Deflazacort

“点击蓝字 关注我们涂家生中国药科大学药学院药剂系教授（二级），博士生导师，博士。先后担任第九、十、十一届国家药典委员会委员、执行委员，现任第十二届国家药典委员会执行委员（药用辅料第一专业委员会主任），美国药典委员会委员，中国药学会药用辅料专业委员会副主任委员、工业药剂学专业委员会委员，中国药品监督管理研究会药品辅料与包材监管研究专委会副主任委员，国家药品监督管理局药用辅料工程技术研究重点实验室学术委员会主任委员，国家药用辅料工程技术研究中心专家技术委员会副主任，国家药品监督管理局药品注册审评专家咨询委员会首批专家委员，Asian JPharm Sci，《中国药科大学学报》编委等。从事药用辅料、药物制剂和药物传递技术等领域研究逾30年。先后承担国家科技重大专项、国家科技支撑计划、国家自然科学基金、国家药品标准提升计划等课题100余项；为《中华人民共和国药典》制修订药典通则、指导原则、通用检测方法等7项，药用辅料质量标准80余项。先后获美国药典委员会标准制定杰出贡献奖、中国药学发展奖食品药品质量检测技术奖突出成就奖等省部以上奖励或荣誉称号。作为主编或编委，主持和参与《各国药用辅料标准对比手册》等多部国家药典委员会专著的编写工作，参与编写英文论著5部；获授权发明专利23项，专利转化7项；以第一作者或通信作者在国内外高水平学术期刊发表论文200余篇。孙春萌中国药科大学药学院药剂系教授，博士生导师，博士，国家高层次青年人才，入选6项省级人才计划。现任中国药科大学发展规划与学科建设处副处长、智库建设管理办公室主任，国家药品监督管理局药物制剂及辅料研究与评价重点实验室副主任；兼任中国药学会药剂专委会委员，中国药学会药用辅料专委会委员，中国药品监督管理研究会药品辅料与包材监管研究专委会委员，Asian J Pharm Sci，《中国药科大学学报》编委等。长期从事药用辅料和药物传递技术研究，先后主持国家自然科学基金4项，国家药品标准提高计划13项，国家科技重大专项子任务、江苏省自然科学基金、校企合作课题等30余项；为国家药典委员会、国家药品监督管理局药品审评中心等制修订行业技术指南和指导原则10余个。参编《中华人民共和国药典》等专著4部、教材5部；获授权发明专利14项；以第一作者或通信作者在 Nat Commun、Adv Sci 等国内外高水平学术期刊发表论文 70 余篇。浅析美国505(b)(2)与我国化药改良型新药的注册要求 PPS 嵇元欣1，廖美齐1，王青松2，孙春萌1*，涂家生1**（1.中国药科大学药学院，江苏 南京210009；2.南京清普生物科技有限公司，江苏 南京211112）[ 摘要 ] 近年来，我国化学药品改良型新药逐渐成为创新药物研究领域的重要方向。自2016年注册分类改革以来，基于新剂型、新适应证、新复方的改良型新药数量逐年增加，不仅为临床未满足需求提供了重要解决方案，也推动企业逐步转变研发理念、提升研发技术水平。通过调研美国505(b)(2)和我国化药改良型新药注册相关法规要求，深入剖析了中美在认定标准、数据引用等方面的异同，并就相关技术要点的优化和细化提出几点思考，以期为改良型新药的立项和研发提供思路与参考。2015年，《国务院关于改革药品医疗器械审评审批制度的意见》（国发〔2015〕44号）将新药的定义由“未曾在中国境内上市销售的药品”调整为“未在中国境内外上市销售的药品”，同时，根据物质基础的原创性和新颖性，将新药分为创新药和改良型新药。2016年《化学药品注册分类改革工作方案》明确化学药品注册分类2类为中国境内外均未上市的改良型新药，指在已知活性成分的基础上，对其结构、剂型、处方工艺、给药途径、适应证等进行优化，且具有明显临床优势的药品。改良型新药的提出，是鼓励以临床价值为导向的药物创新。2016年以来，不仅有多个新剂型、新适应证、新复方的新药产品获批准上市，充分满足患者对于疗效、安全性和顺应性的多种需求，也推动了企业逐步转变研发理念、提升研发技术水平，从以往的简单改剂型、改酸根碱基等，转变为立足于临床需求的产品设计，力求解决现有药物在临床应用中存在的问题，同时企业发挥自身优势，打造多种先进的技术平台，形成了多元化的竞争格局，促进了医药产业升级和发展。2022年，国家药品监督管理局（National Medical Products Administration，NMPA）药品审评中心（Center for Drug Evaluation，CDE）受理改良型化学药品的新药临床试验申请（investigational new drug application，通常简称为IND）282件（168个品种），新药上市申请（new drug application，NDA）53件（34个品种），而在2023年，CDE受理的改良型化学药品IND达410件（229个品种），同比增加45.39%；NDA达72件（46个品种），同比增加35.85%[1-2]。改良型新药的研发路径具有极强的灵活性，因此一直是备受关注的话题。从全球范围来看，美国505(b)(2)与国内改良型新药有相似之处，通过两者的对比探讨可引发对改良型新药的不断思考和深入理解。本文介绍了美国505(b)(2)和我国改良型新药相关的法规指南和案例，旨在为我国改良型新药的立项和研发提供思路与参考。1505(b)(2)简介505(b)(2)是美国食品药品监督管理局（Food and Drug Administration，FDA）的一种新药申请NDA路径，于1984年《药品价格竞争与专利期限补偿法案》（Drug Price Competition and Patent Restoration Act，也称Hatch-Waxman Act）正式确定，此项规定明确允许FDA依据非申请人研发的数据批准药品上市[3]，可帮助避免对上市药品已完成的研究进行不必要的重复，也可有效促进竞争、鼓励创新，满足药品的可及性。505(b)(2)与505(b)(1)共同之处在于均为包含完整的安全性和有效性研究报告的申请，区别在于数据来源及使用权。例如2017年批准的地夫可特片（Emflaza®),最初以505(b)(1)路径提交NDA，后由于资料中使用了公开发表的文献支持上市申请，改为505(b)(2)路径[4]。505(b)(2)的研发路径灵活性高，通过该路径提交的注册申请，其安全性与有效性方面的研究内容可能比较系统，接近505(b)(1)，也可能非常简化，接近505(j)。可见，不同于我国以注册分类为基础的注册申报体系，美国FDA以注册路径[505(b)(1)、505(b)(2)、505(j)]作为注册申报体系的基础，而FDA的新药申请注册分类码（NDA classification code，NDA分类码）则是FDA在对申请药品与美国已上市或批准的药品之间的关系进行评估后，确定的一种分类标识，不表示特定药品的创新程度或治疗价值，在注册审评期间及批准后均可能发生变化，不影响审评过程[5]。1.1 505(b)(2)的标准505(b)(2)以是否使用已有数据支持批准为标准，具体包括以下几种情况。1）新化学实体（new chemical entity，NCE）/新分子实体（new molecular entity，NME），如引用公开文献的NCE、已批准药物的活性代谢物等。在美国首次获批的沙利度胺产品Thalomid®（1998年）、FDA批准的首个氘代产品——氘代丁苯那嗪片Austedo®（2017年），NDA分类码均归属Type1NME，注册路径为505(b)(2)。2）对已批准药品的改变，例如：①改变剂型或给药途径；②改变规格；③改变处方且超出505(j)要求；④改变给药方案；⑤改变活性成分，包括不同的盐、酯、络合物、螯合物、包合物、外消旋体或对映体；⑥全新复方或已有复方中的一种活性成分替换；⑦新适应证；⑧处方药改为非处方药等情形。505(b)(2)申请不可作为无法满足505(j)生物等效性标准、生物利用度差的仿制药的获批途径[3,6]。1.2 505(b)(2)的案例探讨通过505(b)(2)路径，申请人可以在不同程度上借助现有的研究数据来支持产品获批，减少了研发的重复性，同时仍有数据保护和加速审评等通道，可以加快药品上市的进程，为患者提供更多的用药选择，促进市场竞争。例如，满足三要素的临床试验即可获得数据排他性：1）申请人自行开展的；2）非生物利用度研究；3）支持批准所必须开展的临床研究[6]。因此，美国505(b)(2)产品同样享有数据排他性。数据显示，2010—2020年间，通过505(b)(2)途径获批的470个产品中，有226个（48.1%）产品获得了数据排他性[7]。通过505(b)(2)路径提交申请需要明确已批准药品（listed drug，LD），LD是在美国批准上市的新药或仿制药，且未依据第505(e)(1)至505(e)(5)条或第505(j)(6)条被撤销或暂停批准，也未因FDA认定的安全性或有效性问题撤市，药品的LD身份通过FDA《经过治疗等效性评价批准的药品》[Approved Drug Products with Therapeutic Equivalence Evaluations，又称橙皮书（Orange Book）]确定[6]。505(b)(2)研发的挑战性在于，如何依据申报产品和LD的差异，精准定位桥接或补充研究的试验内容，如何确定与产品特点相关的关键指标，聚焦需要研究的关键问题，均需要严谨的逻辑、巧妙的设计以及对505(b)(2)路径和法规的深度理解。例如，可通过引用已有研究数据豁免或减少相关研究。Airsupra®是一款复方产品，引用了5个含有其组分的已上市产品研究数据以及辅料的安全性数据，支持了2个活性成分以及1种关键辅料的使用，未被要求开展新的非临床药理学或毒理学研究[8]。需要注意的是，数据引用需要确保数据的可靠性与适用性，包括数据是否准确、合规等，且需要建立所引用数据与申报产品之间的逻辑关联，包括适当的桥接试验。2023年FDA批准了一款丁丙诺啡长效注射剂（Brixadi®),用于治疗中度至重度阿片类药物使用障碍。Brixadi®采用FluidCrystal®技术，实现了2种缓释周期：8、16、24和32mg规格为1周缓释，64、96和128mg为1个月缓释。对于Brixadi®中使用的2种辅料——二油酸甘油酯（glycerol dioleate，GDO）和N-甲基吡咯烷酮（N-methyl pyrrolidone，NMP），申请人以数据引用和桥接的方式支持了其安全性评价：1）GDO为全新辅料，申请人引用了甘油二酯（diacyl glycerol，DAG）的相关研究支持GDO的致癌性、生育和早期胚胎发育影响评估等，以DAG中GDO含量测算作为引用DAG的桥接支持。2）NMP在该产品中属于以新给药途径使用，申请人提交了一项大鼠经口给药的药代动力学（PK）研究（用于确定大鼠经口给药途径的全身暴露）、一项妊娠大鼠鼻腔吸入的毒代动力学研究（用于确定已发表的大鼠吸入NMP的胚胎-胎儿毒性研究中NMP的全身暴露情况）、两项皮下注射NMP的大鼠生殖毒性研究，建立不同给药途径下系统暴露的相关性，以桥接所引用的文献数据[9]。又如，对于改变剂型同时不改变给药途径的505(b)(2)，可通过生物等效性（bioequivalence，BE）研究桥接已上市产品的安全性和有效性数据，此时需注意不同产品的桥接要求可能存在差异。2023年FDA批准了首款用于治疗急性偏头痛的苯甲酸利扎曲普坦的口溶膜制剂Rizafilm®,其为吞咽困难或因偏头痛产生恶心的急性偏头痛患者提供了一个新的治疗方法。该品种为Type3新剂型，以利扎曲普坦口崩片Maxalt-MLT®（规格：10mg）为LD，活性成分和规格与LD一致，以一项空腹的生物利用度比较研究进行了桥接，研究结果显示生物等效[药峰浓度（Cmax）、AUC的90%置信区间均在80%~125%范围内][10]。FDA基于以下两点同意申请人无需进行食物影响研究。首先，FDA认为苯甲酸利扎曲普坦属于高溶解度、高渗透性药物（BCSⅠ类）：1）利扎曲普坦片剂说明书显示利扎曲普坦在口服后完全吸收；2）苯甲酸利扎曲普坦在25℃水中溶解度约为42g·L-1（游离碱），且体外溶出数据表明，口溶膜和口崩片均溶出迅速，15min溶出超过85%。根据食物影响生物利用度研究指南，高溶解度高渗透性药物的速释制剂的药物吸收往往与pH、位点无关，因此最不可能受到食物影响[11]。其次，利扎曲普坦片剂的说明书显示，与食物同服，利扎曲普坦的血药浓度达峰时间推迟1h，但对生物利用度无显著影响，利扎曲普坦的普通片剂和口崩片未对食物摄入进行限制[11]。同样是改变剂型不改变给药途径，Atorvaliq®是获FDA批准的首款也是唯一一款阿托伐他汀钙口服混悬液（规格：4mg/mL），用于10岁及以上人群，相比于片剂方便调整剂量，可改善患者依从性。Atorvaliq®以辉瑞的阿托伐他汀钙片剂（Lipitor®,规格：10、20、40和80mg）为LD，申请的适应证与Lipitor®相同。由于进食后服用本品会使阿托伐他汀AUC和Cmax产生具有临床意义的降低（分别降低30%和63%），该品种最终以一项在健康志愿者中开展的开放标签、随机空腹生物利用度比较研究[口服混悬液20mL（规格：4mg/mL）与Lipitor®80mg]获批上市，同时对说明书进行了调整：仅允许空腹（餐前1h或餐后2h）服用[12]。此外，当引用已上市的单方制剂数据支持申报的新复方制剂时，需要阐明药物在复方制剂中的作用机制和相互作用，同时复方的临床研究需与单方进行对比。2023年，AstraZeneca与Avillion联合申请的Airsupra®经FDA批准用于18岁及以上哮喘患者按需治疗或预防支气管收缩，并降低病情加重的风险。Airsupra®是沙丁胺醇（短效β2受体激动剂）和布地奈德（皮质类固醇）的组合产品，也是首个在美国被批准的含有皮质类固醇、可用于缓解哮喘急性症状的产品。该疗法可放松肌肉并减少肺气道炎症，从而降低严重哮喘发作的风险。Airsupra®根据哮喘症状，以2次口服方式给药，每次吸入沙丁胺醇90μg和布地奈德80μg的组合（总剂量为沙丁胺醇180μg和布地奈德160μg）。Airsupra®通过505(b)(2)路径申请NDA，其LD包括已批准上市的Pulmicort Respules®（布地奈德吸入混悬液）、Pulmicort Flexhaler®（布地奈德吸入粉剂）和Proventil®-HFA（硫酸沙丁胺醇吸入气雾剂）。作为复方制剂，申请人共提交了6项临床药理研究，包含1项PK相互作用研究、3项PK对比研究、2项剂量探索研究，证明了两种活性成分之间不会产生PK相互影响，以及复方中的布地奈德和沙丁胺醇系统暴露低于已上市产品。由于皮质类固醇未曾被批准用于缓解哮喘急性症状，FDA同意在大样本量下将复方制剂与沙丁胺醇单方进行对比，作为支持组合物有效性的主要证据[8]。最终申请人提交了3项有效性和安全性临床研究数据，其中一项国际多中心、双盲、随机的关键Ⅲ期临床研究（3132例）数据，充分证明了与单独使用沙丁胺醇相比，高剂量组（沙丁胺醇180μg和布地奈德160μg）发生严重哮喘加重的风险降低了26%[13]。2对我国改良型新药的思考与探讨改良型新药以未被满足的临床需求为出发点，首要关注的是临床优势的提出和证明，其次是数据的引用和桥接。CDE发布的《化学药品改良型新药临床试验技术指导原则》《〈化学药品改良型新药临床试验技术指导原则〉问与答（征求意见稿）》《儿童用化学药品改良型新药临床试验技术指导原则（试行）》《改良型新药调释制剂临床药代动力学研究技术指导原则》《化学药改良型新药临床药理学研究技术指导原则（试行）》等指导原则明确了临床优势的定义，提供了明确的改良型新药设计和研究的相关要求和具体案例，为改良型新药研发提供了精准的技术指导。随着实践的不断深入，笔者对改良型新药进行以下思考与探讨。2.1改良型新药的标准与基础改良型新药与505(b)(2)均包括已上市药品的化合物新结构、新剂型、新处方工艺、新给药途径、新适应证等情形。改良型新药是在“改”的基础上提出了“具有明显临床优势”的要求，改良型新药定义下的已上市药品更准确的定义是“改良对象”。改良对象不仅是数据引用的基础，也是论证改良型新药临床优势的基础和前提，目前我国尚无明确的改良对象的定义、选择标准或可选范围。基于改良对象的重要性，笔者认为：改良对象的选择应以国内批准上市的药品为基本范围，对于国外批准而国内未批准上市的药品，由于无法掌握其临床研究的原始数据和真实情形，亦无国内临床应用经验作为基础，改良方向、明显的临床优势是否可以成立存疑，将这类药品选作改良对象时需审慎。一方面，改良型新药的临床优势是国内患者未被满足的临床需求，故而应当将国内的临床研究或国内的临床应用经验作为改良评估的基础。以国内批准上市的药品为基本范围，有助于企业和监管部门基于改良对象的临床研究原始数据和真实情形、国内人群的临床应用经验对改良型新药的临床价值进行评估和判断，实现精准的临床价值评估，同时也有助于我国审评体系独立性的提升。美国505(b)(2)路径下的LD同样是以美国批准上市为前提。另一方面，改良和创新是循序渐进、不断优化的过程，一款改良型新药的获批也是对这一类产品改良和创新方向的肯定。当下，全球医药研发技术愈发趋于同步，而各国药品的评价标准和上市要求并不相同，中国境外上市药品可能并非优选的改良基础。例如美国505(b)(2)产品的优势交给市场判断，获批上市的新药不乏因安全性、有效性或其他原因撤市的情况[14]，此类情形下获批的新药是否可以作为对比的对象值得商榷。在以国内批准上市药品为基本范围的基础上，深入分析已上市药品的优劣势，特别是同活性成分、同适应证有多种类型药品上市的情况下，应当基于“优于现有药品”的思路，充分论证拟定改良方向的优势，避免出现只看最差、择劣而改的情形，如此改良后的药品才能具备市场竞争力，进而持续推动技术进步和药品质量提升。2.2数据引用改良型新药与505(b)(2)的相通之处在于：在阐明引用数据与申报产品之间逻辑关联的基础上，可进行数据引用和桥接，进而豁免相关研究。对于改变给药途径和改变制剂处方的非临床研究，可通过新处方/新给药途径和已批准药品进行全面的PK/吸收（absorption）、分布（distribution）、代谢（metabolism）和排泄（excretion）（ADME）对比，结合体内暴露结果评价已有的全身毒性信息是否充分[15]。例如静脉注射改良型新药的系统暴露量不高于已上市产品，且辅料安全性依据充分的情况下，可仅考虑开展特殊安全性研究。不改变PK特征的新剂型，可通过与改良对象的生物等效性研究，桥接已有的安全性和有效性数据，豁免相关研究。依达拉奉舌下片通过两项健康受试者体内单次、多次给药的安全性、耐受性及药代动力学研究桥接依达拉奉注射液的有效性和安全性数据[16]；苯磺酸氨氯地平干混悬剂通过空腹和餐后与苯磺酸氨氯地平片在健康成年人群中的生物等效性研究，证明了临床优势的同时，桥接了片剂的有效性和安全性数据[17]。数据引用首先需要明确可引用范围和内容，目前我国尚无明确的数据引用规范要求，FDA的相关规定如下：505(b)(2)指南明确，可引用的数据包括公开发表的文献和经FDA批准上市产品的安全性、有效性数据。这里的“文献”指的是，已发表的、支持安全性或有效性的、有良好对照的研究报告；在《联邦公报》上发表的拟议及最终专论；支持《联邦公报》通告中所述某一产品安全性和/或有效性的数据[3]。一般性、常识性信息的文献支持不在此列（如病因、公认的临床终点等）。FDA允许引用已上市产品的说明书，也可以引用美国国家毒理学计划（National Toxicology Program，NTP）发布的报告（例如2014年批准的Xartemis®XR引用NTP发布的报告支持非临床研究）等，但不接受只引用缺乏原始数据的综述性文献以及LD的审评报告 （Summary Basis of Approval，SBA，即FDA批准药品数据库中公布的综述）。引用已上市产品的数据，申请人需要获得已上市产品持有人的授权[6]。例如当申请人认为某药品审评报告中披露的辅料安全性研究数据可以支持其505(b)(2)药品的上市申请时，申请人需要获得该药品持有人的引用授权，FDA方会审阅相关产品的原始报告，以评估是否可以支持该药品的批准。不能获得授权的情况下，申请人可通过自行研究等方式提供完整资料。对于国内改良型新药，建议可以将国内外公开文献、审评报告、说明书等内容作为数据引用的基本范围，例如可引用公开文献、已上市产品（不限于改良对象）的非临床研究数据支持活性成分、辅料的安全性，在此基础上，需注意引用源的可靠性，包括文献数据需要来自遵从药物非临床研究质量管理规范（Good Laboratory Practice，GLP）开展的研究所获得的数据，已上市产品的说明书和审评报告数据需要来自美国、欧盟国家或日本等管理规范的国家。3结语与展望改良型新药立足于现有临床痛点，在已上市药品的基础上进行改进和优化，推动技术创新的同时，增强产业竞争力，促进医药产业发展。企业需要充分了解临床现状，切实以临床需求为出发点，进行药品的改良设计和验证，突出产品临床优势。在行业经验不断积累的基础上，持续细化改良型新药研发相关标准和要求，必定有助于进一步明确改良目标和规范研发流程。此外，监管部门如能给予改良型新药更多的政策支持，例如将改良型新药研发过程中自行取得且未被披露的、除生物等效性研究以外的临床试验数据纳入数据保护范畴，也将会极大地提高制药企业的研发积极性。参考文献 ：[1] 国家药品监督管理局药品审评中心.2022年度药品审评报告[EB/OL].(2023-09-06)[2024-11-19].https://www.cde.org.cn/main/news/viewInfoCommon/849b5a642142fc00738aff200077db11.[2] 国家药品监督管理局药品审评中心.2023年度药品审评报告[EB/OL].(2024-02-04)[2024-11-19].https://www.cde.org.cn/main/news/viewInfoCommon/9506710a7471174ab169e98b0bbb9e23.[3]FDA.Applications covered by section 505(b)(2)[EB/OL].(1999-12-08)[2024-11-19].https://www.fda.gov/regulatory-information/search-fda-guidance-documents/applications-covered-section-505b2.[4] FDA. Approval date(s) and history, letters, labels, reviews for NDA 208684[EB/OL].[2025-01-05].https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208684.[5] FDA. Manual of policies and procedures:NDA classification codes[EB/OL].(2022-12-08)[2024-10-13].https://www.fda.gov/ media/94381/download.[6] National Archives and Records Administration. Code of Federal Regulations Title 21 Part 314-Applications for FDA approval to market a new drug.[EB/OL]. (2024-11-08)[2024-11-19]. https://www. ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314.[7] Ravula J D, Nirogi R, Janodia M D. Review on 505(b)(2) drug products approved by USFDA from 2010 to 2020 emphasizing intellectual property and regulatory considerations for reformulations and new combinations[J]. JPharm Sci, 2023, 112(8): 2146-2175.[8] FDA. Approval date(s) and history, letters, labels, reviews for NDA 214070[EB/OL]. (2023-04-28)[2024-11-19]. https://www. accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview. process&ApplNo=214070.[9] FDA. Approval date(s) and history, letters, labels, reviews for NDA 210136[EB/OL]. [2024-11-19]. https://www.accessdata.fda.gov/scripts/ cder/daf/index.cfm?event=overview.process&ApplNo=210136.[10] FDA. Approval date(s) and history, letters, labels, reviews for NDA205394[EB/OL]. [2024-11-19]. https://www.accessdata.fda.gov/scripts/ cder/daf/index.cfm?event=overview.process&ApplNo=205394.[11] FDA. Guidance for industry: food-effect bioavailability and fed bioequivalence studies[EB/OL] . (2002-12-01)[2024-11-19] . https://www.fda.gov/regulatory-information/search-fda-guidance- documents/food-effect-bioavailability-and-fed-bioequivalence- studies.[12] FDA. Approval date(s) and history, letters, labels, reviews for NDA 213260[EB/OL]. [2024-11-19]. https://www.accessdata.fda.gov/scripts/ cder/daf/index.cfm?event=overview.process&ApplNo=213260.[13] Papi A, Chipps B E, Beasley R, et al. Albuterol-budesonide fixed- dose combination rescue inhaler for asthma[J]. NEngl J Med, 2022, 386(22): 2071-2083.[14] 魏利军 , 雷继锋 . 美国 505(b)(2) 路径对我国改良型新药设计与 开发的启示 [J]. 中国食品药品监管 , 2024, 7: 56-67.[15] 戴学栋 , 孙涛 , 黄芳华 , 等 . 改良型新药非临床研究的一般考虑 及需要关注的问题 [J]. 中国新药杂志 , 2017, 26(18): 2121-2127.[16] 国 家 药 品 监 督 管 理 局 药 品 审 评 中 心 . 依 达 拉 奉 舌 下 片（CXHS2101030）申请上市技术审评报告 [EB/OL]. (2023-04-18) [2024-11-19]. https://www.cde.org.cn/main/xxgk/postmarketpage?acc eptidCODE=46b5cb3baacbbeb5add1c6f9d0b7059a.[17] 国家药品监督管理局药品审评中心 . 苯甲酸氨氯地平干混悬剂（ CXHS2200031）申请上市技术审评报告 [EB/OL]. (2024-08-21)[2024-11-19].https://www.cde.org.cn/main/xxgk/postmarketpage?acc eptidCODE=196e4e67dcfc4880a2f5d666bdca03da.美编排版：杨雨菲感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2025年第 3 期《药学进展》杂志由国家教育部主管、中国药科大学和中国药学会共同主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。联系《药学进展》↓↓↓编辑部官网：pps.cpu.edu.cn；邮箱：yxjz@163.com；电话：025-83271227。欢迎投稿、订阅！往期推荐“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航我知道你在看哟

– Full year 2024 revenue of $807 million, exceeding guidance – – All 2024 clinical and regulatory milestones were achieved on schedule, including four NDA submissions, all of which were accepted for filing – – License and collaboration agreement with Novartis for PTC518 Huntington's disease program closed in January 2025 – – Cash of over $2.0 billion as of January 2025 – WARREN, N.J., Feb. 27, 2025 /PRNewswire/ -- PTC Therapeutics, Inc., (NASDAQ: PTCT) today announced a corporate update and financial results for the fourth quarter ending December 31, 2024. "Our strong fourth quarter rounds out a year of significant accomplishment across every part of our company," said Matthew B. Klein, M.D., Chief Executive Officer. "In 2024, our commercial team delivered another outstanding performance, we achieved all clinical and regulatory milestones on schedule and we solidified our balance sheet. We now have over $2 billion in cash to support our planned commercial and R&D activities in 2025 and beyond. With the many accomplishments of 2024 and our team's demonstrated ability to execute across every part of the business, we have built a strong foundation for continued success." Key Corporate Updates: Fourth quarter 2024 total revenue of $213 million Fourth quarter 2024 revenue for the DMD franchise of $144 million, including net product revenue for Translarna™ of $94 million and for Emflaza® of $50 million Sold Rare Disease PRV received with FDA approval of Kebilidi™ for $150 million License and collaboration agreement signed with Novartis for PTC518 Huntington's disease program, closed in January 2025 Key Clinical and Regulatory Milestones: PTC submitted four regulatory approval applications to FDA in 2024, all of which have been accepted for review: Kebilidi (eladocagene exuparvovec-tneq) gene therapy for the treatment of AADC deficiency in the U.S., approved in November 2024 Sepiapterin for children and adults with PKU, with a target regulatory action date of July 29, 2025 Vatiquinone for children and adults with Friedreich's ataxia, granted priority review with a target regulatory action date of August 19, 2025 Translarna for nmDMD PTC submitted several additional marketing authorization applications outside the U.S. for sepiapterin in 2024, with CHMP opinion on sepiapterin MAA expected in Q2 2025 and a regulatory decision in Japan expected in Q4 2025. Type C meeting with FDA held in December 2024 to discuss HTT lowering as potential surrogate endpoint to support accelerated approval for PTC518 for HD. The Agency was aligned with the scientific rationale for HTT lowering as a potential surrogate endpoint and asked that PTC provide additional clinical data, such as those being collected in PIVOT-HD, to show associations between HTT lowering and changes in clinical outcome measures. 12-month results from the PIVOT-HD Phase 2 study of PTC518 expected in Q2 2025. Fourth Quarter and Full Year 2024 Financial Highlights: Total revenues were $213.2 million for the fourth quarter of 2024, compared to $307.1 million for the fourth quarter of 2023. Total revenue was $806.8 million for full year 2024, compared to $937.8 million for full year 2023. Total revenue includes net product revenue across the commercial portfolio of $154.7 million for the fourth quarter of 2024 and $601.0 million for full year 2024, compared to $155.1 million for the fourth quarter of 2023 and $661.2 million for full year 2023. Total revenue also includes royalty, collaboration, and manufacturing revenue of $58.5 million in the fourth quarter of 2024 and $205.8 million for full year 2024, compared to $152.0 million for the fourth quarter of 2023 and $276.6 million for full year 2023. Translarna net product revenues were $93.7 million for the fourth quarter of 2024, compared to $75.2 million for the fourth quarter of 2023. Translarna net product revenues were $339.9 million for full year 2024, compared to $355.8 million for full year 2023. Emflaza net product revenues were $50.5 million for the fourth quarter of 2024, compared to $67.4 million for the fourth quarter of 2023. Emflaza net product revenues were $207.2 million for full year 2024, compared to $255.1 million for full year 2023. These results were driven by the expiration of Emflaza's orphan drug exclusivity in February 2024. Roche reported Evrysdi® full year 2024 sales of approximately 1,631 CHF million, resulting in royalty revenue of $203.9 million to PTC for full year 2024, as compared to $168.9 million for full year 2023. Also in the fourth quarter of 2023, PTC recorded a sales milestone of $100.0 million for the achievement of $1.5 billion in worldwide annual net sales from Evrysdi. This sales milestone was recorded as collaboration revenue. Based on U.S. GAAP (Generally Accepted Accounting Principles), GAAP R&D expenses were $124.8 million for the fourth quarter of 2024, compared to $121.4 million for the fourth quarter of 2023. GAAP R&D expenses were $534.5 million for full year 2024, compared to $666.6 million for full year 2023. The slight increase in R&D expense for the fourth quarter of 2024 reflects additional costs due to manufacturing, regulatory filings, and inspections primarily related to Kebilidi and sepiapterin. The decrease in R&D expense for full year 2024 relates to decreases in program spend related to our strategic portfolio prioritization as we continue to focus our resources on our differentiated, high potential research and development programs. R&D expense also included a total of $65.0 million regulatory success-based milestones paid to the former Censa securityholders for the year ended December 31, 2024, as compared to a $30.0 million success-based development milestone payable to the former Censa securityholders for the year ended December 31, 2023. Non-GAAP R&D expenses were $116.0 million for the fourth quarter of 2024, excluding $8.8 million in non-cash, stock-based compensation expense, compared to $113.2 million for the fourth quarter of 2023, excluding $8.1 million in non-cash, stock-based compensation expense. Non-GAAP R&D expenses were $497.9 million for full year 2024, excluding $36.6 million in non-cash, stock-based compensation expense, compared to $613.6 million for full year 2023, excluding $52.9 million in non- cash, stock-based compensation expense. GAAP SG&A expenses were $84.7 million for the fourth quarter of 2024, compared to $76.3 million for the fourth quarter of 2023. GAAP SG&A expenses were $300.9 million for full year 2024, compared to $332.5 million for full year 2023. The increase in SG&A expense for the fourth quarter of 2024 reflects our continued investment to support commercial activities, including expanding our commercial portfolio. The decrease in SG&A expense for full year 2024 was primarily due to lower employee costs as a result of the reduction in the workforce in 2023. Non-GAAP SG&A expenses were $76.3 million for the fourth quarter of 2024, excluding $8.4 million in non-cash, stock-based compensation expense, compared to $67.9 million for the fourth quarter of 2023, excluding $8.4 million in non-cash, stock-based compensation expense. Non-GAAP SG&A expenses were $262.9 million for full year 2024, excluding $38.0 million in non-cash, stock-based compensation expense, compared to $283.8 million for full year 2023, excluding $48.7 million in non- cash, stock-based compensation expense. The change in the fair value of deferred and contingent consideration was a gain of $10.2 million for the fourth quarter of 2024, compared to a gain of $2.7 million for the fourth quarter of 2023. Change in the fair value of deferred and contingent consideration was a gain of $4.5 million for full year 2024, compared to a gain of $127.7 million for full year 2023. The full year 2024 change is primarily related to the Company's strategic portfolio prioritization and decision to discontinue its preclinical and early research programs in its gene therapy platform in May 2023, which included programs for FA and Angelman syndrome. The intangible asset impairment was $159.5 million for the fourth quarter and full year 2024, compared to $0.0 million for fourth quarter and $217.8 million for the full year 2023, which represented a non-cash charge. For the fourth quarter and full year 2024, we impaired $159.5 million related to a decrease in projected cash flows due to refinements in current market assumptions and the timing of patient treatments for AADC. For the full year 2023, we fully impaired the FA and Angelman syndrome intangible assets and recorded impairment expense of $217.8 million. Net loss was $65.9 million for the fourth quarter of 2024, compared to net loss of $155.8 million for the fourth quarter of 2023. Net loss was $363.3 million for full year 2024, compared to net loss of $626.6 million for full year 2023. Cash, cash equivalents, and marketable securities was $1,139.7 million on December 31, 2024, compared to $876.7 million on December 31, 2023. Shares issued and outstanding as of December 31, 2024, were 77,704,188. PTC Full Year 2025 Financial Guidance: PTC anticipates total revenues for full year 2025 to be between $600 million and $800 million, including in-line products, potential new product launches, and royalty revenue from Evrysdi. PTC anticipates GAAP R&D and SG&A expenses for full year 2025 to be between $805 million and $835 million. PTC anticipates non-GAAP R&D and SG&A expenses for full year 2025 to be between $730 million and $760 million, excluding estimated non-cash, stock-based compensation expense of $75 million. Non-GAAP Financial Measures: In this press release, the financial results of PTC are provided in accordance with GAAP and using certain non-GAAP financial measures. In particular, the non-GAAP R&D and SG&A expense financial measures exclude non-cash, stock-based compensation expense. These non-GAAP financial measures are provided as a complement to financial measures reported in GAAP because management uses these non-GAAP financial measures when assessing and identifying operational trends. In management's opinion, these non-GAAP financial measures are useful to investors and other users of PTC's financial statements by providing greater transparency into the historical and projected operating performance of PTC and the company's future outlook. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. Quantitative reconciliations of the non-GAAP financial measures to their respective closest equivalent GAAP financial measures are included in the table below. Acronyms: AADC: Aromatic L-Amino Acid Decarboxylase CHF: Confoederatio Helvetica Francs (Swiss francs) CHMP: Committee for Medicinal Products for Human Use DMD: Duchenne Muscular Dystrophy FA: Friedreich's Ataxia FDA: U.S. Food and Drug Administration GAAP: Generally Accepted Accounting Principles HD: Huntington's Disease HTT: Huntingtin MAA: Marketing Authorization Application NDA: New Drug Application nmDMD: Nonsense mutation Duchenne muscular dystrophy PKU: Phenylketonuria PRV: Priority Review Voucher R&D: Research and Development SG&A: Selling, General, and Administrative Today's Conference Call and Webcast Reminder: To access the call by phone, please click here to register and you will be provided with dial-in details. To avoid delays, we recommend participants dial in to the conference call 15 minutes prior to the start of the call. The webcast conference call can be accessed on the Investor section of the PTC website at . A replay of the call will be available approximately two hours after completion of the call and will be archived on the company's website for 30 days following the call. About PTC Therapeutics, Inc. PTC is a global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to children and adults living with rare disorders. PTC's ability to globally commercialize products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need. The company's strategy is to leverage its strong scientific expertise and global commercial infrastructure to maximize value for its patients and other stakeholders. To learn more about PTC, please visit us at and follow us on Facebook, X, and LinkedIn. For More Information: Investors: Ellen Cavaleri +1 (615) 618-6228 [email protected] Media: Jeanine Clemente +1 (908) 912-9406 [email protected] Forward-Looking Statements: This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this release, other than statements of historic fact, are forward-looking statements, including the information provided under the heading "PTC Full Year 2025 Financial Guidance", including with respect to (i) 2025 total revenue guidance and (ii) 2025 GAAP and non-GAAP R&D and SG&A expense guidance, and statements regarding: the future expectations, plans and prospects for PTC, including with respect to the expected timing of clinical trials and studies, availability of data, regulatory submissions and responses, commercialization and other matters with respect to its products and product candidates; PTC's strategy, future operations, future financial position, future revenues, projected costs; and the objectives of management. Other forward-looking statements may be identified by the words, "guidance," "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions. PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may commercialize in the future; PTC's ability to maintain its marketing authorization of Translarna for the treatment of nmDMD in Brazil, Russia, the European Economic Area (EEA) and other regions, including whether the European Commission adopts the negative opinion from the Committee for Medicinal Products for Human Use (CHMP) for the conditional marketing authorization for Translarna in the EEA, or PTC's ability to identify other potential mechanisms by which it may provide Translarna to nmDMD patients in the EEA; PTC's ability to use the clinical data from its international drug registry study and real-world evidence concerning Translarna's benefits to support a continued marketing authorization for Translarna for the treatment of nmDMD in the EEA; PTC's ability to use the results of Study 041, a randomized, 18-month, placebo-controlled clinical trial of Translarna for the treatment of nmDMD followed by an 18-month open-label extension, and from its international drug registry study to support a marketing approval for Translarna for the treatment of nmDMD in the United States; whether investigators agree with PTC's interpretation of the results of clinical trials and the totality of clinical data from its trials in Translarna; expectations with respect to PTC's license and collaboration agreement with Novartis Pharmaceuticals Corporation including its right to receive development, regulatory and sales milestones, profit sharing and royalty payments from Novartis; expectations with respect to Upstaza/Kebilidi, including commercialization, manufacturing capabilities, and the potential achievement of sales milestones and contingent payments that PTC may be obligated to make; expectations with respect to sepiapterin, including any regulatory submissions and potential approvals, commercialization, and the potential achievement of regulatory and sales milestones and contingent payments that PTC may be obligated to make; expectations with respect to vatiquinone, including any regulatory submissions and potential approvals, commercialization, and the potential achievement of regulatory and sales milestones and contingent payments that PTC may be obligated to make; expectations with respect to the commercialization of Evrysdi under PTC's SMA collaboration; expectations with respect to the commercialization of Tegsedi and Waylivra; significant business effects, including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates; PTC's scientific approach and general development progress; PTC's ability to satisfy its obligations under the terms of its lease agreements; the sufficiency of PTC's cash resources and its ability to obtain adequate financing in the future for its foreseeable and unforeseeable operating expenses and capital expenditures; and the factors discussed in the "Risk Factors" section of PTC's most recent Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory, or prove to be commercially successful, including Translarna, Emflaza, Upstaza, Kebilidi, Evrysdi, Tegsedi, Waylivra, sepiapterin or vatiquinone. The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law. SOURCE PTC Therapeutics, Inc. 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