Rapastinel

现有抗抑郁药起效慢、治愈率低，有诸多未满足的临床需求，其研发难度与居高不下的研发成本及当前对于抑郁症发病机制认识的局限性有关。为方便药物研发者及时了解抗抑郁药研发前沿、拓展研究思路，本文综述了抗抑郁药的临床研发现状及管线分析，梳理了当前全球抗抑郁药临床研发趋势及我国抗抑郁药临床研发的发展方向。 在我国成人中，抑郁障碍的终生患病率为6.8%，年患病率为3.6%，据估计是导致健康寿命损失的第二大原因，且造成的疾病负担仍在攀升[1-3]。药物治疗是抑郁症的重要治疗方式，但却存在药物选择不多、起效慢、治愈率低、安全性有待提高[4]、患者依从性不足等问题。有关抗抑郁药的诸多未满足的临床需求不仅与新药研发的高时间成本和高经济成本有关，也一定程度上反映了当前对于抑郁症发病机制认识的局限。为方便药物研发者及时了解抗抑郁药研发前沿、拓展研究思路，本文综述了抗抑郁药的临床研发现状及管线分析以供参考。 1 抗抑郁药未满足的临床需求 抗抑郁药未满足的临床需求集中在疗效、安全性、依从性和药物经济学4个方面，此外还需考虑特殊人群的需要。目前常用的抗抑郁药一般需2~4周起效，有效率为50%~60%，缓解率仅为20%~30%[5-6]。缓解的抑郁症患者中，90%存在残留症状，如睡眠障碍和食欲/体重障碍[7]。抑郁症的复发率很高，1/3~1/2的抑郁症患者停止治疗后1年内再次出现抑郁症状，50%患者会再次或多次发作[8-9]。不同年龄、性别的患者中，不同抗抑郁药的疗效差别也很大[10]。故起效更快、有效率及缓解率更高、症状残留更少是抗抑郁药创新研发所需关注的首要疗效需求。此外，还应当探索巩固期和维持期治疗药物的研发，降低复发风险。小症状群如认知症状（执行功能、注意力、记忆力、信息加工速度等方面功能受损）可出现于抑郁症前驱期、急性发作期（发生率为76.9%~94%）及缓解期（发生率为32.4%~44.0%）[11-12]，是抑郁症患者功能损害及症状缓解后未能实现功能恢复的重要原因[13]，也是值得持续投入研发的方向。在安全性方面，需尽可能减少不良反应的发生频率、降低不良反应的严重程度。在药物经济学方面，对于考虑纳入医保的产品，充分的药物经济学评估可更好地发挥医保的“兜底”作用，更具策略性地把医保基金用于患者急需的具有突破性和创新性的药物。 2 抗抑郁药临床研发现状 目前抑郁症患者诊疗率并不高[2]，随着社会对抑郁症等精神障碍的认知逐渐提高，国家财政投入、医疗资源下沉等政策效果逐渐显现，中国抑郁症诊疗率的提升将是中国抗抑郁药市场规模扩展的主要驱动力之一。然而近10年来抗抑郁药临床研发缓慢，根据美国FDA[14]、欧洲EMA[15]及日本医药品医疗器械综合机构（PMDA）[16]等公布的药品审评结果，自2010年至今，全球仅有6个抗抑郁新药上市（见表1）。对比抗肿瘤药等热门研发领域，抗抑郁药的研发可谓处于瓶颈期。新型抗抑郁药上市速度放缓与市场需求相悖，背后有多重原因。 2.1 时间与经济成本 新药研发的时间和资金成本巨大，过去的30年间，新药开发的成本飞涨，将新药推向市场所需的时间也几乎翻了1倍。自2000年初氯胺酮的抗抑郁效果被验证，到2019年美国上市的基于氨基酸系统理论的艾司氯胺酮和别孕烯醇酮，20年的时间已经过去。即便是仿制药，在重磅专利到期前，企业也常需提前4~5年布局。据估计，1987年上市的氟西汀研发成本约为2.3亿美元，2004年上市的度洛西汀研发成本超过9亿美元。到2010年，新药的平均开发上市成本已经超过20亿美元[17]。 2.2 抗抑郁药临床试验失败原因分析 中枢神经系统（CNS）新药研发的成功率与其他疾病领域相比较低，早期临床试验中的夭折率尤其高[18]。即便进入Ⅲ期临床试验，仍有超过50%的机率无法成功上市，大大高于抗肿瘤药的研发失败率。临床前及早期临床试验阶段常见的失败原因包括靶点不合适、成药性差、缺少合适的动物模型，药动学/药效学（PK/PD）特征不符合预期、剂量选择不合适及毒性问题。进入Ⅱ~Ⅲ期临床试验，46%由于缺少优于安慰剂的有效性宣告失败[19]，评估工具也是影响试验结果的重要因素[20]。虽然2019年艾司氯胺酮和别孕烯醇酮的上市代表着抗抑郁药研发的重大突破，但其分子各有独特的药理学性质，成功案例难以复制。与艾司氯胺酮同时期的其他分子包括AZD6765（lanicemine），GLYX⁃13（rapastinel）及4⁃CL⁃KYN（4chlorokynurenine）均在早期研究中展现了潜力，在大规模的验证临床试验中却未能显示明显的症状改善[21]。zuranolone（SAGE⁃217）是别孕烯醇酮类似物，但在Ⅲ期临床研究中主要临床终点上也未显示相较于安慰剂的优势。 2.3 抗抑郁药临床研发概况 根据国际临床试验注册平台（ICTRP）收录的临床试验信息，截至2021年12月，全球在研（近5年内存在临床试验记录）抗抑郁新药共78个，最高研发状态为Ⅲ期、Ⅱ期及Ⅰ期临床试验的抗抑郁新药数分别为21，42，15个（见表2）。作用于氨基酸类神经递质靶点的药物共26个，占33.3%；作用于单胺类神经递质靶点的药物共18个，占23.1%。 《中国新药注册临床试验现状年度报告（2020年）》显示，中国临床试验迅速发展，2020年度登记的临床试验数较2019年增长9.1%，新药占比57%，但化学药和生物制品临床试验的适应证集中在抗肿瘤药物，远超排名第2的适应证。图1展示了国际临床试验注册平台登记的2011—2021年中国和美国抑郁症领域临床试验数量。 在《关于开展仿制药质量和疗效一致性评价的意见》的政策影响下，近5年来（2017—2021年）中国的生物等效性试验占抑郁症相关临床试验总量的70%~80%。中美抑郁症领域临床试验总数虽接近，但除去为支持仿制药上市的生物等效性试验，中美临床试验数差距十分明显。2021年6月绿叶制药公司宣布其自主研发的抗抑郁新药盐酸安舒法辛正式被国家药品监督管理局药品评审中心受理，才有望打破国内多年来一线抗抑郁新药研发的僵局。 3 抗抑郁药病因学进展及研发管线概览 目前常用的抗抑郁药主要针对单胺靶点，此外还有针对谷氨酸、γ⁃氨基丁酸（GABA）受体和褪黑素受体等靶点的药物及中药。 3.1 单胺类神经递质靶点 单胺类神经递质假说自提出到现在已有半个世纪，该假说认为抑郁症是大脑中单胺类神经递质5⁃羟色胺（5⁃HT）、多巴胺（DA）和去甲肾上腺素（NE）含量降低和功能缺陷所致，可通过增加突触间隙的单胺类神经递质浓度治疗。20世纪80年代起，蓬勃发展的抗抑郁药研发主要基于单胺通路，包括选择性5⁃羟色胺再摄取抑制剂（SSRIs）和5⁃HT与NE再摄取抑制剂（SNRIs）。表3和图2汇总了全球近5年基于单胺神经递质靶点的在研产品管线。此类新型抗抑郁药的研发目标正在从单纯阻断单胺再摄取逐渐转向具有多重转运体/受体的作用机制，发挥更为全面的药理作用。18个在研药物中，有8个药物可对多个神经递质通路同时产生作用。Ⅱ期临床试验阶段的GH001和MIN117都对5⁃HT1A及5⁃HT2A型受体有高亲和性。正在进行Ⅲ期临床试验的lumateperone可作用于5⁃HT2A型受体和DA2型受体。已在中国递交上市许可申请的安舒法辛为5⁃HT，NE，DA三重再摄取抑制剂。 此外，一些过去在西方国家存在滥用问题的致幻剂，正在被开发为治疗重症或难治型抑郁的抗抑郁药，包括裸盖菇素（psilocybin）、麦角二乙基酰胺（LSD）和亚甲二氧基甲基苯丙胺（MDMA）等[22]。此类药物的抗抑郁作用与5⁃HT2A型受体功能关系密切[23]，起效快、疗效显著，但由于其物质滥用及依赖性问题，如何认识、开发及应用此类药物在我国尚需讨论。 3.2 氨基酸类神经递质靶点 γ⁃氨基丁酸（GABA）发现于20世纪50年代，越来越多的证据显示GABA系统和谷氨酸系统与抑郁症有关。2000年以来，氨基酸系统理论开始得到关注[24]。2019年3月，美国FDA相继批准别孕烯醇酮（商品名Zulresso®）和艾司氯胺酮（商品名Spravato®），这是自1990年以来全球上市的抗抑郁药中唯独的2个作用于氨基酸靶点的药品。表4和图3展示了近5年基于氨基酸神经递质靶点的在研抗抑郁创新药，γ⁃氨基丁酸受体（GABAR）、N⁃甲基⁃D⁃天门冬氨酸受体（NMDAR）和α⁃氨基羧甲基唑丙酸受体（AMPAR）都是当下的热门靶点。 靶向NMDAR的在研创新药占所有氨基酸靶点在研药物的64.6%。用于治疗难治性抑郁的艾司氯胺酮鼻喷剂是以NMDAR为靶点且成功上市的第一款药品。作用于NMDAR的在研药物中，第一个潜力分子为老药新用的氯胺酮。研究证明，低剂量的氯胺酮可以在几小时到几天的时间内快速达到可持续的抗抑郁效果，且对难治性抑郁症同样有效[25-26]。有多家企业正在积极探索氯胺酮以及艾司氯胺酮的不同结构和剂型，在降低依赖性风险的同时，加快起效速度，为难治型抑郁、自杀行为等症状提供更好的治疗。 氨基酸神经递质抗抑郁药靶点中排名第2的是GABAR。别孕烯醇酮（商品名Zulresso®）是GABA A型受体正变构调节剂，Sage公司与渤健公司研发的zuranolone同样作用于GABA A型受体，用于治疗产后抑郁和重度抑郁症，该药目前正处于Ⅲ期临床试验阶段。另外，作用于氨基酸靶点的创新药物也在探索同时靶向多个受体，如同时具有NMDAR拮抗和AMPAR激活作用的XW10508（凯瑞康宁公司）。 3.3 中药在抗抑郁药领域的发展 中医药在抑郁症的治疗与康复调护中发挥了重要作用[27]。中药复方有多成分、多靶点、多效应、毒副作用小、协同作用强等特点，但抗抑郁机制尚不明确。经国家药品监督管理局正式批准且纳入《中国抑郁障碍防治指南（第二版）》的中药或天然药物包括圣约翰草提取物片、舒肝解郁胶囊和巴戟天寡糖胶囊，主要用于治疗轻中度抑郁障碍。根据我国药物临床试验登记与信息公示平台公布的临床试验信息，目前我国共有10项中药/天然药物处于临床在研阶段（见表5）。 4 结论 综上所述，生物医药研发的初衷始终是未被满足的临床需求，中国从基础科研到成果转化的途径和方式尚有较大进步的空间。从临床前到早期临床研究，再到大型多中心Ⅲ期临床试验，各个阶段的药物研发均面临不同挑战。提升从实验室到临床的科研成果转化率是需要研究者、药企、政府监管部门共同思考并携手解决的问题，加大对CNS领域基础和转化研究的投入、增加进入临床试验阶段的药物数量，从设计到实施各阶段优化抗抑郁药试验、降低安慰剂效应、改善结局指标的反应度，基于替代终点或有限的临床数据批准新疗法，以上都是可进一步探索的方向。 在抗抑郁药种类方面，目前氨基酸靶点抗抑郁药的研发热点集中在对难治型抑郁、自杀意念/行为以及产后抑郁的治疗，而单胺靶点药物的研发思路则更多在探索不同新型受体亚型[28]，中药在抑郁症的药物治疗中地位也得到了一定程度的认可。有关方面需紧跟基础科研进展，拓宽研发思路，提升研发管线的多样化，促进良性的市场竞争。 中药是中国传统文化瑰宝，需进一步加大对有效改善患者抑郁状态的活性成分及各类药物之间相互作用关系的探索，使独具特色的传统中医药充分发挥其在治疗抑郁症方面的作用，从而更好地服务于抑郁症患者，满足抑郁症领域不断增长的医疗和市场需求。 中国生物医药已全面进入创新发展阶段，如果企业聚焦于抑郁症领域，需了解具体赛道的市场现状和趋势、针对性的或未满足的临床需求、重要靶点和研发管线、差异性和优劣势，前期诸多的失败经验也具有借鉴意义。 参考文献 《中国新药杂志》2023年第32卷第3期 内容来源于网络，如有侵权，请联系删除。

Funding rounds this week saw money flow into innovative drug discovery and delivery platforms, cancer imaging and RNA synthesis, while pharma powerhouse Pfizer wrapped up two high-value neuro deals. EnPlusOne’s Enzyme-Based RNA Synthesis Platform Earns $12M Seed With $12 million in seed financing, biotech startup EnPlusOne Biosciences Inc. launched last week with its cutting-edge enzymatic RNA synthesis platform ezRNA. The funding round was led by Northpond Ventures; Breakout Ventures, Coatue and angel investors participated. The culmination of more than six years of development, the ezRNA synthesis platform uses enzymes to generate RNA oligonucleotides and can incorporate a wide variety of nucleotide modifications. EnPlusOne will use the seed proceeds to further develop and scale ezRNA and expand its team. The young company is led by Daniel Wiegand, its chief executive officer. Dr. Jonathan Rittichier, Ph.D., is its chief scientific officer, while Dan Ahlstedt is the chief operating officer. All three spun EnPlusOne from the Wyss Institute for Biologically Inspired Engineering at Harvard University. Wiegand and Rittichier are the company’s technical founders. Unique Approach to Drug Discovery Scores Cellarity $121M in Series C Cambridge, MA-based Cellarity made $121 million in its recent Series C financing round, the company announced Tuesday. It plans to use the proceeds to strengthen its platform, expand its talent base and drive its programs to the clinic. Cellarity’s approach goes beyond individual molecular targets and focuses on the entire cell to identify factors influencing the transition to a diseased state. Deep learning models combined with high-dimensional transcriptomic data allow Cellarity to design medicines targeting a disease’s cellular structure, which could lead to treatments for previously undruggable targets. The funding round was led by venture capital firm and Cellarity founder Flagship Pioneering. Four new investors also threw their support behind Cellarity, including Hanwha Impact Partners and Kyowa Kirin Co. Ltd. Since Cellarity was founded in 2017, it has already raised $274 million. Voyager Earns $10M from Pfizer’s License Option for its Next-Generation AAV Capsid On Tuesday, pharma giant Pfizer exercised its license option to Voyager Therapeutics’ novel AAV capsid, triggering a $10 million payment to the latter. According to a company spokesperson, Voyager will use these proceeds to further develop its proprietary TRACER discovery platform and ongoing pipeline programs. The exercise option is part of a licensing agreement between Voyager and Pfizer, inked October last year, which entailed a $30 million upfront payment for the capsid program that could be used to deliver potential gene therapies for a still undisclosed rare neurologic disorder. Voyager remains eligible for up to $290 million in milestones and tiered royalties. The company is banking on an external partnership strategy to help it advance its technology and pipeline. “Voyager also announced in March 2023 a license option agreement with Novartis under which Novartis may exercise options to license TRACER generated AAV capsids for potential use with three undisclosed CNS targets and options to access capsids for two additional rare disease targets to be agreed on in the future,” the spokesperson told BioSpace. Series B Pumps $21.5M Into Vergent’s Fluorescent Tumor Imaging Agent With its Series B round of financing closing Tuesday, Vergent Bioscience posted proceeds of $21.5 million, which the company will use to further advance the clinical development of VGT-309, its tumor-targeted fluorescent imaging agent. Delivered via a short infusion a couple of hours before surgery, VGT-309 contains a molecule that covalently bonds to cathepsins, a group of proteins known to be over-expressed in a wide variety of solid tumors, including lung cancer. This action allows surgeons to spot previously undetectable or hard-to-visualize tumor tissues during minimally invasive or robotic surgeries. Orlando Health Ventures led Vergent’s Series B. The Minneapolis, MN-based company earned new investors during this round, including Rex Health Ventures, Windham Venture Partners and Intuitive Surgical, Inc. Pfizer Completes $11.6 Billion Biohaven Buyout First revealed in May, Pfizer announced Monday that it had completed its migraine leader Biohaven Pharmaceuticals acquisition in a deal valued at $11.6 billion. The industry giant bought all outstanding shares of Biohaven at $148.50 per share. Biohaven is now a wholly-owned subsidiary of Pfizer. As a result of the buyout, Pfizer now holds the rights to Nurtec ODT (rimegepant), for the treatment of migraines in adults, with or without auras, and for the prevention of episodic migraine. The deal also gives Pfizer Zavegepant, an intranasal spray under review by the FDA for acute migraine relief. The regulatory body is set to arrive at a decision early next year. The acquisition also grants Pfizer a portfolio of pre-clinical calcitonin gene-related peptide receptor antagonists. Drug Discovery Technologies Win Alloy $42M in Series D Biotech ecosystem company Alloy Therapeutics counted $42 million in earnings during its recent Series D financing round. The proceeds will be used to bolster the company’s pre-competitive drug discovery technologies in new biologic modalities, as well as support new partnership models to foster innovation in the drug discovery community. Launched in 2017, Alloy initially provided human antibody mouse discovery capabilities using a suite of transgenic mouse strains. With its Series C in March 2021, the company was able to extend its discovery technologies and services into T cell receptors and genetic medicines. Monday’s Series D will also help Alloy expand its offerings across its six modalities, including peptides and cell therapies. The Series D was led by existing investors 8VC and Mubadala Capital. Returning supporters, Thiel Capital, Founders Fund and Presight Capital, and other unnamed funds, participated. After Stealth Exit, Gate Counts $25M in Financing Precision medicine biotech Gate Neurosciences announced last week that it had earned a total of $25 million in funding from a cadre of life science-focused investors, including ThornApple Capital, Innoviva, Biocrossroads and Luson Bioventures, among others. Alongside its financing, the company touted a new peer-reviewed publication highlighting the novel mechanism and pharmacology of its lead program Zelquistinel. The paper shows that a single dose of the molecule can modulate NMDA receptors and enhance synaptic plasticity in specific brain regions, which leads to a rapid and durable antidepressant effect. Gate launched in 2019 and emerged from stealth in August. The company has previously acquired the Zelquistinel, Apimostinel and Rapastinel depression programs from pharma giant AbbVie, and has recently earned exclusive rights to Eli Lilly’s preclinical mGlu2/3 receptor antagonists for sleep disorders.