Vutrisiran Sodium

一、政策失衡：单一豁免重创孤儿药研发生态2022 年《通胀削减法案》（IRA）实施以来，罕见病药物研发领域正遭遇前所未有的政策冲击。美国国家制药委员会（NPC）最新报告显示，获得第二个孤儿药适应症认定的药物数量锐减 48%，而这一现象直接源于 IRA 中一项争议性条款 —— 仅对单一适应症的孤儿药免除政府价格管制，若企业寻求第二个罕见病适应症，其价格将纳入谈判范围。“IRA 的孤儿药豁免设计完全背离了《孤儿药法案》的立法初衷。”Arnold & Porter 律所合伙人 Eva Temkin 指出。回溯 1983 年《孤儿药法案》，其通过税收优惠、市场独占期等激励机制，推动超 650 种孤儿药获批，却在 IRA 实施后陷入 “一药一症” 的困局。数据显示，2003-2022 年间获批的 280 种孤儿药中，63 种曾拓展至第二个适应症，29 种覆盖 3 个以上适应症，而如今这条研发路径正被政策利刃切断。二、企业求生：从临床弃研到战略收缩政策震荡已切实传导至产业一线。2022 年 10 月，Alnylam 宣布取消 RNAi 疗法 vutrisiran 针对 Stargardt 病的 III 期试验，直接原因是该药物已凭 ATTR 淀粉样变性适应症获得孤儿药豁免，若再获新适应症认定，将丧失价格保护权。这款 2024 年为公司带来 9.7 亿美元营收的核心产品，因 IRA 条款被迫放弃潜在的适应症拓展。更多罕见病药企陷入两难。Amylyx 的 AMX0035 同时在 Wolfram 综合征和进行性核上性麻痹中开展研究，尽管首席医学官强调 “科学优先”，但业内透露，若该药物获得第二个孤儿药认定，其商业化收益可能面临 30%-50% 的政府砍价。这种 “研发即风险” 的政策环境，使得原本旨在 “一药多治” 的研发策略纷纷搁浅。三、立法博弈：两党法案的突围与搁浅面对产业危机，两党曾联手推出《ORPHAN Cures 法案》，试图将 IRA 的价格豁免扩展至所有孤儿药适应症，并延迟非孤儿适应症获批后的谈判资格。2023 年众议员 John Joyce 与 Wiley Nickel 提出法案，2025 年 5 月参议员 Barrasso 与 Heinrich 在参议院跟进，BIO 首席执行官 Rachel King 称其 “重构 IRA 的激励逻辑”。但上周，该法案在参议院共和党版本的 “One Big Beautiful Bill Act” 中被删除，立法进程受挫。Save Rare Treatments Task Force 尖锐指出：“当前政策正系统性扼杀罕见病研发，亟需修正。” 而更具矛盾性的是，FDA 近期释放的监管创新信号 —— 如专员 Marty Makary 提出的 “科学合理机制” 快速审批路径，与 IRA 的抑制性条款形成鲜明对立，凸显政策体系的内在撕裂。四、监管悖论：平台技术与政策框架的冲突在基因治疗领域，Sarepta Therapeutics 本月获得 FDA 首个 “平台技术认定”，其 rAAVrh74 载体同时用于杜氏肌营养不良症和肢带型肌营养不良症的治疗开发。这种 “一平台多适应症” 的模式本可大幅提升罕见病治疗效率，却与 IRA 的单一豁免条款直接冲突。“开发基因治疗平台的初始成本高达数亿美元，” 前 FDA 政策副总监 Temkin 强调，“但 IRA 在第二个适应症开发时就关闭豁免大门，这等于扼杀了技术迭代的可能。”NPC 报告已明确指出，IRA 对孤儿药二次开发的抑制是 “政策设计的重大失误”，而随着 CRISPR 疗法成功救治罕见病患者 KJ 等案例的涌现，政策与科学的脱节正引发行业深度焦虑。五、未来拷问：当救命药遇上价格谈判站在 2025 年的时间节点，罕见病领域正经历 “冰火两重天”—— 监管层释放加速审批的积极信号，而 IRA 的价格管制阴云却让药企研发热情骤降。数据显示，IRA 实施后首个孤儿药认定数量虽暂稳，但二次认定的暴跌已预示未来获批药物的适应症单一化趋势，这意味着 3000 万罕见病患者将面临治疗选择减少、用药成本飙升的双重困境。当 Alnylam 的 vutrisiran 因政策放弃 Stargardt 病开发，当《ORPHAN Cures 法案》在国会搁浅，这场关乎千万患者生命质量的政策博弈已到关键节点。正如 Temkin 所言：“IRA 对罕见病研发的负面影响已确凿无疑，现在需要的是政治勇气去修正这个系统性漏洞。” 而在政策转向之前，罕见病治疗的希望，或许只能寄托于监管创新与资本良知的艰难平衡之中。参考来源：https://www.biospace.com/policy/ira-leaves-orphan-drugs-stranded-even-as-regulators-promise-progress识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观不本站。

Created with Canva Dreamlab † The Inflation Reduction Act includes an exemption for orphan drugs for a single indication, but experts say this is far from sufficient to maintain momentum in the rare disease space. Since the passage of the Inflation Reduction Act’s drug price negotiation program in August 2022, investigational medicines designated as orphan drugs by the FDA have become much less likely to receive that designation again for a new indication. In fact, the percentage of orphan drugs that doubled down on the regulatory status decreased by nearly half, according to a recent report by the National Pharmaceutical Council. The IRA contains a clause exempting orphan drugs for rare diseases from price controls—but only for a single indication. If the drug wins a second orphan drug designation, its price would be subject to negotiation with the government. Fewer orphan drug designations could limit the number of patients that may benefit from certain scientific breakthroughs, experts agree. The Orphan Drug Act, passed in 1983, enables the FDA to grant the designation to drugs intended to treat diseases affecting fewer than 200,000 people in the U.S. More than 30 million Americans are afflicted with one of these diseases, and fewer than 5% have an FDA-approved treatment. Orphan drug designation qualifies sponsors for tax credits for qualified clinical trials, exemption from user fees and seven years of guaranteed market exclusivity following approval. These incentives have been largely successful, David Gibson of the Amyloidosis Research Consortium wrote in a 2024 article , with more than 650 orphan drugs approved since the law was passed. Then came the IRA. For Eva Temkin, a partner at the law firm Arnold & Porter, the orphan drug exclusion (ODE) isn’t enough. “I do think that the way that the orphan exception to the IRA is structured is insufficient to continue incentivizing orphan drug development in the face of the costs and various externalities imposed by the IRA,” she told BioSpace . “And it does sort of go against decades of Congress trying to catalyze orphan drug development and things like the Orphan Drug Act.” Indeed, a National Pharmaceutical Council (NPC) Policy & Evidence Brief , published May 15, found that the number of drugs receiving a first orphan designation each year has remained largely consistent since the passage of the IRA, while those that went on to secure a second designation decreased by 48%. “Patient groups, policymakers, and other leaders have all said they wanted to know if these early signals are showing up—and they are,” Jon Campbell, chief science officer at NPC, told BioSpace in an email. “We believe good policy starts with good evidence.” If this narrow exemption holds, it could limit rare disease research. Of 280 evaluable orphan drugs approved by the FDA between 2003 and 2022, 63 were approved for one follow-on indication, according to a 2023 study published in JAMA , while another 29 were approved for three or more indications. The Orphan Cures Act, bipartisan legislation to exclude orphan drugs with more than one rare disease approval from the Medicare drug price negotiations, has been introduced in both the House and Senate. But last week, the bill was dropped from Senate Republicans’ version of the Trump administration’s “One Big Beautiful Bill Act.” The IRA’s Impact on Orphan Drug Development The 48% drop in second orphan drug designations indicates a slowing of momentum that had been building prior to 2022. NPC found the percentage of first orphan drug designation winners that went on to secure a second “increased steadily” over the four years prior to the IRA’s passage. The report’s authors cautioned that the data are “descriptive and exploratory in nature and should be viewed as hypothesis-generating.” They note, for example, the potential impact of COVID-19 on orphan drug designations as a confounding variable. Moreover, the analysis focused only on granted designations as opposed to those that were approved, pending or withdrawn, with a maximum follow-up period of 18 months. “Further post-IRA observation time will add to the robustness of future analyses,” Campbell said. Nevertheless, these early data have been proven out in the business decisions of some biopharma companies. In October 2022, Alnylam canceled a planned Phase III trial of its RNAi therapy vutrisiran in Stargardt disease. At the time, Christine Lindenboom, the company’s senior vice president of investor relations and corporate communications, told BioSpace the decision was due to vutrisiran’s orphan drug designation. Essentially, if Alnylam were to go forward with investigating vutrisiran in Stargardt, the drug, marketed in the U.S. as Amvuttra in ATTR amyloidosis, may lose its exemption from drug price negotiations, potentially costing Alnylam substantial profits. Amvuttra brought in more than $970 million for the company in 2024—approaching half of its total revenue. Lindenboom declined to comment further for this article, but Stargardt disease does not appear in Alnylam’s current pipeline . Several other rare disease–focused companies are currently testing lead molecules for multiple indications and could eventually find themselves in the crosshairs of the IRA’s single ODE. One of these companies is Amylyx, which is studying AMX0035 in both Wolfram syndrome and progressive supranuclear palsy. Amylyx Chief Medical Officer Camille Bedrosian told BioSpace the issue of ODE has not yet come up for AMX0035, “but our approach is to always focus on whether the science and the emerging data with a drug/drug candidate in the various diseases could make a difference for the people living with the diseases. If yes, we pursue the development.” As with many other aspects of the IRA’s drug price negotiation program, there has been pushback to the ODE. Somewhat uniquely, however, efforts to reform the ODE are bipartisan. In 2023, Congressmen John Joyce (R-PA) and Wiley Nickel (D-NC) introduced the ORPHAN Cures Act, which BIO CEO Rachel King said at the time “changes the incentive structure within IRA to encourage follow-on investment into orphan drug development.” Then, on May 23, Senators John Barrasso (R-WY) and Martin Heinrich (D- NM) brought the bill forward in the Senate. The proposed legislation would extend the IRA’s exemption from price negotiations to include orphan drugs without any non-orphan indications regardless of how many orphan indications it had, as well as delay negotiation eligibility for orphan drugs that lose exclusion because a non-orphan indication has been approved. “The changes in the ORPHAN Cures Act are critically needed to correct an unintended consequence in current law that is hampering the research and development of new treatments for rare diseases,” a spokesperson for the Save Rare Treatments Task Force wrote to BioSpace in an email. After last week’s removal of the Orphan Cures Act from the “One Big Beautiful Bill Act,” the legislation will still need to pass through the entire Senate and House, though Republican senators aim to hand a final package to Trump by July 4. Rare Disease Space Gains Momentum The IRA and subsequent controversy comes at a time when momentum is ramping up in the rare disease space. Last month, a young patient named KJ enthralled the gene therapy world when news broke that a CRISPR treatment created just for him appeared to have succeeded in saving his life. The Trump administration has expressed support for rare disease drug development. In one of his first interviews after being confirmed, FDA Commissioner Marty Makary proposed a new regulatory pathway for rare disease drugs, allowing for their conditional approval based on a “scientifically plausible mechanism.” Center for Biologics Evaluation and Research Director Vinay Prasad made similar comments last week at an event organized by the National Organization for Rare Disorders, committing to give rare disease patients rapid access to “products that are even small steps forward” during his tenure. Their boss, Health and Human Services Secretary Robert F. Kennedy Jr., backed them up at an FDA roundtable focused on cell and gene therapies (CGT) on June 6. On the CGT front, Sarepta Therapeutics earlier this month became the first company to announce receipt of the FDA’s Platform Technology Designation . The designation, which Sarepta snagged for a viral vector called rAAVrh74, allows the recipient to use a “platform technology” to make more than one drug or biologic, with the aim of streamlining reviews and creating predictability for new drug applications created using the same technologies. Sarepta is using rAAVrh74 in both its approved Duchenne muscular dystrophy gene therapy Elevidys and its investigational gene therapy for limb-girdle muscular dystrophy. Notably, the IRA’s current provision for only one orphan drug designation per molecule appears to directly conflict with the spirit of this new designation. The initial cost to develop these technologies can be very high, said Temkin, who previously served as acting deputy director for policy staff the FDA’s Office of Therapeutic Biologics and Biosimilars, “but once the product is developed, it can be useful in treating multiple rare diseases, and those kinds of products, in particular, I think, are not given the benefit of the exception, which closes the door as soon as the second rare disease development program is designated.” Ultimately, Temkin said, “I am not surprised by the conclusion that the [NPC] report reaches, which is that the IRA has, overall, had quite a negative impact on rare disease drug development, and in particular, second orphan indications. I think it’s one of many unintended consequences of the IRA on drug development.”