Ultragenyx Pharmaceutical, Inc.

▎药明康德内容团队编辑 Ultragenyx Pharmaceutical日前宣布，美国FDA已受理其AAV基因疗法UX111（ABO-102）用于治疗IIIA型黏多糖贮积症（MPS IIIA）患者的生物制品许可申请（BLA），并授予优先审评资格。该申请的PDUFA日期为2025年8月18日。根据新闻稿，如果获得批准，UX111将成为获美国FDA批准用以治疗MPS IIIA的首款疗法。 MPS IIIA是一种常染色体隐性遗传病，由编码N-磺基葡萄糖胺磺基水解酶（SGSH）的基因发生突变所引起。SGSH酶可分解并回收硫酸乙酰肝素（HS）。HS调控着一系列重要的生理过程，但是当编码SGSH的基因发生突变而导致酶失活时，HS会在器官中积聚并破坏器官的正常功能，特别是造成中枢神经系统的功能损伤，患者可能出现发育迟缓、行为障碍、癫痫发作等认知或生理异常状况。 图片来源：123RF UX111的BLA主要基于进行中的关键性Transpher A研究的数据。研究显示，接受UX111治疗后，患者的脑脊液（CSF）HS水平迅速且持续降低，且CSF HS的持续降低与长期认知发育的改善相关，相较于自然病程数据中观察到的认知能力下降，治疗效果显著。迄今为止，最常见的治疗相关不良事件是肝酶升高，其中大多数事件为轻度（1级）或中度（2级）且均已恢复。 UX111是一种用于治疗MPS IIIA的新型体内基因疗法，目前处于1/2/3期开发阶段。UX111旨在通过一次性静脉输注完成给药，使用AAV9载体将功能性SGSH基因递送至细胞中。该疗法的设计目的是解决SGSH酶缺乏这一根本问题，该缺陷会导致脑内糖胺聚糖（如硫酸乙酰肝素）的异常积累，从而引发进行性细胞损伤和神经退行性病变。UX111已获美国FDA授予再生医学先进疗法（RMAT）认定、快速通道资格、罕见儿科疾病认定和孤儿药资格，并在欧盟获得PRIME资格和孤儿药资格。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] Ultragenyx Announces FDA Acceptance and Priority Review of the Biologics License Application (BLA) for UX111 AAV Gene Therapy to Treat Sanfilippo Syndrome Type A (MPS IIIA). Retrieved February 19, 2025 from https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-fda-acceptance-and-priority-review 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。 版权说明：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「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

For the first time, the FDA will consider whether to approve a trio of drugs for tiny patient populations based on trials that are using biological signals as outcomes, rather than a placebo comparison. It’s a crucial moment not just for the three companies and the drugs, but also a chance to remove what’s long been seen as a major roadblock to developing treatments for ultra-rare disease populations. It also comes as the FDA has signaled an openness to leaning on biomarkers, which would let companies prove treatments work with a single clinical trial and later confirmatory evidence. “From a broader rare disease perspective, this would be something that, if I was looking at other drugs, it would serve as favorable precedent,” Stifel analyst Paul Matteis said. The drugs come from Denali, Ultragenyx and Regenxbio, which will ask the FDA this year to grant them accelerated approval based on a biomarker that’s never been used as the basis of one. They are developing drugs that aim to correct two of the many single-enzyme mutations, which collectively affect millions of patients worldwide . That’s why the potential blueprint from these companies could offer an economic lifeline for other biotechs that have struggled to make a financial case for developing rare disease medicines, especially those in demand among the smallest patient populations . If accelerated approval is granted, the three companies would have to run a single trial and later get confirmatory data. That would be less than the typical requirement, which is at least two placebo-controlled trials. For some companies, the cost of running multiple placebo-controlled studies can be daunting, as can finding enough patients for them. Biomarkers are used for all accelerated approvals and can be simple measurements, like the shrinking of tumors or lower cholesterol levels. Historically, broad approaches to rare disease development have been difficult, said Scott Weintraub, senior VP of US business at Alexion. That’s because rare diseases are highly varied, both in genetics and prevalence. Sickle cell disease, Duchenne muscular dystrophy and n-of-1 disorders are all classified as rare diseases despite having few symptoms in common. “There is no translational model for most of these diseases,” Weintraub said. “There is no developmental endpoint agreement with the FDA or any regulatory agency at first. The companies don’t know what endpoints are going to move clinically in a lot of these diseases at first.” So far, the FDA has relied on biomarkers to grant accelerated approval for more common rare conditions, such as Sarepta’s gene therapy for Duchenne muscular dystrophy that’s indicated to treat many of the 250,000 patients in the US with the disease . (The FDA has since broadened the label and converted most of it to full approval.) The three drugmakers aim to show that they’re reducing levels of heparan sulfate, a complex carbohydrate that builds up in toxic levels in a handful of deadly neurological diseases. Of those, Denali and Regenxbio are targeting Hunter syndrome, while Ultragenyx is going after Sanfilippo syndrome. All are expected to present updated data this week at the annual WORLD Symposium conference. For patients with severe Hunter syndrome, an infant’s decline can begin as early as 18 months old. Many babies suffer frequent upper respiratory infections and swelling around the brain and spinal cord. It affects an estimated 2,000 patients worldwide . Sanfilippo syndrome type A, meanwhile, results in most patients dying before they turn 20. It’s estimated that there are fewer than 5,000 cases in “commercially accessible regions,” according to Ultragenyx . Scientists have known of heparan sulfate’s existence since the 1940s, but its potential as a biomarker didn’t come into focus until recently. The companies believe heparan sulfate is innately linked across MPS, or mucopolysaccharidoses, due to only a single enzyme being affected by the genetic mutations. “For any of these single-enzyme diseases, you will have a substrate that can be measured,” Denali chief medical officer Carole Ho said. “Because it’s the driver of the disease, theoretically if you stop that, you know accumulation of that substrate, by correcting it, you will get clinical benefit.” That could mean other drug developers will be able to create future drugs targeting other single-enzyme mutations. Drug developers’ approaches to these conditions — disorders like cystic fibrosis and Huntington’s disease both result from single genetic mutations — have historically been scattershot and tailored to disease pathology. But every disease or mutation is different, meaning attempts to replicate what these companies are doing won’t be an exact 1-to-1 copy. The companies’ efforts also come at a time when the FDA is developing a policy to encourage so-called platform technologies that allow drugmakers to simultaneously target multiple diseases. Drugmakers taking a multi-disease approach may one day be able to get accelerated approval, though that’s more hope than reality right now. The path for Ultragenyx in particular is one that may make it more financially viable for drug developers to make rare disease treatments. The company acquired its potential Sanfilippo syndrome treatment after a partner, Abeona Therapeutics, halted development during a corporate restructuring. Among Ultragenyx’s challenges was finding enough patients to run a placebo-controlled clinical trial. Instead, the FDA last year indicated it’s open to accelerated approval , based on the biomarker, to speed up testing. It’s part of a broader shift at the agency, which last summer launched a Rare Disease Innovation Hub after failing to reach a consensus on the types of evidence and trial designs needed to evaluate therapies for such conditions. The idea is to align the two main divisions of drug evaluation, CDER and CBER, under a framework that can be used consistently. But the FDA’s embrace of accelerated approvals hasn’t been without controversy. The Sarepta approval came only after CBER chief Peter Marks overruled his deputies , and industry watchdog ICER pushed back on the therapy’s potential conversion to full approval . It’s also not yet clear how the new presidential administration under Donald Trump will affect the FDA’s shift. For now, most biopharma companies have been operating as usual. Ultragenyx CEO Emil Kakkis said that patients’ heparan sulfate levels fall within two to three weeks, giving the drugmakers confidence that they’re treating the underlying cause of MPS diseases rather than a downstream effect. “That’s the thing that needs to go to zero,” Kakkis said. “We need to look at heparan sulfate, because that’s the source of the disease, and we’ll make better decisions off of it.” After the FDA signaled its support for the biomarker, Ultragenyx submitted its application for accelerated approval late last year. Regenxbio plans to finish its application by the first quarter, and Denali plans to do the same early this year. All three companies say they expect the FDA to make decisions before the end of 2025. Going the route of accelerated approval and following established models like in cancer and heart disease would make things much easier for drug developers — and potentially speed up development timelines. “Looking at biomarkers based on validated biological pathways is a very reasonable way to go; that’s going to be a lot faster,” TD Cowen analyst Yaron Werber said. In practice, the path to getting confirmatory data may vary by company — but all three already have their studies up and running, suggesting the FDA may want to see a clear path to obtaining such data before agreeing to accelerated approval. Denali expects to get their results from the second portion of a Phase 2/3 trial, while Ultragenyx and Regenxbio plan to do so from the final cohort of a Phase 1/2/3 trial. Ultimately, all of the discussion from the last few years is going to spur more research into new biomarkers, Regenxbio CEO Curran Simpson said. Pharma companies and regulators will also need to continue working together to advance treatments, regardless of how rare the disease is. “It will probably bring back some level of investment that might have been avoided or unfunded, if you will, in the past,” Simpson said.

Nippon Shinyaku has paid $110 million upfront for the rights to sell two of Regenxbio’s gene therapies for mucopolysaccharidosis in the US and Asia. The deal also provides for potential milestone fees of up to $700 million — $40 million for development and regulatory goals and $660 million in sales milestones. Regenxbio would also get double-digit royalties on net sales in the US and Asia, according to a Tuesday release . The assets in question are RGX-121, a therapy for mucopolysaccharidosis (MPS) II, also known as Hunter syndrome, and RGX-111, intended for MPS I or Hurler syndrome. MPS type I and II patients cannot produce particular enzymes that break down large sugar molecules. The sugars accumulate in patients’ tissues, causing various physiological and neurological symptoms. Regenxbio’s gene therapies are administered to the cerebrospinal fluid and deliver genes encoding the missing enzymes. RGX-121 achieved significant cuts in levels of a disease biomarker called heparan sulfate according to data released in February 2024 . In November, Regenxbio said that a BLA submission for RGX-121 via the accelerated approval pathway was expected to be completed in Q1 2025. If the agency gives a green light, RGX-121 could become the first gene therapy for MPS II, the companies say. Other companies are also seeking accelerated approval for forms of MPS based on biomarker findings. Denali Therapeutics is conducting a Phase 2/3 trial of its Hunter syndrome candidate DNL310, and Ultragenyx has submitted a BLA for its gene therapy for Sanfilippo syndrome type A — both using heparan sulfate. RGX-111 is earlier in development. It was well tolerated in eight patients in a Phase 1/2 study, according to data Regenxbio released two years ago. It also showed a decrease in levels of a disease biomarker in the CSF of “the majority of patients.” Regenxbio will continue to lead the clinical development of the assets, and the US biotech retains all rights to the priority review voucher it will receive if RGX-121 gains approval. It will also take charge of manufacturing.