Arimoclomol

中国药科大学尤启冬教授 2024年首创性小分子药物研究实例浅析 来源 《药学学报》2025年 作者 王磊，尤启冬 中国药科大学, 江苏省创新药物设计与成药性优化重点实验室； 中国药科大学药学院药物化学系 摘要 2024年新药研发持续发力, 首创性药物的上市数量再创新高。美国FDA药物评价和研究中心在过去一年里共计批准了50款新药, 其中包括30款小分子药物及20款大分子药物。新药总数相比2023年的55款略有下降, 但首创性药物占比明显增加。本年度获批24款首创性药物(48%), 涵盖13款小分子首创性药物和11款大分子首创药物, 多数集中于肿瘤、内分泌及代谢疾病领域。其中, 多个首创性小分子药物具有突破性的临床价值, 例如首个M1/M4毒蕈碱受体激动剂/外周毒蕈碱受体拮抗剂呫诺美林/曲司氯铵, 首个甲状腺素受体β亚型激动剂瑞司美替罗, 首个用于高血压治疗的内皮素受体A及内皮素受体B受体双重拮抗剂阿普昔腾坦等。首创性药物具有巨大的临床价值、学术价值及商业价值, 受到来自患者、研究人员及企业的广泛关注。本文通过药物化学角度浅析本年度3个代表性首创性小分子药物的研发背景、研发过程和治疗应用, 以期为首创性药物的研发提供更多的研究方向与方法。 关键词 首创性药物; 新药研发; 小分子药物 _ 正文 _ 新药研发在保障人民健康、推动科技创新、促进经济发展等多个方面具有重要意义。按照新药的创新程度划分, 已上市的新药主要可以分为首创性药物(first-in-class)和跟随性药物(me-too, me-better)。首创性药物是指通过全新的、独特的作用机制来治疗疾病的药物, 可以为药物研发指明方向, 为深入的科研探索提供驱动力, 更重要的是为患者提供更多的治疗选择。目前, 许多复杂疾病存在无药可用、机制未知或频繁耐药等问题, 使患者缺乏有效的治疗方案。这些长期未满足的临床需求激励着药物研发人员不断积累经验, 探索未知的疾病机制, 思考创新的药物设计方法, 整合临床用药经验, 为人民健康和生活质量的提升带来福祉。 2024年, 美国FDA药物评价和研究中心(Center for Drug Evaluation and Research, CDER)共批准上市新药50款, 包括30款小分子药物及20款大分子药物, 相较于去年的55款新药略有下降。首创性药物的获批数量相较去年(20款)有所提高, 今年共批准了24款首创性药物, 占获批药物总数的48%。从获批新药的疾病适应症上看, 肿瘤仍是药物研究的主攻方向, 有17款抗肿瘤药物进入市场, 占总数的34%, 相较于2023年(13款药物, 占比24%)数量和比例均在上升。紧随其后的是内分泌与代谢疾病, 今年在该领域内共有8款药物获批, 占比为16%; 用于血液疾病治疗的新药数量位居第3位, 有7款药物被批准上市, 占比为14%; 而新药上市数量一直位居前列的神经疾病领域在今年仅有3款药物上市, 占比为6%。在疾病靶点方面, 以酶为靶点的药物获批数量持续领跑, 有16款药物上市, 占比为32%, 紧随其后的是GPCR受体, 有7款药物上市, 占比为14%。根据美国FDA的官方文件, 今年获批上市的孤儿药总数仍较高, 有26款药物上市, 占比为52%, 有18款药物被美国FDA授予突破疗法, 有28款药物(56%)被优先审批, 7款药物(14%)被加速审批进入市场, 有34款药物(68%)首次在美国FDA获批上市(www. fda. gov)。 在2024年上市的24款首创性药物中, 有13款是首创性小分子药物(表1), 数量和2023年持平, 有多款首创性小分子药物值得关注, 例如1月5日批准的首款用于传染性软疣治疗的局部使用处方药柏达姆钠(berdazimer sodium); 3月14日批准的首款用于由脂肪肝疾病导致的肝脏瘢痕治疗的药物瑞司美替罗(resmetirom); 3月19日批准的首款治疗高血压的内皮素受体亚型(endothelin receptor A/B, ETA/B)双重拮抗剂阿普昔腾坦(aprocitentan); 3月21日批准的首款用于杜氏营养肌不良的组蛋白去乙酰化酶(histone deacetylases, HDACs)抑制剂吉维司他(givinostat); 3月29日批准的达尼可泮(danicopan)则是继2023年首款补体因子B抑制剂上市后的该通路的又一首创性药物, 该药与首款补体因子D抑制剂同样用于阵发性睡眠性血红蛋白尿的治疗; 6月6日批准的首款端粒酶抑制剂伊美司他(imetelstat), 用于治疗低至中危骨髓增生异常综合征; 9月20日批准的罕见病尼曼匹克病(Niemann-Pick disease, NPD)的首款疗法阿莫氯醇(arimoclomol); 9月26日批准的首款M1/M4毒蕈碱受体激动剂/外周毒蕈碱受体拮抗剂呫诺美林/曲司氯铵(xanomeline and trospium chloride), 用于治疗精神分裂症以及阿尔茨海默症引起的精神失调症; 12月13日批准的首款口服选择性促肾上腺皮质激素释放因子1型受体(corticotropin-releasing factor 1, CRF1)拮抗剂可瑞舍封(crinecerfont), 用于罕见病典型先天性肾上腺皮质增生症的治疗。其中有一些药物实现了在重大疾病治疗中的首次突破, 也有许多药物开辟了疾病治疗的新靶点新选择, 本文从中选取了3个有代表性的首创性小分子药物, 全面阐述药物的研发背景、研发过程及临床治疗应用, 希望为未来的药物设计提供更多研究思路。 1 呫诺美林/曲司氯铵(xanomeline and trospium chloride) 呫诺美林/曲司氯铵是全球首款M1/M4毒蕈碱受体激动剂/外周毒蕈碱受体拮抗剂组合药, 用于治疗精神分裂症以及阿尔茨海默症引起的精神失调症。 1.1 研发背景 精神分裂症是一种严重的神经疾病, 临床表现主要包含阳性症状和阴性症状, 也有2/3患者会产生不同程度的认知损伤。阳性症状指妄想、幻觉和思维障碍等疾病特征, 阴性症状则主要表现为缺乏意志力、言语输出减少以及情绪体验和表达减少, 精神分裂症患者往往与社交冷漠、不良生活习惯、高失业率以及降低的生活期待相联系, 给社会经济发展及个人生活质量带来沉重的负担。 该疾病同时也是全球性疾病, 影响着全球1%的人口, 在男性中更为普遍。相关的疾病症状一般出现在青春期晚期或成年早期, 造成疾病的原因主要涉及遗传因素、环境因素以及某些神经因子的影响例如多巴胺、γ-氨基丁酸和谷氨酰胺。现有的精神分裂症治疗药物主要是多巴胺D2/3受体的阻断剂, 尽管该类药物对许多患者的精神症状是有效的, 但是对阴性症状及认知损伤疗效有限且带有不同程度的不良反应, 已有15%~30%的患者产生了耐药性抵抗, 新机制药物亟待被开发用于疾病治疗。 1.2 研发过程 针对多巴胺D2/3受体的阻断剂的缺陷和精神分裂症患者未满足的临床需求, 新机制疗法, 例如痕量胺相关受体1(trace amine associated receptor1, TAAR1)激动剂, 毒蕈碱乙酰胆碱受体(muscarinic acetylcholine receptors, mAChR)激动剂、代谢型谷氨酸受体2/3(metabotropic glutamate receptor2/3, mGLuR2/3)激动剂、甘氨酸I型转运蛋白(glycine transporter1, GlyT1)抑制剂以及Kv3.1和Kv3.2钾离子通道调控剂等不断被开发出来用于疾病治疗。其中, mAChR激动剂是其中进展较快的疗法之一, 有多款候选药物进入临床评价阶段。 mAChR包含5个亚型(M1~M5), 属于GPCR受体, 作为抑制性自身受体发挥作用, 减少对中脑多巴胺神经元的刺激性胆碱能输入, 从而抑制下游多巴胺神经传递, 使用特异性激动剂增加这些受体的传递可能会间接地减少异常多巴胺信号传导。尽管抗精神病药物发挥治疗效果的具体机制还未完全明确, 但是已有大量的实验表明对受体M4亚型的作用能够诱导在腹侧被盖区(ventral tegmental area, VTA)及黑质区域(substantia nigra, SN)的多巴胺神经元去极化阻断或失活，激动在胆碱能中间神经元的M4受体也可以减少乙酰胆碱的释放最终抑制多巴胺末端的激活。M1受体的激动作用在精神分裂症的治疗中也是不可忽视的, M1受体可以调节突到VTA DA神经元自上而下的回路, 对M1的激动会促进抑制性的GABAergic中间神经元的活动, 激动锥体神经元, 降低谷氨酸肽输入到VTA, 导致VTA中多巴胺神经元的抑制(图 1A)。 Figure 1 Discovery and development of xanomeline and trospium chloride. A:Mechanism of xanomeline and trospium chloride; B: Discovery and structure-based optimization of xanomeline 传统的mAChR激动剂受限于其亚型选择性在临床研究中屡屡受挫, 对M2或M3的额外激动作用往往引发一系列不良反应, 因此开发对M1和M4具有高度选择性的mAChR激动剂尤为重要。2024年上市的Cobenfy是呫诺美林/曲司氯铵(xanomeline and trospium chloride)复方用药, 药物组合中的呫诺美林(xanomeline)就是M1和M4的选择性激动剂, 该药物最初是将arecoline作为先导化合物设计出来的。Arecoline(1)是临床研究失败的M1激动剂, 该分子包含一个1位被甲基取代的1, 2, 3, 6-四氢吡啶环及一个共轭的酯基, 研究人员对羧酸酯基用不同的芳香杂环的电子等排体替换得到了3位被R基取代的吡嗪系列(2)、1, 2, 5噁二唑系列(3)和1, 2, 5-噻二唑系列(4)化合物, 将上述的杂环换成噁唑或呋喃, 都会导致活性的减弱, 而R基则是不同长度的饱和直链烷氧基、直链烷巯基或直链烷氨基, 经过对链长和杂原子的替换, 得到了体外活性较好的烷基长度为6的烷氧基取代化合物5, 其IC50值为9.7 nmol·L-1, 继续延长碳链长度则会导致活性下降。研究人员还发现当烷氧基长度固定时, 对M1受体的体外活性顺序为1, 2, 5-噻二唑系列>吡嗪系列>1, 2, 5-噁二唑系列化合物。3位侧链R基长度为4~6的1, 2, 5-噻二唑化合物展现了最佳的M1受体选择性, 其中化合物5在用于表征M1受体激动活性的家兔电刺激抽搐反应模型中测得的对家兔抽搐反应的最大抑制率及IC50分别为94%和0.008nmol·L-1, 而在表征M3受体激动活性的豚鼠模型中最大抑制率仅为20%, IC30>27000 nmol·L-1, 显示了良好的选择性, 后续的实验中进一步确证了该化合物对M1/M4受体的强激动效应(M1 EC50=67.3±13nmol·L-1, M4 EC50=229±155 nmol·L-1)。该化合物即为药物分子呫诺美林, 在2024年9月26日被美国FDA批准进入市场(图 1B)。 1.3 治疗应用 呫诺美林/曲司氯铵是首创性的毒蕈碱受体激动剂和毒蕈碱拮抗剂联合用药, 用于治疗精神分裂症以及阿尔茨海默症相关的精神失调。其中M1/M4受体激动剂呫诺美林可以透过血脑屏障, 改善与精神分裂症和阿尔茨海默症相联系的精神疾病症状及认知损伤, 并且区别于传统的多巴胺受体阻断剂, 该激动剂不会直接影响多巴胺受体, 但是由于对外周毒蕈碱受体的激动作用会引发胃肠道不良反应。而曲司氯铵恰好是不能透过血脑屏障只在外周组织发挥非选择性毒蕈碱受体拮抗作用的药物分子, 两者的结合既可以保持呫诺美林的疗效又可以缓解其不良反应, 起到药效互补的治疗效果。 文章内容由凡默谷小编查阅文献选取，排版与编辑为原创。如转载，请尊重劳动成果，注明【来源：凡默谷公众号】。 2 阿普昔腾坦(aprocitentan) 阿普昔腾坦是全球首款用于高血压治疗的ETA及ETB受体双重拮抗剂。 2.1 研发背景 高血压是全球所有心血管疾病中的最重要的易变风险因素, 现有的治疗药物主要涵盖血管紧张素II受体阻断剂、血管紧张素转换酶抑制剂、钙离子通道阻断剂及利尿剂等, 有大约10%的患者在服用抗高血压药后仍然会经受血压升高的风险和危害, 即患有顽固性高血压。临床上利用现有药物控制血压所面临的困境表明血压升高的相关疾病通路及抗高血压的治疗靶点仍然值得继续探索。 内皮素(endothelins, ET)是维持血管张力和整体心血管稳态的心血管功能调节因子, 人体的内皮素肽主要分为3类ET-1、ET-2及ET-3, 通过激活内皮素受体的两个亚型ETA及ETB发挥作用。其中ET-1在心血管系统中起效, 而ET-2及ET-3则相对集中表达在胃肠道和大脑。不同于其他的血管调节因子例如血管紧张素II, ET-1分布更加广泛并且效果持久, 主要负责调节血管功能和血液流动, 其激动ETA时会导致血管的收缩, 另外还会诱发多种细胞系的增殖, 引起炎症和纤维化。在心脏, ET-1充当旁分泌肥大因子, 成纤维细胞产生的ET-1通过ETA受体结合还能诱导心肌细胞肥大。而激动ETB时会促进以一氧化氮为主的血管扩张剂的释放, 并且还能诱导ET-1的移除, 从而反馈调节ETA激动所引起的血管收缩。与激活ETA和ETB相反的是, 抑制ETA和ETB会导致血管舒张。此外, 研究还发现ETA及ETB的双重阻断可以发挥抗炎和抗纤维化作用, 并促进心肌肥大的逆转, 这进一步表明了ETA及ETB受体双重拮抗剂在高血压治疗的明显优势, 值得继续研究并发展不同于以往机制的抗高血压药物(图 2A)。目前, 已有一些内皮素受体拮抗剂正在被探索用于反复发作的高血压及各种肾脏疾病的治疗。 2.2 研发过程 阿普昔腾坦(aprocitentan)是已上市的ETA及ETB受体双重拮抗剂马昔腾坦(macitentan)的活性代谢产物。马昔腾坦是由同为ETA及ETB受体双重拮抗剂的药物分子波生坦(bosentan, 6)作为先导化合物进行结构改造而发现的一系列烷氨磺酰氨基取代的嘧啶类化合物(图2B)。化合物6对ETA及ETB受体具有较高的亲和力, 活性达到纳摩尔级。在化合物6中心嘧啶环的4位乙二醇末端引入新的嘧啶环得到化合物7。化合物7中新引入的嘧啶环可以与TYR129及TRP319两个氨基酸残基形成π-π相互作用后提升活性, 对ETA及ETB的活性相较于6分别提升了10和3倍。继续引入溴原子以及对结构中苯磺酰氨基侧链改造得到化合物8, 活性得到保持, 新引入的溴原子会与ASP126形成额外的卤键(图2C)。在化合物8的基础上去除中心嘧啶环2位嘧啶取代基, 得到的化合物9, 化合物9的亲和力并没有产生明显变化, 说明2位取代基对分子亲和力的贡献并不大。为了降低分子质量, 将化合物9的磺酰氨基侧链烷基上的芳环替换成长链的饱和烷基, 并用4-溴代苯环替换结构中的2-甲氧基苯氧基得到了化合物10。化合物10中的4-溴代苯环与TRP319、VAL169、HIS323以及LEU259等氨基酸残基形成疏水相互作用, 该化合物在体内活性测试中表现了较好的降压效果, 该化合物即为马昔腾坦。马昔腾坦在体内发生N-脱烷基代谢得到主要活性代谢产物11, 即为今年新上市的ETA及ETB受体双重拮抗剂阿普昔腾坦。 Figure 2 Discovery and development of aprocitentan. A: Discovery and structure-based optimization of aprocitentan; B: Co-crystal structure of ETA inhibitor; C: Mechanism of aprocitentan. Maximal mean arterial blood pressure reduction as extracted from the moving average over 6 h. Area between curve (ABC) as calculated from the blood pressure recordings 24 h before and after administration of 3 mg·kg-1 of the compound to conscious hypertensive Dahl salt-sensitive rats; max ΔMAP = maximal reduction in mean arterial blood pressure; n = number of animals in the experiment 2.3 治疗应用 阿普昔腾坦是具有口服活性的ETA及ETB受体双重拮抗剂, 半衰期为44h, 较少出现药物−药物相互作用。在一项III期临床(NCT03541174)中, 阿普昔腾坦在对患有顽固性高血压患者超过48周的治疗中, 血压得到了明显降低及持续性控制, 其被认为是一种针对顽固性高血压行之有效且具有良好耐受性的新疗法。虽然阿普昔腾坦作为顽固性高血压的新机制疗法得到了美国FDA的批准, 但是相较于其他抗高血压药物, 其心脏保护作用、与其他药物联用的效果及水肿等不良反应仍然值得进一步评估, 而其临床地位也需要在应用于各级高血压之后才能确定。 3 瑞司美替罗(resmetirom) 瑞司美替罗是全球首款用于由脂肪肝疾病导致的肝脏瘢痕治疗的药物。 3.1 研发背景 代谢相关脂肪性肝炎(metabolic dysfunction-associated steatohepatitis, MASH), 曾称为非酒精性脂肪性肝炎(non alcoholic steatohepatitis, NASH), 由过量的脂肪细胞堆积在肝脏中所引发, 会导致炎症、瘢痕及肝脏疾病的恶化等不良危害, 甚至更易诱发肝癌。目前该病影响着全球1.5%~6.45%的人口, 其诱发因素复杂多样, 包括不同患者的代谢情况、基因遗传因素、肠道菌群及环境因素等。该病也往往与高血压及2型糖尿病相关联, 对该疾病的治疗策略主要集中在血糖、血脂控制, 以及体重减轻这3个方面, III期临床的评价终点是逆转肝纤维化或者实现肝脏脂肪酸控制, 在此之前, 美国FDA并未批准过有关该病的任何疗法, 肝移植是该疾病的主要治疗方式之一, 通过调整饮食结构和锻炼来改变生活方式也能影响疾病进展, 但长期以来未满足的临床需求仍亟待有效的治疗药物获批(图3A)。 Figure 3 Discovery and development of resmetirom. A: Mechanism of NASH; B: Function of THR-β; C: Discovery and structure-based optimization of resmetirom 3.2 研发过程 甲状腺激素调节着肝脏中甘油三酯的合成、脂肪酸的β氧化、肝鞘脂和磷脂代谢, 以及胆固醇代谢等许多过程, 其发挥功能主要依赖于两个受体亚型即甲状腺激素受体α及β(THR-α/β), 其中甲状腺激素受体β主要集中表达在肝脏, 在肝脏脂质代谢中发挥重要作用。已有临床数据表明NASH患者的甲状腺功能减退症状比一般人群要更显著, 其肝脏的甲状腺激素水平更低, 目前该受体亚型已成为NASH的潜在治疗靶点。 瑞司美替罗(resmetirom)作为首个上市的THR-β激动剂, 其结构优化是从化合物12开始, 减少富电子的芳环, 因为富电子芳环可能会带来潜在的代谢和安全性问题。化合物12的选择性并不佳, 对甲状腺激素受体α和β亚型的亲和力接近(THR-α IC50=0.01 μmol·L-1, THR-β IC50=0.015μmol·L-1)。通过将苯环用吡嗪酮环进行生物电子等排体替换, 并将结构中的碘取代替换为了氯取代, 为了降低分子的极性将侧链上的氨基移去得到了吡嗪酮类化合物13, 该化合物对两种受体亚型的选择性有所改善, 但是亲和力不佳。后续改造中将两个芳环之间的氧连接替换为C或S连接, 氯取代基改为溴, 发现轻微的改造并不能对亲和力带来明显改善。研究中发现化合物12侧链的氨基对化合物的活性有较大影响, 故对化合物13进行了较大结构变化的优化, 在苯环上乙酸基取代的位置换成了氰基取代的1, 2, 5-三嗪得到了化合物14, 活性和选择性均得到了较大的提升(THRα IC50=3.74 μmol·L-1, THR-β IC50=0.21 μmol·L-1), 该化合物即为被批准上市的药物分子瑞司美替罗。 3.3 治疗应用 瑞司美替罗作为美国FDA批准的首个治疗NASH的药物, 其重要性和开创性意义不言而喻。在III期临床试验中, 该药物分子能够减少肝脏脂肪含量并缓解肝脏纤维化, 对NASH有明显的治疗效果, 同时还能改善与该疾病相关联的肝脏瘢痕, 并且该药物没有因为THR-α激动而产生的毒副作用。此外, 该药物能降低动脉粥样硬化脂质/脂蛋白的比例, 即降低了NASH患者诱发心血管疾病的风险, 后续还会继续评估该药物长期用药对肝脏的治疗效果。值得注意的是, 尽管瑞司美替罗在临床上对NASH有效, 但是仅仅只有25%~30%的受试患者产生了积极的治疗效果, 对NASH治疗药物的研究仍任重道远。 4 结语与展望 除了上文中浅析的首创性小分子药物, 本年度批准上市的新药还有多款值得深入挖掘和分析, 例如, 显像药物氟[18F]比哒嗪(flurpiridaz F18)是用于心肌缺血和梗死诊断评估的新型正电子发射断层扫描心肌灌注成像示踪剂; IDH1/2双重抑制剂伏昔尼布(vorasidenib)则是几十年来首个用于神经胶质瘤治疗的新分子, 预测该药物的市值顶峰能达到2亿美元。首创性药物或重磅药物的上市不仅可以为原创企业带来丰厚的经济利润, 更能代表生物医药领域的重大突破, 能给患者带来全新的治疗选择和治疗效果。 根据国家创新药品名录(https: //www. nmpa. gov. cn/zhuanti/cxylqx/cxypxx/index. html), 2024年度共有43款创新药进入中国市场, 涵盖22款小分子药物、15款大分子药物、3款中药, 以及3款皮肤点刺液。从疾病领域来看, 中国国家药品监督管理局批准的药物中抗肿瘤药物获批数量最多, 有17款药物是抗肿瘤药物, 占比39.5%。在作用靶点方面, 则是以酶为靶点的药物数量最多, 有19款药物以酶为靶点, 占比为44.2%。国产药物也在本年度获得持续突破, 全球首个针对肺癌脑转移的EGFR-TKI(epidermal growth factor receptor-tyrosine kinase inhibitor), 国产创新药佐利替尼(zorifertinib)于2024年11月20日在国内获批上市; 6月18日上市的国内自主研发的JAK-1(Janus kinase 1)抑制剂, 戈利昔替尼(golidocitinib)则是全球首个且唯一靶向JAK-STAT通路治疗复发性或难治性外周T细胞淋巴瘤的药物。近年来, 国产创新药在首创性药物研发中不断崭露头角, 呈现良好的创新药发展态势, 期待在生物医药领域有更多的中国声音、中国力量为人类公共健康事业做出更大的贡献。  喜欢我们文章的朋友点个“在看”和“赞”吧，不然微信推送规则改变，有可能每天都会错过我们哦~ 免责声明 “汇聚南药”公众号所转载文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请在留言栏及时告知，我们会在24小时内删除相关信息。 信息来源：凡默谷公众号 往期推荐 本平台不对转载文章的观点负责，文章所包含内容的准确性、可靠性或完整性提供任何明示暗示的保证。

iStock, Orla Congress did not reauthorize the rare pediatric disease priority review program at the end of 2024. Advocates say the ripple effect is already being felt across biopharma. The FDA has never handed out more priority review vouchers than it did in 2024. Depending on who you ask, that’s a sign that the program is working or that pharma is reaping huge benefits in a quid pro quo situation of the government’s own making. But now rare disease biotechs have been left scrambling, as Congress did not renew the rare pediatric disease portion of the program at its end of year deadline despite bipartisan support. “The impact on the rare disease drug developers and the investment community [is] already being felt because of the destabilizing effect of the failure to reauthorize the program prior to its expiration,” Stacey Frisk, executive director of the Rare Disease Company Coalition, told BioSpace in an interview. Her group is lobbying for a renewal to be tacked on to congressional efforts to address a looming March 14 budget deadline. “So really, the timeline is as soon as possible.” The priority review voucher (PRV) rare disease program, which began in 2012, had unanimous renewal support from the 118th Congress, which ended on Jan. 3, according to Frisk. The program passed the House without issue and was listed among the priorities for the resolution to avoid a government shutdown. But the health programs that included the PRV program—which had already begun to sunset—were stripped from the continuing resolution at the last minute. Despite the bipartisan support, the PRV program “got caught” as Congress’ timelines and priorities changed at the last minute, Matthew Winton, chief operating officer of Inozyme Pharma and a rare disease advocate , told BioSpace . A bill called the Give Kids a Chance Act of 2024 has now been proposed to get the PRV program moving again, as Congress works to avoid the shutdown. “Time is . . . sort of running out,” Winton said. “We need action on this immediately to continue the program but also continue investment in these pediatric rare diseases.” The FDA notified drugmakers in the fall that, absent the renewal passing, the agency would have to stop handing out the coveted fast-pass vouchers, which expedite the drug review timeline from 12 months to about 6 . The vouchers can be bought and sold, which provides a valuable fundraising boost for tiny rare disease biotechs. The current going rate on the open market is $150 million, the price Zevra Therapeutics earned just last week for its voucher that was granted from the September 2024 approval of Miplyffa. According to Winton, the cost of PRVs has risen to this rate as companies foresee the end of the program. Without renewal, the FDA began sunsetting the program as of December 20, 2024. The agency cannot award any new vouchers unless the drug already had the rare pediatric disease designation. If Congress does not act, companies with existing designations will only have until September 30, 2026, to get their drugs approved in order to earn a voucher. Already, companies with the rare pediatric disease designation for drugs in development are reeling, with many starting to warn investors in Securities and Exchange Commission filings that they may never get their coveted vouchers despite working for years to position for one. Winton said that companies make decisions to develop a drug years in advance, so having the rug pulled out suddenly due to a policy change can halt external investment. “With that uncertainty, you’re going to get a slowdown in decision making. You’re going to get a slowdown in people investing in R&D programs,” Winton said. See BioSpace ’s full analysis here . Quid Pro Quo The industry has spent at least $513 million on buying vouchers that were earned in 2024, although more could have been sold without public disclosures. These non-dilutive proceeds are often used by smaller companies to bolster their overall clinical programs. In a recent case that underscores the stakes, bluebird bio fought hard to get one for its sickle cell disease gene therapy Lyfgenia, which was approved in December 2023 . Bluebird had already lined up a buyer before it even received the approval, according to SEC documents dated October 2023. Novartis agreed to pay $103 million for the voucher if it were granted. While bluebird was granted rare pediatric disease designation in May 2020 for the treatment, the FDA did not hand out the coveted voucher. Bluebird appealed and was ultimately rejected three times. The agency did, however, hand one out to Vertex Pharma for rival gene therapy Casgevy, which was developed with CRISPR Therapeutics and approved on the same day as Lyfgenia . This unsuccessful effort was cited in bluebird’s recent announcement that it would sell itself to private equity firms in a deal valuing the gene therapy maker at just $30 million. Bluebird did not have enough cash to operate past the first quarter but had spied positive revenue later in the year. Eleven of the valuable trading cards were handed out to biopharma companies over 2024, across the three different programs that offer the vouchers. For the rare disease program specifically, indications that benefitted include sickle cell, Niemann-Pick type C, Duchenne muscular dystrophy and glioma, among others. With the pediatric rare disease program sunset announced, the FDA has handed out two already this year to Novo Nordisk for hemophilia A therapy Alhemo and Neurocrine Biosciences for congenital adrenal hyperplasia drug Crenessity. There are two other ways to get one beyond the rare disease program: through the development of drugs for tropical disease or a biological threat, such as COVID-19. Four have been awarded since the pandemic began for COVID-19: to Moderna, BioNTech, Pfizer and Gilead for their vaccines and antivirals. Neither of these programs are impacted by Congress’ recent actions, and so far, the FDA has granted one voucher under the tropical disease program this year: to Bavarian Nordic for its chikungunya virus vaccine Vimkunya. Bavarian Nordic has already indicated plans to sell the voucher “when appropriate.” Opponents of the voucher programs say the fast passes are not doing their job to expedite the approval of drugs to help fill unmet needs in the rare and tropical disease communities. In a December 2024 paper , U.K. researchers Piero Olliaro and Els Torreele called the program “a misconceived quid pro quo, whereby much is given for little public health return, promoting and rewarding monopoly pricing of high-revenue products, with no strings attached—which indeed makes it attractive to pharmaceutical companies and investors.” Bigger companies that earn or buy the vouchers use them to skip the line at the FDA for any drug they want. These vouchers are hard to track, as the companies do not have to report exactly where they got the voucher from when they use them. The FDA in recent years has occasionally posted Federal Register documents noting that a voucher was used for a particular drug, but these documents do not indicate where the voucher came from. From various records, it’s clear that many major blockbuster drugs of recent years have used these hall passes, from Eli Lilly’s Mounjaro, to AbbVie’s Rinvoq to Gilead’s portfolio of HIV meds and many more. In mid-February, Alnylam Pharmaceuticals cashed one in for a speedy review of Amvuttra in ATTR amyloidosis with cardiomyopathy, an indication that is one of the hottest market battles at the moment with offerings from Pfizer and BridgeBio now available. Vertex Pharmaceuticals did the same in July 2024 for cystic fibrosis triple med Alyftrek, receiving an FDA nod less than six months later, in December 2024. Novartis has by far been the most frequent patron of the fast passes, with as many as eight bought or earned over the years. The company has used the passes on Mayzent, Beovu, Kesimpta, Fabhalta and Kisqali, according to records. Gilead has spent as much as $621 million on known purchases of priority review vouchers. Olliaro and Torreele argue that the program does not actually encourage drug sponsors to ensure the availability of the medicines that get approved under the program, especially for tropical diseases. For instance, the makers of tuberculosis therapies Sirturo and Dovprela, a medicine that was approved under the tropical disease program as pretomanid, have been criticized for keeping the prices for the therapies too high to help in countries with a high tropical disease burden. Sirturo is manufactured by Johnson & Johnson while Dovprela (previously pretomanid) was developed by the TB Alliance . Frisk and Winton are aware of the criticisms but say that the rare disease program is working. You just have to look at the ramp up of drugs that have received a voucher over the years, with more handed out recently. That means that more companies are making these drugs and more rare diseases are getting new options for patients. As for the criticism of a handout for Big Pharma, Winton says this is a tax neutral program. No taxpayer funds are being given to these companies; it’s simply a market-based solution that ultimately helps smaller companies do what they do best: develop rare disease drugs for smaller populations. “Some of these drugs may not be developed or invented at all” without the voucher program, Winton said. “These [vouchers] are not necessarily going to the 17th, 18th statin—not that there’s anything wrong with that—but these are also going to feed the cycle of innovation and bringing drugs to patients in the U.S. who have no other options.” Planning Funerals One pediatric rare disease that has particularly benefitted is Duchenne muscular dystrophy, which has had seven drugs approved under the PRV program, including four from Sarepta Therapeutics. Each time, Sarepta sold its voucher and used the funds to continue its clinical programs. Another rare disease that now has multiple options is spinal muscular atrophy. Winton previously worked at Biogen as head of the SMA franchise, where he oversaw work on Spinraza, which received a PRV in March 2017. “That disease state has completely changed. You were used to planning funerals. And now you’re celebrating birthdays and you’re celebrating graduation into high school,” Winton said. “That’s an amazing success story.” These patients now have several different modalities to choose from, including Novartis’ gene therapy Zolgensma and Genentech’s Evrysdi, both of which received priority review and were granted vouchers at approval. These seminal approvals of complex technologies like gene therapy have also helped fuel other innovations in the modality, which is another legacy of the PRV program, Winton noted. Similarly, Biogen advanced its antisense oligonucleotide technology with Spinraza, which earned a voucher in March 2017 and was sold for $103 million last year . “When you talk to patients, when you talk to the rare disease community, the one thing they always say is ‘move faster.’ The one thing they don’t have is time,” Winton said. “The message we always take away when we talk to them is try to work hard or hurry up. This program does that. It speeds up our ability to get drugs to market. It speeds up our ability to do more research.” About the data: BioSpace compiled the list of priority review vouchers through dozens of sources, including the FDA, Federal Register, SEC, GAO, company reports, news articles and more. Still, the list may not be comprehensive, as some PRV transactions go unreported.