Cyprium Therapeutics, Inc.

一个刚出生的宝宝，看起来一切正常。但不到三个月，头发开始变得像钢丝一样卷曲脆弱，接着出现难以控制的癫痫，发育倒退，大多数孩子活不过三岁——这不是恐怖电影，而是一种叫Menkes病(门克斯病)的罕见遗传病。最近，这个六十多年来无药可医的绝症，终于迎来了首款FDA批准的特效药。身体的“铜线安装工”坏了 如果把人体比作一座精密的电子工厂，铜就是必不可少的“电线”——它负责把能量传递到各个器官。而安装这些电线的“电工”，就是一个叫ATP7A的蛋白质。它的工作是从肠道吸收铜，然后跨过血脑屏障，把铜送到大脑和全身需要的地方。 Menkes病就是因为ATP7A这个“安装工”的基因突变了。铜在肠道里堆积，却进不了血液循环；大脑严重缺铜，导致多种铜依赖的酶活性暴跌。这些酶管着胶原蛋白交联、能量产生、抗氧化防御——一旦失灵，全身系统都会崩溃。 流行病学上，这是个X连锁隐性遗传病，几乎只影响男孩。全球发病率大约在1/10万到1/25万活产婴儿之间，算下来中国每年可能有几十个新发患儿。但实际确诊的往往更少，因为很多孩子在明确诊断前就已经夭折。隐匿的“钢丝发”与漫长的误诊路 典型Menkes病的孩子，出生时看起来正常，甚至头几个月还能微笑、抬头。但转折点通常在2-4个月出现：头发逐渐变稀、褪色，形成特有的“钢丝样”卷曲（医学上叫pili torti）。 同时，肌张力低下、喂养困难、体温不稳定这些非特异性症状也开始显现。真正的危机在神经系统：癫痫发作（从局灶性进展到婴儿痉挛）、发育里程碑倒退、视听觉退化。血管异常、骨质疏松、膀胱憩室等结缔组织问题也接踵而至。 如果不治疗，90%的经典型患儿活不过三岁。诊断的难点恰恰在于早期症状太不典型。很多孩子被误诊为脑瘫、代谢病甚至婴儿痉挛症，辗转多家医院才能确诊。 Zycubo：巧妙绕过遗传缺陷 六十年的等待，在2026年1月12日画上了句号。FDA正式批准了Zycubo（组氨酸铜注射液），这是首款针对Menkes病的特效药。 它的设计思路非常巧妙：既然肠道吸收铜的路径断了，那就直接绕过它。Zycubo是一种生物可利用的铜-组氨酸复合物，通过每日皮下注射，把铜直接送进血液循环。组氨酸就像一辆“专车”，载着铜离子穿过组织屏障，到达需要它的酶系统。 支撑获批的关键临床数据来自两项开放标签的单臂试验。研究对比了早期治疗（出生4周内开始）与未治疗外部对照组的生存差异。 结果令人震撼： 早期治疗组死亡风险降低了78% 中位生存期从17.6个月延长到177.1个月（约14.8年） 近一半早期治疗患儿存活超过6年，部分超过12年 而未治疗对照组无一例活过6年 这个数据虽然来自单臂研究，但生存获益的幅度如此巨大，足以改变疾病的自然史。当然，Zycubo也有局限性：需要终身每日注射；铜可能蓄积产生毒性；常见副作用包括感染、呼吸问题、癫痫等（部分也与基础病相关）。基因疗法：从根源修复 铜替代治疗治标，基因疗法治本。Cyprium Therapeutics与美国国立卫生研究院（NIH）合作，正在开发一种AAV介导的基因疗法——AAV-ATP7A。 它通过病毒载体将正常的ATP7A基因递送到患者细胞，从根源修复铜转运功能。这款疗法已经获得FDA孤儿药认定，临床前数据显示：在动物模型中能恢复铜稳态，改善神经功能。 研究者设想未来可能形成联合治疗方案：先用Zycubo维持生命，等孩子状况稳定后，用基因疗法实现持久治愈。研发挑战与未来机遇 Menkes病的药物研发面临几个核心挑战： 超罕见性：患者数量极少，临床试验招募困难 时间窗口极窄：必须在神经系统损伤前（出生4周内）开始治疗 血脑屏障：如何把铜或基因有效送进大脑 长期安全性：铜毒性监测与管理 但反过来看，这也催生了创新机遇： 新生儿基因筛查普及：随着测序成本下降，越来越多地区将Menkes病纳入筛查panel，有望实现“症状前诊断” 真实世界证据（RWE）应用：对于超罕见病，监管机构越来越接受单臂试验+RWE的组合，加速审批 支付模式创新：Zycubo获批后，其开发商Cyprium获得了罕见儿科疾病优先审评券（PRV），随后以2.05亿美元出售——这种“券经济”为罕见病研发提供了额外资金激励 联合治疗范式：铜替代+基因治疗+支持性护理的多层次方案，可能成为未来标准六十四年的坚持 从1962年John Menkes首次描述这个疾病，到2026年首款药物获批，整整六十四年。这背后是几代研究者、临床医生、患者家庭的坚持，也是转化医学从基础发现到临床应用的一个完整缩影。 今天聊的Menkes病，其实反映了很多罕见病的共同困境：诊断难、患者少、研发投入大。但Zycubo的案例也证明，只要找准病理关键点，科学创新真的能改写‘绝症’的命运。结语 罕见病虽然单个病种患者少，但7000多种罕见病累加起来，全球患者总数超过3亿。每一个疾病的突破，都意味着成千上万个家庭的希望。Zycubo的批准不仅为Menkes病患儿带来了生机，也为其他罕见病的药物研发提供了范例——即使面对最严峻的挑战，科学创新永不放弃。

The trend of increasing priority review voucher sale values comes even as the FDA advances a new initiative called the commissioner's national priority voucher. Only a month after Jazz Pharmaceuticals said it had signed a deal to sell an FDA priority review voucher (PRV) for $200 million, a new PRV transaction involving Fortress Biotech and an unnamed buyer shows that the trend of rising voucher prices is still going strong.Monday morning, Fortress said its subsidiary, Cyprium Therapeutics, has entered into an agreement to sell a recently received rare pediatric disease priority review voucher for $205 million. Cyprium got its hands on the PRV as part of the FDA's recent approval of injected copper replacement therapy Zycubo as the first treatment approved in the U.S. for the rare neurodegenerative disorder Menkes disease.While another company, Sentynl Therapeutics, is handling development and commercialization of Zycubo under a 2023 agreement, the deal called for Sentynl to transfer the PRV back to Fortress/Cyprium after the approval.  Following the Jan. 12 approval of Zycubo, Cyprium wasted no time in striking a PRV sale. The $205 million transaction follows last month's disclosure from Jazz that it had agreed to sell its own PRV for $200 million. Before that, PRV transfers last year ranged between $150 million and $175 million.PRVs are awarded in conjunction with certain rare pediatric disease approvals and enable users to shorten FDA reviews from the agency's standard 10-month window to about six months. For a company with a promising launch waiting in the wings, a PRV could be worth hundreds of millions of dollars in order to help speed a highly anticipated drug to market. In the case of Cyprium and Zycubo, the company said it remains eligible for tiered royalties based on the drug's sales and up to $129 million in milestones. Further, the company stressed that it must pay 20% of the PRV sale proceeds to the Eunice Kennedy Shriver National Institute of Child Health and Human Development.The trend of increasing PRV sale values comes even as the FDA advances a new initiative called the commissioner's national priority voucher. Winners of these vouchers—which are handed out at the agency's discretion based on certain national priorities—are entitled to ultrafast FDA reviews spanning one to two months.The controversial program has already yielded one rejection, with Disc Medicine's bitopertin being spurned earlier this month.

Fortress Biotech and its subsidiary Cyprium have agreed to sell a priority review voucher for $205 million, one of the highest publicly- announced price tags in recent years for the right to a potential regulatory shortcut. Priority review vouchers, or PRVs, are awarded by the FDA to certain companies that develop treatments for rare pediatric diseases. The vouchers may be transferred or sold, and once redeemed, they can shorten the FDA’s standard 10-month review period for a different drug to a target of about six months. Cyprium had received its voucher in connection with the agency’s approval of Zycubo to treat children with a rare neurodegenerative disorder called Menkes disease. Fortress didn’t disclose a buyer, but said 20% of the proceeds will go to the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Sentynl Therapeutics currently holds the development and commercial rights to Zycubo following a 2023 deal that left Cyprium in control of the voucher. Cyprium is also eligible for tiered sales royalties on Zycubo and up to $129 million in development and sales milestones. While PRVs sold for an average of $100 million between January 2020 and July 2024, according to publicly disclosed data assessed by the advisory firm Kybora, prices have risen in recent years. Merck KGaA announced that in September it sold a right to priority review for $175 million. Last month, Jazz Pharmaceuticals said it sold a PRV for $200 million. Earlier this month, President Donald Trump signed a government funding extension that reauthorized the FDA’s ability to issue rare pediatric PRVs into 2029. The program had expired and began to wind down in late 2024.