ALGS Collaboration (Travere Therapeutics)

▎药明康德内容团队报道2023年上半年已结束。据不完全统计，截至6月30日，今年有将近50款新药首次获得中国国家药监局（NMPA）批准上市，其中大约76%为小分子化药，此外还有多款生物药。从治疗领域来看，这些新药仍以抗肿瘤产品居多，其次是罕见病和抗感染领域治疗产品。值得一提的是，有将近37%的新药是得益于优先审评、附条件批准等政策，加速来到了患者身边。与此同时，2023上半年还有30多款新药在中国迎来了新适应症，包括多款JAK抑制剂和抗PD-1单抗。此外，还有多款生物类似药也在中国获批。本文中，就让我们来一起看看今年上半年在中国获批的新药都有哪些？它们都惠及了哪些患者？（向《医药观澜》微信号回复“2023上半年”即可下载2023上半年中国获批新药完整表格）———✦40多款新药首次获批✦———注：本文首次获批新药统计范围含化学药品1类和5.1类，及治疗用生物制品1类、2.2类和3.1类等；不包含改良型新药、生物类似药、中药、疫苗等；以NMPA药品批准证明文件中公示的批准日期计算根据NMPA官网批件信息，上半年共有近50款新药在中国首次获批，其中6月份获批新药数量最多，达到17款。从药物获批类型来看，小分子新药占比约76%，包括针对CDK4/6、MET、BTK、MEK、PI3K、DPP-4、ALK等靶点的创新抑制剂等。此外，还有12款生物药在中国获批，包括CAR-T产品、ADC、GLP-1RA复方制剂、长效粒细胞集落刺激因子（G-CSF）、单克隆抗体等等。梳理这些获批新药，我们发现多款产品创下了“首个”获批的记录，为患者带来了全新的治疗选择。例如：武田（Takeda）的琥珀酸莫博赛替尼胶囊，是全球首个获批治疗EGFR 20号外显子插入突变患者的口服靶向药物，本次在中国获批治疗EGFR 20号外显子插入突变的局部晚期或转移性非小细胞肺癌（NSCLC）；罗氏（Roche）的注射用维泊妥珠单抗，是全球首个获批的靶向CD79b的ADC，本次在中国获批治疗治疗弥漫性大B细胞淋巴瘤（DLBCL）成人患者；驯鹿生物与信达生物联合开发的伊基奥仑赛注射液，是中国首款获批的BCMA靶向CAR-T产品，本次获批治疗复发或难治性多发性骨髓瘤（MM）成人患者；阿斯利康（AstraZeneca）和默沙东（MSD）共同开发的MEK抑制剂司美替尼，是中国首个获批的I型神经纤维瘤病（NF1）治疗药物；北海康成引进的IBAT抑制剂迈芮倍口服液，是中国首个获批治疗阿拉杰里综合征（ALGS）患者胆汁淤积性瘙痒的药物……从治疗领域来看，上半年获批的新药仍以抗肿瘤产品居多。而从癌症细分适应症来看，获批最多的是肺癌药物，其中包括：齐鲁制药ALK/ROS1抑制剂伊鲁阿克、海和药物MET抑制剂谷美替尼、贝达药业第三代EGFR-TKI贝福替尼等，均获批治疗非小细胞肺癌；恒瑞医药抗PD-L1单抗阿得贝利单抗则获批治疗广泛期小细胞肺癌。在淋巴瘤治疗领域，上半年也迎来了4款新药，分别是阿斯利康新一代BTK抑制剂阿可替尼、拜耳（Bayer）PI3K抑制剂可泮利塞、罗氏ADC疗法维泊妥珠单抗和博锐生物抗CD20单抗泽贝妥单抗。在乳腺癌领域，诺华（Novartis）CDK4/6抑制剂琥珀酸瑞波西利片和阿斯利康和第一三共（Daiichi Sankyo）联合开发的HER2靶向ADC注射用德曲妥珠单抗的获批也为患者带来了新选择。此外，肾细胞癌领域也迎来了贝达药业的多靶点激酶抑制剂伏罗尼布。抗感染是另一获批新药较多的治疗领域，其中包括：恒瑞医药引进的抗真菌新药奥特康唑胶囊、吉利德科学（Gilead Sciences）侵袭性真菌病一线治疗产品注射用两性霉素B脂质体、云顶新耀治疗成人复杂性腹腔内感染的注射用盐酸依拉环素、圣和药业治疗慢性丙型肝炎病毒感染的奥磷布韦等。同时，还有3款新药获批用于治疗治疗新型冠状病毒感染（COVID-19），分别来自先声药业、旺实生物和众生药业。在罕见病领域，上半年也迎来多款新药，为不同类型的罕见病患者带来治疗希望。除了上文提及的司美替尼和氯马昔巴特口服溶液，另外还有：百时美施贵宝公司的奥扎莫德和梯瓦（Teva）公司的醋酸格拉替雷均获批治疗多发性硬化、苏庇医药尼替西农获批治疗1型遗传性酪氨酸血症、维健医药引进的苯丁酸甘油酯获批用于尿素循环障碍患者的长期治疗、Recordati子公司锐康迪卡谷氨酸分散片获批治疗多种罕见高氨血症、希而欧生物西罗莫司凝胶获批用于治疗结节性硬化症皮肤损害等。 此外，上半年获批的新药还有很多，根据不同疾病领域划分具体如下：•在内分泌和代谢领域，有阿斯利康达格列净二甲双胍缓释片、恒瑞医药瑞格列汀、赛诺菲（Sanofi）甘精胰岛素利司那肽注射液等降糖药，以及亿腾医药降脂药二十碳五烯酸乙酯软胶囊、安进（Amgen）甲旁亢新药依特卡肽等；•在消化系统领域，有分别来自轩竹生物安奈拉唑钠肠溶片和柯菲平医药盐酸凯普拉生片等质子泵抑制剂等；•在血液系统领域，有分别来自亿一生物和特宝生物的中性粒细胞减少症治疗产品艾贝格司亭α注射液和拓培非格司亭注射液、亿腾医药引进的血小板减少症新药芦曲泊帕片、豪森药业慢性肾病贫血新药培莫沙肽注射液等；•在骨科领域，有亿帆医药治疗膝骨关节炎的丁甘交联玻璃酸钠注射液等；•在皮肤科领域，有康哲药业引进的银屑病新药甲氨蝶呤注射液和替瑞奇珠单抗、美纳里尼（Menarini）荨麻疹新药比拉斯汀片等；•在神经或精神疾病领域，有杨森（Janssen）创新抑郁症疗法盐酸艾司氯胺酮鼻喷雾剂、康哲药业引进的抗癫痫新药地西泮鼻喷雾剂等。———✦30多款新药收获新适应症✦———除了首次获批的新药，2023上半年还有30多款新药在中国获批新适应症。其中，小分子占比约61%，包括针对BTK、JAK、SGLT2、CDK4/6、TKs、RET等靶点的抑制剂；生物药占比约39%，主要是针对PD-1、RANKL、VEGF、CD38、TNF-α、EGFR、IL-12/IL-23、IL-4/IL-13、IgE等靶点的单抗类产品，以及靶向CD19的CAR-T产品、GnRH类似物等。从药品作用机制来看，抗PD-1单抗斩获新适应症最多。来自百时美施贵宝、康方生物/正大天晴、复宏汉霖、百济神州、信达生物和恒瑞医药等公司的6款抗PD-1单抗共计斩获8项新适应症，涵盖小细胞肺癌、非小细胞肺癌、尿路上皮癌、胃或胃食管结合部腺癌、食管鳞状细胞癌、肝细胞癌等不同瘤种。注：NMPA批准日期按药监局批件中批准日期计其次是小分子JAK抑制剂，来自辉瑞（Pfizer）枸橼酸托法替布缓释片、艾伯维（AbbVie）乌帕替尼缓释片、礼来（Eli Lilly and Company）巴瑞替尼片、诺华磷酸芦可替尼片等4款JAK抑制剂的新适应症上市申请先后在中国获批，治疗溃疡性结肠炎、急性移植物抗宿主病、斑秃等疾病。值得一提的是，巴瑞替尼片斑秃适应症的获批，使其成为中国首款用于系统性治疗重度斑秃的创新靶向药物，为中国重度斑秃患者带来获得显著毛发再生的治疗新选择。此外，还有多种靶向疗法获批新适应症，根据不同疾病领域划分有：在肿瘤领域，有恒瑞医药TKI新药吡咯替尼和阿帕替尼及CDK4/6抑制剂羟乙磺酸达尔西利片、基石药业RET抑制剂普拉替尼、复星凯特CD19靶向CAR-T产品阿基仑赛注射液、百济神州BTK抑制剂泽布替尼、诺诚健华BTK抑制剂奥布替尼、诺华CDK4/6抑制剂瑞波西利、拜耳雄激素受体抑制剂（ARi）达罗他胺、百泰生物抗EGFR单抗尼妥珠单抗等获批不同肿瘤适应症，涵盖肺癌、乳腺癌、淋巴瘤、胃癌、肝癌、胰腺癌、前列腺癌等； 在皮肤科领域，有杨森IL-12/IL-23抑制剂乌司奴单抗获批治疗儿童银屑病，赛诺菲/再生元（Regeneron）IL-4/IL-13抑制剂度普利尤单抗获批治疗婴幼儿特应性皮炎，诺华奥马珠单抗预充式注射液获批治疗慢性自发性荨麻疹等；在内分泌和代谢领域，有益普生（IPSEN）GnRH类似物注射用双羟萘酸曲普瑞林获批治疗性早熟等群体；勃林格殷格翰（Boehringer Ingelheim）/礼来SGLT2抑制剂恩格列净获批糖尿病新适应症；拜耳非甾体选择性盐皮质激素受体拮抗剂非奈获批拓展适应症至慢性肾脏病早期阶段；在罕见病领域，有罗氏SMN2基因mRNA剪接修饰剂利司扑兰口服溶液用散获批治疗脊髓性肌萎缩症（SMA），阿斯利康C5补体抑制剂依库珠单抗注射液获批全身型重症肌无力等；在抗感染领域，有葛兰素史克（GSK）HIV新药多替拉韦钠分散片获批治疗儿童患者；在骨科领域，有安进抗RANKL单抗地舒单抗获批治疗男性骨质疏松症；在血液系统领域，有诺华TPO受体激动剂艾曲泊帕乙醇胺片获批治疗重型再生障碍性贫血等；在神经或精神领域，有大冢制药（Otsuka Pharmaceutical）非典型抗精神病药物注射用阿立哌唑等；此外，还有益普生注射用双羟萘酸曲普瑞林六月超长效剂型、卫材（Eisai）抗癫痫药吡仑帕奈口服混悬液等新剂型获批等。———✦多款生物类似药陆续获批✦———近年来，由中国公司开发的生物类似药陆续获批上市，一些产品还实现了海外授权。在今年上半年NMPA批准的产品中，9款生物类似药首次获批，1款生物类似药获批新适应症。这些产品有阿达木单抗、贝伐珠单抗、地舒单抗、利拉鲁肽注射液、利妥昔单抗、曲妥珠单抗、托珠单抗等，获批适应症包括癌症、自身免疫性疾病等（详见下表）。注：NMPA批准日期按药监局批件中批准日期计除了上述新药，今年还有许多其它类别的新药在中国获批，限于篇幅，此处不再一一介绍。祝贺这些新药在中国获批上市，希望它们的到来可以造福更多患者！同时也期待下半年迎来更多进展，有更多新药好药获批来到患者的身边，让科学的力量持续为患者健康带来积极的改变。参考资料：[1]中国国家药监局（NMPA）官网[2]各公司新闻稿及公告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「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。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。

When Travere Therapeutics initially fell short of providing sufficient clinical data to support an application seeking accelerated drug approval in a rare kidney disorder, the FDA told the biotech last year that carrying out a Phase 3 study could support an application seeking a traditional approval. Preliminary data now available show the drug missed the main goal in that pivotal test. The biotech acknowledges the trial failure but points to encouraging trends in the data. Management of San Diego-based Travere said Monday evening that they plan to speak with regulators to determine a path forward for the drug, sparsentan, as a treatment for focal segmental glomerulosclerosis (FSGS). FSGS is characterized by scarring in small sections of the glomeruli, the tiny filtering units in the kidneys. The condition can progress to end-stage renal disease. There are no drugs specifically approved for FSGS, but the disorder is managed with off-label treatments such as anti-inflammatory and immunosuppressive drugs that stop the immune system from attacking glomeruli. Other treatments include blood pressure medications and diuretics. Sparsentan is a small molecule designed to block two pathways associated with the progression of chronic kidney diseases. In February, the FDA approved the once-daily pill as a treatment for immunoglobulin A nephropathy (IgAN), where the drug carries the brand name “Filspari.” It’s projected to become a blockbuster seller in that indication. Separate clinical trials have been assessing the molecule in FSGS. The Phase 3 test in FSGS compared sparsentan to irbesartan, a blood pressure medication used to treat the kidney disorder. The main goal was to measure the change in estimated glomerular filtration rate (eGFR) at week 108. A second main goal was measuring for changes in protein levels in urine. Travere reported that results in the treatment arm showed improvement in eGFR, but not enough to be statistically significant compared to the active control arm. After 108 weeks of treatment, the average reduction in urine protein levels was reduced by 50% in the sparsentan arm compared to 32% in the irbesartan group. On measures of safety, the Travere drug was well tolerated and showed a safety profile comparable to irbesartan. In an investor presentation, Travere said the next steps are to conduct a complete evaluation of data from the Phase 3 study. The company will also speak with the FDA about a supplemental new drug application (sNDA) submission in the U.S. Working with its partner, CSL Vifor, Travere will talk to the European Medicines Agency regarding potential conditional marketing authorization. Speaking during a Monday evening conference call, Chief Medical Officer Jula Inrig said Travere will conduct additional subgroup analyses to better understand the results. These analyses will not be made available prior to discussion with regulators, though she said she expected that in time they will be presented at medical meetings and published in journals. Asked whether Travere expects another clinical trial would be needed, CEO Eric Dube said it’s too early to say. “We have a lot to learn from what we would consider a landmark trial within this space,” he said. “This is the largest study ever conducted within FSGS. I think we have just started to understand what the disease, as well as what this mechanism with sparsentan can do, so I think it would be premature for us to talk about whether there’s a need to do a second study and also how we might go about that. But we definitely want to make sure we’re contributing to our understanding of FSGS, and certainly have discussions with regulators before commenting on a potential path.” In a note sent to investors Tuesday, William Blair analyst Tim Lugo wrote that he does not see sparsentan’s clinical trial failure in FSGS reading through to the ongoing Phase 3 test of the drug in IgAN, which is expected to report data in the fourth quarter of this year. The FSGS study required a two-week washout period of prior therapies before patients were randomized, while the IgAN study requires patients to be on a maximally tolerated blood pressure reduction drug up to randomization. Lugo said this difference likely results in a larger effect on the blood flow’s effect on eGFR in the FSGS study than should be expected in the IgAN study. In addition, Lugo said FSGS is more heterogeneous, meaning it has multiple root causes. Consequently, the disease progresses in a relapsing and remitting manner, which is different than the more consistent decline in IgAN. Lugo emphasizes the point by pointing to SLGT2 inhibitors, a class of diabetes that block glucose reabsorption in the kidneys. Studies of these drugs in FSGS have been more challenging than in IgAN due to the heterogeneity and variable progression of the disease. Despite the failure of sparsentan in the FSGS study, called DUPLEX, Lugo still sees a potential path forward for the drug. “While the failure to meet the primary endpoint of DUPLEX certainly brings the likelihood of approval in FSGS into question, we believe the totality of the data suggest that sparsentan is having a therapeutic benefit in FSGS,” Lugo said. “Given that the FDA has acknowledged the high unmet need and lack of available therapies in this rare disease, and that this would be an sNDA and not a new application, we believe there is still a chance of approval and are lowering our probability of success in the indication from 85% to 40%.” Public domain image by Flickr user Internet Archive Book Image