study of ABBV-RGX-314 supporting that treatment continues to be well-tolerated and demonstrates long-term, durable treatment effect up to four years. "The publication of the ABBV-RGX-314 Phase I/IIa trial results in The Lancet reinforces the encouraging long-term clinical data observed using subretinal delivery and underscores the potential of ABBV-RGX-314 gene therapy to offer a new approach to the clinical management of wet AMD," said Jeffrey S. Heier, M.D., Director of the Vitreoretinal Service and Director of Retina Research at Ophthalmic Consultants of Boston and primary investigator for the trial. "Wet AMD is a chronic, life-long disease and real-world evidence shows patients are losing significant vision over time, and the burden of frequent anti-VEGF injections needed to manage their wet AMD is a major reason why. A single treatment of ABBV-RGX-314 that can potentially provide long-lasting treatment outcomes and a strong safety pro offer a novel approach to treating this serious and blinding disease." ABBV-RGX-314 is currently being evaluated in patients with wet AMD in two pivotal trials called ATMOSPHERE® and ASCENT™. Enrollment is on track and these trials are expected to support global regulatory submissions with the U.S. Food and Drug Administration and the European Medicines Agency in late 2025 through the first half of 2026. About ABBV-RGX-314 ABBV-RGX-314, being developed in collaboration with AbbVie, is being investigated as a potential one-time treatment for wet AMD, diabetic retinopathy, and other chronic retinal conditions. ABBV-RGX-314 consists of the NAV® AAV8 vector, which encodes an antibody fragment designed to inhibit vascular endothelial growth factor (VEGF). ABBV-RGX-314 is believed to inhibit the VEGF pathway by which new, leaky blood vessels grow and contribute to the accumulation of fluid in the retina. REGENXBIO is advancing research in two separate routes of administration of ABBV-RGX-314 to the eye, through a standardized subretinal delivery procedure as well as delivery to the suprachoroidal space. REGENXBIO has licensed certain exclusive rights to the SCS Microinjector® from Clearside Biomedical, Inc. to deliver gene therapy treatments to the suprachoroidal space of the eye. About Wet AMD Wet AMD is characterized by loss of vision due to new, leaky blood vessel formation in the retina. Wet AMD is a significant cause of vision loss in the United States, Europe and Japan, with up to 2 million people living with wet AMD in these geographies alone. Current anti-VEGF therapies have significantly changed the landscape for treatment of wet AMD, becoming the standard of care due to their ability to prevent progression of vision loss in the majority of patients. These therapies, however, require life-long frequent, repeated intraocular injections to maintain efficacy. Due to the burden of treatment, it is difficult for patients to adhere to frequent injections, which can lead to a decline in vision over time. 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 . 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, 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, 2023, 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 WWW.SEC.GOV. 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. Zolgensma® is a registered trademark of Novartis Gene Therapies. SCS Microinjector® is a trademark of Clearside Biomedical, Inc. All other trademarks referenced herein are registered trademarks of REGENXBIO. 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

ROCKVILLE, Md., March 27, 2024 /PRNewswire/ -- REGENXBIO Inc. (Nasdaq: RGNX) today announced it will participate in Cantor Fitzgerald's Virtual DMD and Other Dystrophy Days on Wednesday, April 3, 2024. Cantor Fitzgerald's Virtual DMD and Other Dystrophy Days Fireside Chat: Wednesday, April 3, 2024 at 9:50 a.m. EDT Location: Virtual A live webcast of the fireside chat can be accessed in the Investors section of REGENXBIO's website at . An archived replay of the webcast will be available for approximately 30 days following the presentation. 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 . Contacts: Dana Cormack Corporate Communications [email protected] Investors: Chris Brinzey, ICR Westwicke 339-970-2843 [email protected] SOURCE REGENXBIO Inc.