Trigriluzole

遗传性小脑萎缩共济失调（Hereditary Ataxia, HA）是一组以小脑功能障碍为核心表现的神经退行性罕见病，具有高度异质性——不同亚型的遗传模式、致病机制、临床表型差异显著，这也导致其治疗研发长期面临“精准分型难、靶向给药难”的双重困境。 截至2026年3月，全球HA治疗已从“单纯对症支持”向“疾病修饰治疗”加速突破，尤其是弗里德赖希共济失调（FRDA）已迎来首款疾病修饰药物，脊髓小脑共济失调（SCA）等核心亚型的在研管线也进入关键临床阶段。一、HA核心分型：以遗传模式为基准，聚焦临床常见亚型 HA的分类核心以“遗传模式”为首要依据，结合致病基因、临床特点可分为四大类，其中常染色体显性遗传的脊髓小脑共济失调（SCA）与常染色体隐性遗传的弗里德赖希共济失调（FRDA），占据临床HA病例的80%以上，是研发布局的核心方向。精准基因检测是HA分型的核心前提，尤其是SCA各亚型、FRDA，基因型明确直接决定后续治疗方案选择及在研药物适配性。 遗传模式 代表亚型 致病机制 临床特点 发病率 常染色体显性（ADCA） 脊髓小脑共济失调（SCA）：SCA1、SCA2、SCA3（最常见）、SCA6、SCA7；齿状核红核苍白球路易体萎缩症（DRPLA）；发作性共济失调（EA） SCA：CAG三核苷酸重复扩增（编码多聚谷氨酰胺）；DRPLA：ATN1基因扩增 成年起病为主，渐进性共济失调（步态异常、肢体震颤），可伴锥体束/锥体外系症状、认知障碍 SCA占所有HA的60%，SCA3在中国占SCA病例的45%-55% 常染色体隐性（ARCA） 弗里德赖希共济失调（FRDA）；共济失调毛细血管扩张症（AT） FRDA：FXN基因GAA重复扩增，致frataxin蛋白缺失；AT：ATM基因突变 FRDA：青少年起病，伴心肌病、糖尿病；AT：伴免疫缺陷、肿瘤易感性 FRDA是最常见的隐性HA，全球发病率约1:40,000 X连锁 脊髓延髓共济失调（SMAX1） ATP7A基因突变 罕见，儿童起病，伴铜代谢异常 极罕见，临床病例报道不足百例 线粒体遗传 MELAS、MERRF 线粒体DNA突变 多系统受累，伴乳酸升高、癫痫、肌病 极罕见，多为散发病例 二、全球药物研发格局：上市药物稀缺，在研管线聚焦精准靶向 目前HA治疗仍以“对症支持”为基础，改善共济失调症状、延缓疾病进展；疾病修饰疗法（可逆转/阻断疾病进程）是重点研发方向，其中基因沉默（ASO/RNAi）、小分子靶向、基因疗法已取得突破性进展。1、脊髓小脑共济失调（SCA）：无疾病修饰药，在研管线冲刺中 SCA是HA中最常见的亚型，目前全球尚无获批的疾病修饰药物，仅日本有一款对症治疗药物上市；在研管线以“基因沉默技术”和“小分子神经保护”为核心，聚焦SCA3等高发亚型，多个药物进入临床关键阶段。 药物名称 研发公司 作用机制 适应症 研发状态 他替瑞林（Taltirelin/Ceredist） 日本味之素 促甲状腺激素释放激素（TRH）类似物 SCA、脊髓小脑变性 日本获批（2000年） FY015A 中国安天圣施 反义寡核苷酸（ASO），沉默突变ATXN3 mRNA SCA3 中国IIT临床（首例给药2024.6） CRD-002 Cure Rare Disease ASO，沉默突变ATXN3基因 SCA3 临床前 AMT-150 uniQure AAV递送miRNA，沉默突变ATXN3 SCA3 临床I/II期筹备 Troriluzole（VYGLXIA） Biohaven 第三代利鲁唑前药，增强谷氨酸清除 SCA1/2/3/6/7等多亚型 NDA被FDA拒绝（2025.11），计划补充数据重提2、弗里德赖希共济失调（FRDA）：唯一有疾病修饰药上市 FRDA是目前HA中唯一有获批疾病修饰药物的亚型，2022年首款药物上市后，多款在研药物进入后期临床，2026年有望迎来第二款上市药物，治疗格局逐步完善。 药物名称 研发公司 作用机制 研发状态 关键节点 奥马佐洛酮（Omaveloxolone/Skyclarys） Reata Nrf2激活剂，抗氧化、抗炎 FDA/EMA获批（2022年） 首个FRDA疾病修饰药物，可显著改善患者运动功能 Nomlabofusp（CTI-1601） Larimar 重组融合蛋白，靶向递送frataxin蛋白，线粒体铁代谢 临床III期 FDA授予突破性疗法（BTD），2026年6月计划提交BLA，寻求加速批准 DT-216 Design Therapeutics 小分子，增强FXN基因剪接 临床I/II期 2026年下半年公布多剂量研究数据 EPI-743 PTC Therapeutics 抗氧化剂，减轻线粒体氧化应激 临床III期 重点评估运动功能与心肌病改善效果3、其他罕见亚型：研发滞后，多处于临床前阶段除SCA、FRDA外，DRPLA、共济失调毛细血管扩张症（AT）、发作性共济失调（EA）等亚型因发病率极低，研发布局相对滞后，目前尚无上市药物，仅少数早期项目在研发中。 三、总结与展望目前HA研发的核心方向集中在两大领域：一是基因沉默技术（ASO/RNAi），精准靶向突变基因，从根源阻断毒性蛋白产生，是SCA、DRPLA等亚型的核心研发路径；二是小分子药物，以“线粒体功能修复”（FRDA）、“神经兴奋性毒性抑制”（SCA）为主要策略，兼顾安全性与可及性。2026年将是HA治疗研发的关键一年：Nomlabofusp有望成为第二款FRDA上市药物；Troriluzole补充临床数据后或重新提交NDA，有望填补SCA疾病修饰药空白；国产SCA3 ASO药物FY015A将推进临床数据读出，助力国产罕见病药物研发。遗传性小脑萎缩共济失调作为罕见病领域的“难治性疾病”，近年来随着基因编辑、RNAi等技术的发展，研发格局已实现从“无药可治”到“有药可期”的转变。2026年，随着多款核心在研药物的临床推进，有望进一步打破治疗困境，为全球HA患者带来新的希望。 往期精选：1、继ADC之后的下一个新赛道：全球临床阶段的抗体核酸偶联药物（AOC）玩家大盘点！2、一文读懂AOC（Antibody-Oligonucleotide Conjugator）：抗体核酸偶联药物的作用机制与研发困局!3、2026年前两月FDA批准首次进入临床一期的5款小分子药物全解析：涵盖炎症、肿瘤、神经退行性疾病！4、2026，FDA获批新药预测TOP10：基于最新三期临床数据，这些药物将改写临床治疗格局！5、国产KRas G12C四强争霸？从药物设计到临床疗效，一文读懂四款新药的前世今生！

By 2032, rare disease drug sales will account for more than 21% of all prescription drugs, up from 15% in 2022, according to Evaluate's 2026 Orphan Drugs Report. The rare disease field is navigating a period of significant turbulence, caught between a “temperamental” FDA and competition for investor attention from mainstream blockbusters like obesity treatments. Yet, despite the “stormy waters,” global sales of orphan drugs are projected to grow and exceed $400 billion by 2032, according to the newly released 2026 Orphan Drugs Report from Evaluate.The massive $409 billion that rare disease treatments are forecast to generate in annual revenue represent more than 21% of the nearly $1.9 trillion in global prescription medicines sales worldwide in 2032. That marks an increase from 15% in 2022, according to the new report published Thursday, March 12. While the outlook is bullish, the journey to $400 billion is likely anything but a straight line. Despite a few recent policy wins such as an updated Inflation Reduction Act (IRA) exception and the reauthorization of the rare pediatric disease priority review voucher program, the market remains vulnerable to a more scrutinizing FDA and potential pricing pressures. Charting the growthTen existing therapies are expected to lead the pack as the bestselling orphan drugs in 2032, with eight of them projected to rake in more than $6 billion in annual sales each. Johnson & Johnson is poised to wear the orphan drug crown both as a company and from a product perspective.The company’s multiple myeloma therapy Darzalex (daratumumab) is projected to be the top-selling orphan drug with $11.8 billion in sales. While that marks a decline from the drug’s $14.4 billion sales in 2025, a subcutaneous formulation is extending its market exclusivity, effectively doubling the franchise’s commercial lifespan.J&J’s position is further bolstered by Legend Biotech-partnered multiple myeloma CAR-T therapy, Carvykti, which secures the No. 8 spot with $6.3 billion in forecast sales.Thanks to those meds, J&J will claim the title as the biggest company by orphan drug sales, with nearly $31 billion in projected revenue from this category in 2032, according to Evaluate.  Vertex is the other company with two drugs on the top 10 list. The Boston biotech’s Alyftrek, a once-daily triple combination for the treatment of cystic fibrosis, is poised to become the second-highest-selling orphan drug globally, with $9.3 billion in projected sales by 2032. Meanwhile, the firm’s older Trikafta will take the final spot with $4.9 billion in sales. Alnylam’s fast-growing transthyretin amyloidosis (ATTR) RNA interference drug Amvuttra (vutrisiran) is tipped to take third place, with $7.5 billion in 2032 sales. There have been some questions around the growth potential of the drug—and the entire ATTR market—given the expected loss of market exclusivity for Pfizer’s first-in-class tafamidis.  Perhaps the most dramatic shift in the rankings is the rise of argenx. Dubbed a “gate-crashing” force, argenx is forecast to displace Pfizer in the orphan drug sales rankings in 2032, driven by the successful launch of the autoimmune drug Vyvgart (efgartigimod alfa). The $11.2 billion in projected total orphan drug sales put the Dutch biotech in 8th place among companies, ahead of Merck & Co. ($9.9 billion) and Bristol Myers Squibb ($9.7 billion). Argenx also holds the distinction of being the only firm on Evaluate’s list with 2032 revenue derived entirely from orphan drugs. AstraZeneca’s complement inhibitor Ultomiris, Merck’s pulmonary arterial hypertension med Winrevair, BeOne Medicines’ blood cancer drug Brukinsa and Roche’s hemophilia A therapy Hemlibra round out the top orphan drugs list.Among the 10 companies, Merck boasts the fastest orphan sales increases, at 23% compound annual growth rate between 2025 and 2032, followed by argenx’s 22%.In contrast to an overall share gain of orphan drugs in the entire pharmaceutical market, their footprint in the R&D pipeline is beginning to shrink. Evaluate analysts expect the percentage of rare disease candidates in development within overall drug sales to fall from a projected peak of 30% in 2027 to 22% in 2032. “This likely reflects growing interest and investment in big drugs for big diseases—including most prominently GLP-1 based therapies,” Evaluate analysts noted. As large pharmas face a collective $300 billion patent cliff by the end of the decade, the need to develop drugs for large indications remains high, the team added. Policy pushes and pullsJ&J’s Darzalex and argenx’s Vyvgart get to protect their hefty sales outlooks thanks, in no small part, to a recent IRA revision. Under the original IRA, only drugs with single orphan indications were exempt from U.S. government price negotiations. As part of President Donald Trump’s One Big Beautiful Bill Act, the provision has expanded the orphan exemption to cover drugs with multiple indications. In another significant amendment that favors the industry, the countdown toward eligibility for price reduction under the IRA won’t start until after the first non-orphan approval.However, the regulatory environment has recently become unpredictable for rare disease drug developers, no thanks to what Evaluate calls “mixed signals” from the FDA.While the FDA has introduced the “plausible mechanism pathway” to accelerate individualized therapies targeting genetic abnormalities behind rare diseases, the agency has also turned down several rare disease drugs, fueling industrywide outcry. Prominent among these rebuffs is uniQure’s Huntington’s disease gene therapy candidate, AMT-130. The one-time therapy showed a 75% reduction in Huntington’s disease progression three years after treatment when compared with external control. However, after uniQure said in 2024 that it had reached an agreement with the FDA to use the external control design to seek an accelerated approval, the agency has recently rejected that plan, demanding instead an internal sham-controlled study to support an application. In two other recent rebuffs against rare disease candidates that also involve the use of external controls, the agency declined to approve Regenxbio’s Hunter syndrome gene therapy and rejected Biohaven’s troriluzole in spinocerebellar ataxia.In a recent interview with Fierce Biotech, Biohaven CEO Vlad Coric, M.D., decried a “systemic problem” at the FDA and warned of a “dire time” for rare disease patients.Following the FDA’s controversial moves, Republican Sen. Ron Johnson of Wisconsin has launched an investigation into the agency’s rejections for rare disease drugs. And FDA official Vinay Prasad, M.D., who leads the agency’s Center for Biologics Evaluation and Research overseeing gene therapies, is stepping down at the end of April. Despite the regulatory uncertainties, Evaluate analysts argue the fundamentals of the orphan drug sector remain “steady,” and that the “core drivers of orphan drug R&D remain strong.” These incentives include law-encoded tax credits and market exclusivities. Besides, the rare disease market remains largely untapped, as today’s orphan drugs only address roughly 5% of all rare conditions, the Evaluate report noted. That doesn’t mean there is no additional volatility ahead. As more rare disease drugs reach the market at high prices, payers face increased pressure to control costs.China’s rise as a biotech powerhouse might worsen the pricing pressure if molecules licensed from China add more competition, Evaluate warns. “Renewed investor interest in biopharma, after a multiyear downturn, may mitigate pricing and policy uncertainty around orphan drugs,” the analysts wrote in the concluding paragraph. “But those questions could just as likely send investors flocking to what they know: tried and tested modalities in much bigger markets.”