D2 receptor x 5-HT2 receptor

11月24日，中国国家药监局（NMPA）官网公示，有四款新药在中国获批上市或迎来新适应症，分别为李氏大药厂旗下兆科药业申报的洛沙平吸入剂、武田（Takeda）的富马酸伏诺拉生片、云顶新耀的布地奈德肠溶胶囊、以及勃林格殷格翰（Boehringer Ingelheim）与礼来（Eli Lilly and Company）联合开发的恩格列净片。本文中就让我们看看这4款新药的获批都给哪些患者带来了治疗选择？ 公开资料显示，洛沙平（loxapine）属于二环芳基类药物，主要被用于治疗精神分裂症等精神疾病，其主要作用机制为阻断多巴胺D2受体和血清素5-HT2受体，从而减轻精神分裂症患者的阳性症状，如幻觉、错觉和思维混乱等。此外，洛沙平也可能通过影响其他神经递质系统，如乙酰胆碱、组胺和肾上腺素等发挥作用。本次获批的洛沙平吸入粉雾剂最初由Alexza公司开发，李氏大药厂拥有该药在中国内地、香港和澳门地区的经销许可。 2020年9月，李氏大药厂宣布洛沙平于中国的关键3期临床已完成揭盲和主要数据的统计分析。这是一项多中心、随机、双盲、安慰剂对照、平行设计的3期临床研究，旨在评估洛沙平针对精神分裂症或双相情感障碍患者激越时的急性控制的有效性及安全性。数据显示，该研究达到主要终点指标，给药后两小时得出的阳性和阴性症状量表兴奋因子（PEC）评分与基线的变化有显著统计差异，证明该产品能快速起效。 11月24日，武田中国宣布富马酸伏诺拉生片的新适应症正式获得NMPA批准，用于与适当的抗生素联用以根除幽门螺杆菌。幽门螺杆菌是一种与多种重大慢性疾病相关的致病菌，具有传染性，可引发包括慢性胃炎、消化性溃疡、胃黏膜相关淋巴样组织（MALT）淋巴瘤等多种胃肠道内外疾病。 此次伏诺拉生根除幽门螺杆菌新适应症的获批主要基于一项在中国人群多中心3期临床研究。内酸抑制的程度（即pH值）和持续时间占比（即HTR）为影响幽门螺杆菌根除率的重要因素。目前，胃内pH＞6且HTR＞75%已成为临床根除Hp的抑酸标准。作为一款创新型钾离子竞争性酸阻滞剂（P-CAB），伏诺拉生具有不受餐食影响，且不受CYP2C19基因多态性影响等特点。研究数据显示，一天服用两次伏诺拉生胃内pH>6 HTR达85%，在根除幽门螺杆菌的临床治疗中起重要作用，能有效提高幽门螺杆菌的根除率。 11月24日，云顶新耀宣布，布地奈德迟释胶囊（Nefecon，中文商品名：耐赋康）获得NMPA批准上市，用于治疗具有进展风险的原发性免疫球蛋白肾病（IgA肾病）成人患者。Nefecon最初由Calliditas Therapeutics公司开发，云顶新耀拥有该产品在大中华区、新加坡和韩国的开发以及商业化权利。 IgA肾病是中国最常见的原发性肾小球疾病，发病年龄较轻，预后不佳，易进展至终末期肾病，给患者和社会带来沉重的疾病负担。根据云顶新耀新闻稿，Nefecon是靶向肠道的黏膜免疫调节剂，其通过特殊的制作工艺，将布地奈德靶向释放于回肠末端的黏膜B细胞，胶囊溶解后，三层包衣微丸持续稳定释放布地奈德，高浓度覆盖整个靶区域，从而减少诱发IgA肾病的半乳糖缺陷的IgA1抗体（Gd-IgA1）产生，进而干预发病机制上游阶段，达到治疗IgA肾病的作用。 全球3期临床研究NefIgArd的完整数据表明，Nefecon能够保护肾功能，延缓患者进展至透析或肾移植，显著降低蛋白尿和血尿，且安全性、耐受性良好。在中国人群数据分析中，Nefecon显示出能减少肾功能衰退达66%。该药本次获批将为中国IgA肾病患者带来全新的治疗选择。 11月24日，勃林格殷格翰与礼来联合宣布，SGLT2抑制剂欧唐静（恩格列净）的新适应症获得NMPA批准，用于治疗成人慢性肾病（CKD）。此前，该药已在中国获批治疗成人2型糖尿病、射血分数降低的成人心力衰竭和射血分数保留的成人心力衰竭、以及联合胰岛素治疗2型糖尿病。 CKD通常呈渐进性进展，以估算肾小球滤过率（eGFR）下降和高白蛋白尿为特点。由于CKD发病过程隐匿，早期就诊率和治疗率低。CKD患者一旦进入终末期肾脏病（ESKD），需进行肾脏替代治疗（包括血液透析、腹膜透析或肾移植）以维持生命，严重影响患者生活质量。 恩格列净本次新适应症的获批是基于EMPA-KIDNEY临床试验。试验数据显示，恩格列净可使慢性肾病患者显著获益，与安慰剂相比可将肾病进展或心血管死亡事件的相对风险降低28%。与安慰剂相比，恩格列净可将因任何原因住院率的相对风险降低14%，具有统计学意义。该试验显示总体安全性数据与之前的研究结果基本一致。 参考资料：[1]神速！神速！李氏大药厂洛沙平吸入剂阿达苏®III期临床试验仅用72天顺利完成入组招募 . Retrieved July 14，2020，from https://mp.weixin.qq.com/s/vEp28pFnJYDZyHFkQJ8p0g [2]李氏大药厂自愿性公布 - 有关引进并研发一种研究性抗精神病吸入剂产品的最新情况. Retrieved Sep 3，2020，from http://www.cninfo.com.cn/new/disclosure/detail plate=hke&orgId=gshk0008221&stockCode=00950&announcementId=1208391141&announcementTime=2020-09-03%2023:59 [3]Alexza公司官网. From https://www.alexza.com/pipeline/pipeline-opportunities/ [4] 武田富马酸伏诺拉生片根除幽门螺杆菌新适应症在中国获批. Retrieved Nov 24，2023, from https://www.prnasia.com/story/428339-1.shtml [5] 云顶新耀宣布中国国家药品监督管理局批准全球首个对因治疗IgA肾病药物耐赋康®的新药上市许可申请. Retrieved Nov 24，2023, from https://mp.weixin.qq.com/s/Nu1vS3cG4ZAATqlUaP23fg [6]重磅｜欧唐静®（恩格列净）成人慢性肾病适应症在华获批.Retrieved Nov 24，2023, From https://mp.weixin.qq.com/s/V0PTtFJZkzDdzxSTWE9DAg 内容来源于网络，如有侵权，请联系删除。

药物研发进展 1.诺华first-in-class口服PNH新药盐酸伊普可泮胶囊申报上市 6月14日，CDE官网显示，诺华盐酸伊普可泮胶囊（iptacopan）上市申请获受理，用于成人阵发性睡眠性血红蛋白尿症（PNH）患者的治疗。APPOINT-PNH（NCT04820530）是一项单臂、开放标签、多中心、III期临床试验，旨在评估iptacopan单药治疗未接受过补体抑制剂（包括抗C5抗体）治疗的PNH成人患者的疗效和安全性。主要终点是24周以内在不输注红细胞（RBCT）情况下达到血红蛋白水平较基线升高≥2g/dl的患者比例。结果显示，试验达到主要研究终点，92.2%患者在不输注红细胞（RBCT）情况下达到血红蛋白水平较基线升高≥2g/dl。次要终点显示出临床意义上的改善，97.6%的患者避免输血，62.8%的患者在不输注红细胞的情况下达到血红单白水平持续≥12g/dl。安全性方面与此前报道的数据一致。阵发性睡眠性血红蛋白尿症（PNH）是一种补体介导的慢性罕见血液疾病。据统计，PNH发病率约百万分之一到二，亚洲人群发病率高于欧美，可在任何年龄发生，常见于30-40岁人群。PNH患者体内PIG-A基因突变，导致血细胞表面上重要的补体调节蛋白CD55和CD59缺失。因此，细胞更易被补体激活。临床主要表现为溶血、骨髓造血功能衰竭和血栓形成等。抗补体C5疗法(依库珠单抗或Ravulizumab)是既往国际公认的PNH标准治疗，但在抗C5治疗后，仍有大部分患者有残留贫血、疲乏和输血依赖，严重影响生活质量。Iptacopan是由诺华研发的first-in-class、靶向补体旁路途径B因子的口服抑制剂。该产品作用于C5末端通路的上游，同时控制血管内溶血和血管外溶血，弥补了抗C5抗体的不足，同时为患者提供了口服单药的选择。今年2月，Iptacopan获CDE突破性治疗药物认定。 2.甘李药业门冬胰岛素生物类似药上市申请获FDA受理 6月14日，甘李药业发布公告称，其生物类似药门冬胰岛素注射液的生物制品许可申请（BLA）已获FDA正式受理，进入实质审查阶段。在美国境内，门冬胰岛素注射液的主要供货商为诺和诺德，诺和诺德作为原研厂家，其门冬胰岛素产品NovoRapid在2022年的全球销售额为154.6亿丹麦克朗（约22.16亿美元），其中美国市场的销售额为56.41亿丹麦克朗（约8.09亿美元）。门冬胰岛素注射液是一种速效胰岛素类似物，又称餐时胰岛素，皮下注射后 10~20 分钟内起效，最大作用时间为注射后 1~3 小时，作用持续时间为 3~5 小时，可以有效地控制餐后血糖。门冬胰岛素一般紧邻餐前注射，必要时可在餐后立即给药。门冬胰岛素具有起效快，作用持续时间较短，夜间低血糖风险较低的特点，并通常与长效胰岛素联合使用以实现患者的基础与餐后血糖控制。糖尿病是一种影响身体将食物转化为能量的慢性疾病。患有糖尿病的人，身体无法产生足够的胰岛素，或者无法有效使用其产生的胰岛素。当体内没有足够的胰岛素或细胞对胰岛素停止反应时，过多的葡萄糖就会留在血液中。久而久之，这会导致严重的健康问题，如心脏病、视力下降和肾脏疾病。 3.治疗罕见儿科肝病！益普生ISBT抑制剂新适应症获FDA批准 6月13日，IPSEN官网发布公告称FDA已批准Bylvay（odevixibat）新适应症的上市申请，用于治疗12个月及以上Alagille综合征患者的胆汁淤积性瘙痒。Alagille综合征（ALGS）是一种常染色体显性遗传病，也是婴儿期慢性胆汁淤积性肝病的重要原因之一。ALGS主要表临床现为肝内胆管缺乏和胆汁淤积。相关研究表明，回肠胆汁酸转运蛋白（IBAT）/顶端钠依赖性胆汁酸转运蛋白（ASBT）抑制剂显示出良好的ALGS治疗效果。Bylvay是一种强效、非全身性回肠胆汁酸转运抑制剂（IBATi），其具有最小的全身暴露，仅在肠道内局部发挥作用。2021年7月，Bylvay获得FDA批准，成为首个用于治疗所有亚型的进行性家族性肝内胆汁瘀积症（PFIC）瘙痒的药物。本次获批是基于一项全球、双盲、随机、安慰剂对照的III期ASSERT研究的积极数据。该研究旨在评估Bylvay在ALGS患者中的安全性和有效性，主要终点为瘙痒水平从基线到第6个月（第21～24周）的变化；关键次要终点是血清胆汁酸水平从基线到第6个月（第21～24周）平均值的变化。研究结果显示，与安慰剂组相比，该研究达到了主要终点，即根据PRUCISION观察者报告的挠痒评分（0~4分制）测量的瘙痒症状在基线第6个月（第21～24周）有统计学意义上的显著减少（p=0.002）。该研究还达到了关键的次要终点，即与安慰剂组相比，血清胆汁酸浓度从基线到第20周和24周的平均值有统计学意义的显著降低（p=0.001）。早在第1~4周，与安慰剂组患者相比，多项睡眠参数就有统计学意义上的显著改善，并持续改善至第24周。安全性方面，Bylvay治疗耐受性良好，总体不良事件发生率与安慰剂相似。 4.阿斯利康 AKT 抑制剂Capivasertib申报上市 6月12日，阿斯利康宣布，FDA 已受理其在研 AKT抑制剂Capivasertib 联合 Faslodex（氟维司群）用于治疗激素受体阳性（HR+）、人表皮生长因子受体2阴性（HER2-）局部晚期或转移性乳腺癌患者的新药申请（NDA），这些患者在接受内分泌基础方案治疗过程中或之后疾病复发或进展。FDA 将在 2023 年 Q4 做出审评决定。AKT，也称为磷酸激酶B (PKB)，在涉及细胞生长和分裂、细胞凋亡抑制和血管生成的多种级联信号传导机制中发挥着关键作用。Capivasertib是三种AKT亚型（AKT1/2/3）的高效选择性抑制剂。AKT信号通路的激活，包括PIK3CA、AKT1和PTEN的改变，可出现在许多HR+/HER2-的晚期乳腺癌患者中，但也可能出现在没有这些基因改变的患者中。AKT信号通路与内分泌治疗耐药的发生有关。2022 年 10 月 26 日，阿斯利康制药官网宣布 Capivasertib 联合氟维司群治疗晚期 HR+/HER2 低表达或阴性乳腺癌的 III 期 CAPItello-291 研究达到 PFS 主要终点，包括总体人群和 PI3K/AKT/PTEN 信号通路改变（携带 PIK3CA、AKT1 或 PTEN 基因突变）的人群。在随后的 2022 SABCS 大会期间公布了详细数据。CAPItello-291 是一项全球多中心、双盲、随机的 Ⅲ 期临床试验，旨在评估 capivasertib 联合氟维司群对比安慰剂联合氟维司群治疗局部晚期（不可手术）或转移性 HR+/HER2 低表达或阴性乳腺癌的安全性和有效性。 5.儿童便秘新选择！利那洛肽新适应症获FDA批准 6月12日，Ironwood Pharmaceuticals宣布，FDA已批准Linzess（linaclotide，利那洛肽）新适应症的上市申请，用于治疗6~17岁儿童功能性便秘（FC）。利那洛肽是一种鸟苷酸环化酶-C（GC-C）激动剂，此前已被FDA批准用于治疗成人便秘型肠易激综合征（IBS-C）与慢性特发性便秘（CIC）。本次获批基于一项多中心、双盲的III期研究结果，旨在评估利那洛肽对6~17岁功能性便秘患者的疗效与安全性。该研究共纳入了328名患者，按1:1的比例随机接受利那洛肽 72μg或安慰剂治疗。结果显示，与安慰剂相比，利那洛肽在12周的自发排便频率（SBMs/周）上显示出具有统计学意义和临床意义的改善。与安慰剂组SBMs（1.050）相比，利那洛肽组患者每周SBMs (2.220) 与基线相比的最小二乘均值变化大于两倍 (p<0.0001)。安全性方面，研究中最常见的不良事件是腹泻，利那洛肽治疗组中腹泻发生率为4%，而安慰剂组为2%。儿童FC被定义为排便困难、排便次数少且排便困难或疼痛的病症。FC是所有年龄段儿童的常见问题，全球患病率在0.7%~29.6%。FC的核心症状包括大便次数减少、大便稠度变硬、排便时疼痛和大便失禁。 6.石药帕利哌酮和米拉贝隆仿制药获批 6月14日，石药集团发布公告，称其附属公司开发的两款仿制药已获得国家药品监督管理局（NMPA）批准，分别是帕利哌酮缓释片（3mg、6mg）和米拉贝隆缓释片。帕利哌酮原研产品由强生开发，是第二代抗精神病药，其作用机制被认为是通过对中枢多巴胺2受体和5-羟色胺2受体拮抗的联合作用介导的。临床研究显示，帕利哌酮起效迅速，能有效控制各类精神症状，显著改善患者功能，并降低复发率，安全性良好，是治疗精神分裂症的一线用药。帕利哌酮用于成人及12-17岁青少年精神分裂症的治疗，其采用复杂的三层渗透泵设计原理，实现了药物的持续稳定释放，保证了平稳的血浆浓度，降低了不良反应。帕利哌酮的获批将进一步丰富石药在神经精神领域的产品线。米拉贝隆是一种选择性β3肾上腺素受体激动剂，通过作用于膀胱组织，使膀胱平滑肌松弛，用于成年膀胱过度活动症（OAB）患者尿急、尿频和/或急迫性尿失禁的对症治疗。米拉贝隆的获批为国内膀胱过度活动症患者的治疗提供更多选择。 7.Seagen公布维布妥昔单抗一线治疗cHL II期数据 6月13日，Seagen公布了一项II期单臂试验（SGN35-027） Part C的最新疗效和安全性结果，该试验评估了抗体偶联药物Adcetris（维布妥昔单抗）与PD-1抑制纳武利尤单抗和标准化疗药物多柔比星和达卡巴嗪（AN+AD）联合用于早期经典霍奇金淋巴瘤（cHL）患者的一线治疗的疗效和安全性。SGN35-027是一项正在进行的开放标签、多中心II期临床试验，旨在评估两种不同Adcetris治疗组合在晚期和早期cHL患者中的疗效。该试验包括三部分(Part A、B、C)。Part A评估了Adcetris联合多柔比星、长春碱、达卡巴嗪（A+AVD）预防原发性粒细胞集落刺激因子（G-CSF）的效果，而Part B和Part C分别评估了Adcetris联合纳武利尤单抗、多柔比星和达卡巴嗪（AN+AD）作为晚期和早期cHL的一线治疗的效果，其中，Part B评估了AN+AD在II期（纵隔肿块≥10cm）、III期或IV期cHL患者的疗效；Part C评估了AN+AD在无大纵隔肿块（＜10cm）的I期或II期cHL患者的疗效。Adcetris+AVD化疗（多柔比星、长春碱、达卡巴嗪）是美国国家治疗指南推荐用于晚期cHL的标准治疗方案，也是唯一一种在6年随访中具有统计学显著总体生存获益的靶向治疗方案，可将患者的死亡风险降低41%。Adcetris在美国获批7个适应症，在欧洲（武田拥有商业化权利）获批5个适应症。 8.迈威生物抗IL-11单抗在美国获批临床 6月14日，迈威生物宣布，其研发的抗IL-11单抗9MW3811注射液临床试验申请正式获得美国FDA批准，可针对特发性肺纤维化开展临床试验。根据迈威生物新闻稿，9MW3811是其研发的靶向人白介素-11（IL-11）的人源化单克隆抗体，可高效阻断IL-11下游信号通路的活化，抑制IL-11诱导的病理生理功能，从而达到对纤维化疾病和肿瘤的治疗效果。临床前研究数据表明，9MW3811能够高亲和力结合IL-11，有效阻断IL-11信号通路的活化，特异性调节肿瘤细胞与T细胞、巨噬细胞以及肿瘤相关成纤维细胞的相互作用，提高肿瘤微环境中炎症性细胞因子的释放，增加T细胞的浸润。在多种实体瘤模型中，可观察到9MW3811与抗PD-1抗体联合抗肿瘤治疗的效果。在纤维化疾病的临床前研究中，该产品可以显著降低纤维化模型小鼠的肺纤维化面积、减少肺胶原含量、改善肺功能。因此，9MW3811在特异性肺纤维化等疾病中具有一定治疗潜力。根据迈威生物新闻稿，9MW3811已在澳大利亚、中国、美国三地分别获批开展临床试验。其中，该产品在澳大利亚开展的临床试验处于剂量爬坡阶段，阶段性数据显示其安全性良好。 9.信达生物申报CD40L抗体 6月13日，信达生物IBI355的临床试验申请获得NMPA受理（受理号：CXSL2300410、CXSL2300411）。IBI355为CD40L抗体，用于治疗自身免疫性疾病，为信达生物在自免领域新一波布局产品的重点，此外还包括OX40L抗体。系统性红斑狼疮（SLE）是一个累及多系统多器官、临床表现复杂、病程迁延反复的自身免疫性疾病，可引起发烧，关节疼痛、皮疹和多器官（大脑、肺、肾脏和心脏）损伤等。我国大约有一百多万SLE患者，并呈逐年增加趋势。系统性红斑狼疮好发于育龄期女性，多为15至45岁女性。在过去的10年中，针对系统性红斑狼疮的药物治疗有了很大的进展，主要是在生物靶向治疗方面。生物靶向治疗是一种相对精准的治疗手段，能最大限度地避开正常的组织细胞，打击靶向目标。目前在探索中的治疗药物基本都是具有一定特异性的“靶向”治疗，针对的靶标也多种多样，包括Ｂ淋巴细胞、Ｔ淋巴细胞、细胞因子和细胞内信号通路等。但是由于系统性红斑狼疮疾病的复杂性，大多数研发的药物都没有成功。目前正处于临床研究阶段的系统性红斑狼疮治疗药物达十余种，为未来系统性红斑狼疮的治疗提供了更多可能的选择。全球范围内，优时比和Biogen的CD40L抗体Dapirozumab pegol已经处于三期临床阶段，用于治疗系统性红斑狼疮。赛诺菲的CD40L抗体Frexalimab处于二期临床阶段，探索多发性硬化症、系统性红斑狼疮、干燥综合征等适应症。 行业资讯 1.阿斯利康与成都市武侯区卫生健康局签订战略合作协议 6月14日，阿斯利康与成都市武侯区卫生健康局宣布，双方签订战略合作协议，将共同共同开展公共卫生和慢病管理研究，此次合作重点关注呼吸系统疾病、肾病、心血管疾病等高发慢性疾病。此次合作将重点关注呼吸系统疾病、肾病、心血管疾病等高发慢性疾病，是阿斯利康全球循证中心中国分部（Global Evidence Powerhub China，简称：GEP China）在慢病领域开展真实世界研究的重要举措之一。按计划，阿斯利康将依托其临床数据可视化平台以及在慢病领域的专业经验，助力完善武侯区慢病数字化平台建设，通过分析当地慢病管理的临床实践和诊疗现状，深入洞察患者未被满足的需求，并提供针对性的专业资源和培训。成都武侯卫健局将提供推动改善患者治疗效果所需的资源，分享临床最佳实践和政策，与阿斯利康共同开展公共卫生和慢病管理研究，推广循证医学实践，推动公众慢病管理教育。成都武侯卫健局田军局长表示：“作为首批全国慢病综合防控示范区之一，武侯区始终高度重视新技术、新理念在临床实践中的应用。近年来，我区卫健局与时俱进，致力于通过数据驱动和数字技术，快速建立有价值的医疗服务体系，不断提高医疗服务质量和效率。此次与阿斯利康达成慢病领域真实世界研究的战略合作，将有助于进一步提升武侯区慢病管理数字化水平，推动慢病临床诊疗规范化，进而增强辖区居民的健康获得感。“阿斯利康中国医学事务部负责人杨海英表示：“阿斯利康深耕中国30年，在肿瘤、心血管、代谢及呼吸等慢病领域积累了深刻的产业洞察。同时，我们拥有全球领先的RWS经验和资源。我们希望发挥自身优势，携手成都武侯卫健局深入发掘患者未满足的需求，借助大数据和循证医学，实现慢病精准管理和提质增效，从而促进公共卫生、提升患者获益。” 2.广济药业与江南大学共同建立联合创新实验室 6月14日，广济药业宣布，公司与江南大学决定共同建立联合创新实验室，专门开展功能性多糖、功能性蛋白（如母乳低聚糖）的绿色制造和生物合成关键技术研究。湖北广济药业股份有限公司始建于1969年，1999年在深交所上市（股票代码000952），是一家致力于生物医药领域的高新技术企业，是湖北省唯一的省属医药上市企业。长江产业投资集团有限公司是广济药业第一大股东。 广济药业主要生产维生素B2、B6以及医药制剂产品，年生产片剂100亿片、颗粒剂3000万袋、乳膏剂300万支、凝胶剂300万支。VB2系列产品的产、销量居世界前列，约占40%的国际国内市场份额，是全球维生素B2产品领域“隐形冠军”。主导产品核黄素（VB2）生产技术曾获国家科技进步二等奖、湖北省科技进步一等奖，被国家商务部列入禁止出口技术目录。广济药业是国内少有的同时兼顾“生物发酵”和“化学合成”技术，并在生物发酵方面具有较强优势的现代化医药企业。设有“武汉-武穴”双总部，下设武穴、咸宁、孟州三大生产基地，广济生物研究院、广济医药科技公司两大研发机构。 “十四五”时期，公司将坚持“内生式拓展+平台化发展+强链补链并购”发展战略，横向扩增医药原料药及制剂、高附加值营养添加剂、生物基材料三大领域的产品管线，纵向按照“原料药+制剂+大健康”战略延伸下游产业链，形成纵横交错的立体产品格局。着力将广济药业打造成为具有世界影响力、国内标杆性的生物发酵“龙头”企业。

- Approval marks fourth indication for VRAYLAR, backed by proven efficacy and well-established tolerability as an adjunctive treatment for major depressive disorder (MDD) with an antidepressant therapy (ADT), showing improvement in symptoms when compared to placebo + ADT - Designed for specific mood disorders, VRAYLAR is now the first and only dopamine and serotonin partial agonist FDA-approved for the most common forms of depression – as an adjunctive treatment for MDD and the treatment of depressive episodes associated with bipolar I disorder - About one in five U.S. adults will experience MDD during their lifetime, and many of them may have partial response to the treatment with an ADT NORTH CHICAGO, Ill. , Dec. 16, 2022 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that the U.S. Food and Drug Administration (FDA) has approved VRAYLAR ® (cariprazine) as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults. Supported by clinical data demonstrating efficacy and well-established tolerability, this additional indication provides a new option for adults who have a partial response to the treatment of an antidepressant. Experience the interactive Multimedia News Release here: https://www.multivu.com/players/English/9107351-vraylar-cariprazine-fda-approval-major-depressive-disorder/ "Many living with major depressive disorder find that their ongoing antidepressant therapy doesn't offer meaningful relief from the symptoms they experience every day," said Thomas Hudson , M.D., senior vice president, research and development, chief scientific officer, AbbVie. "Today's approval of VRAYLAR provides an important new treatment option to meet a critical unmet medical need. AbbVie is committed to driving progress and advancing solutions for patients living with complex neuropsychiatric conditions." MDD is one of the most common mental disorders in the U.S.; approximately one in five adults will experience this disorder during their lifetime. 1 In a large U.S. study of adults with MDD, approximately 50 percent still had depressive symptoms with their first antidepressant. 2 If some symptoms of depression persist while on an antidepressant, adding a different type of medication, often referred to as an adjunctive treatment, to the existing regimen may help. "Patients with inadequate response to standard antidepressant medication are often frustrated by the experience of trying multiple medicines and still suffering from unresolved symptoms. Instead of starting over with another standard antidepressant, VRAYLAR works with an existing treatment and can help build on the progress already made," said Gary Sachs , MD, clinical vice president at Signant Health, associate clinical professor of psychiatry at Massachusetts General Hospital, and lead Phase 3 clinical trial investigator. "For adults living with major depressive disorder, because of inadequate improvement in response to standard antidepressants, VRAYLAR is an efficacious adjunctive treatment option with a well-characterized safety profile." Cariprazine is marketed as VRAYLAR ® in the U.S., and in addition to being approved as an adjunctive therapy to antidepressants for the treatment of MDD in adults, it is FDA-approved to treat adults with depressive, acute manic and mixed episodes associated with bipolar I disorder, as well as schizophrenia. Cariprazine is co-developed by AbbVie and Gedeon Richter Plc. More than 8,000 patients worldwide have been treated with cariprazine across more than 20 clinical trials evaluating the efficacy and safety of cariprazine for a broad range of psychiatric disorders. "When we were in the early stages of development for cariprazine, we focused on designing a compound that covers a range of symptoms for mental health conditions and affects the dopamine D3 receptor," said István Greiner, Ph.D., research and development, director, Gedeon Richter . "While schizophrenia and bipolar manic and mixed episodes were the first indications in the U.S. market, we are thrilled to see the full potential of cariprazine unlocked with approvals in bipolar I depression, and now, as an antidepressant adjunct in major depressive disorder." Highlights from the clinical program supporting the approval include: A Phase 3 Study 3111-301-001 showed a clinically and statistically significant change from baseline to week six in the Montgomery -Åsberg Depression Rating Scale (MADRS) total score for patients treated with cariprazine at 1.5 mg/day + ADT compared with placebo + ADT. A second registration-enabling study, RGH-MD-75, showed a clinically and statistically significant change from baseline to week eight in the MADRS total score for patients treated with cariprazine at 2-4.5 mg/day (mean dose 2.6 mg) + ADT compared with placebo + ADT. Cariprazine was generally well tolerated in 6- and 8-week studies. Mean weight change was < 2lbs and ≤ 3% of patients had a weight increase of ≥ 7%. The starting dosage of VRAYLAR is 1.5 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg once daily on Day 15. In clinical trials, dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions. The maximum recommended dosage is 3 mg once daily. Most common adverse reactions observed in the adjunctive MDD studies (≥ 5% and at least twice the rate of placebo) were: Akathisia, nausea, and insomnia at the recommended doses in 6-week, fixed-dose trials Akathisia, restlessness, fatigue, constipation, nausea, increased appetite, dizziness, insomnia, and extrapyramidal symptoms in one 8-week flexible-dose trial at a titration of less than 14 days About Major Depressive Disorder (MDD) MDD is one of the most common mental disorders in the U.S., characterized by symptoms such as overwhelming feelings of sadness and/or loss of interest that don't go away after two weeks. 3 MDD can cause severe functional impairment, adversely affect interpersonal relationships, and may impact the quality of life. 4 It is a leading cause of disability in the world, 5 and has a lifetime prevalence of 20% for adults in the U.S. 1 Symptoms can include depressed mood, loss of pleasure or interest in activities, feelings of worthlessness, lack of energy, poor concentration, appetite changes, sleep disturbances, suicidal thoughts, and feeling restless or moving or talking more slowly. 3 In the U.S., the estimated economic burden of MDD has been estimated to be around $326 billion in 2020. 6 About Study 3111-301-001 Study 3111-301-001 is a randomized, double-blind, placebo-controlled, multicenter trial with 751 participants conducted in the United States , Bulgaria , Estonia , Germany , Hungary , Ukraine and the United Kingdom . Following a screening period of up to 14 days, patients with an inadequate clinical response to their antidepressant monotherapy (ADT) were randomized into three treatment groups (1:1:1). The first group received cariprazine 1.5 mg/day + ADT, the second group received cariprazine 3.0 mg/day + ADT, and the third group received placebo + ADT. For six weeks, the medication was given once daily in addition to the ongoing ADT treatment. Patients treated with cariprazine 3.0 mg/day + ADT demonstrated improvement in MADRS total score at week six over placebo + ADT but did not meet statistical significance. About Study RGH-MD-75 Study RGH-MD-75 is a randomized, double-blind, placebo-controlled, flexible-dose, outpatient, multicenter trial with 808 participants, conducted in the United States , Estonia , Finland , Slovakia , Ukraine and Sweden . After 7-14 days of screening and washout of prohibited medications, eligible patients entered an 8-week, double-blind treatment period in which they continued antidepressant treatment and were randomized (1:1:1) to adjunctive cariprazine 1-2 mg/day, cariprazine 2-4.5 mg/day, or placebo. Data from Study RGH-MD-75 were published in the Journal of Clinical Psychiatry . 7 Patients treated with cariprazine 1-2 mg/day + ADT demonstrated improvement in MADRS total score at week eight over placebo + ADT but did not meet statistical significance. About VRAYLAR ® (cariprazine) VRAYLAR is an oral, once-daily atypical antipsychotic approved as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults (1.5 or 3 mg/day), for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults (1.5 or 3 mg/day), and for the acute treatment of adults with manic or mixed episodes associated with bipolar I disorder (3 to 6 mg/day). VRAYLAR is also approved for the treatment of schizophrenia in adults (1.5 to 6 mg/day). While the mechanism of action of VRAYLAR is unknown, the efficacy of VRAYLAR is thought to be mediated through a combination of partial agonist activity at central dopamine D₂ and serotonin 5-HT 1A receptors and antagonist activity at serotonin 5-HT 2A receptors. Pharmacodynamic studies with VRAYLAR have shown that it may act as a partial agonist with high binding affinity at dopamine D 3 , dopamine D 2 , and serotonin 5-HT 1A receptors. VRAYLAR demonstrated up to ~8-fold greater in vitro affinity for dopamine D 3 vs D 2 receptors. VRAYLAR also acts as an antagonist at serotonin 5-HT 2B and 5-HT 2A receptors with high and moderate binding affinity, respectively as well as it binds to the histamine H 1 receptors. VRAYLAR shows lower  binding affinity to the serotonin 5-HT 2C and α 1A - adrenergic receptors and has no appreciable affinity for cholinergic muscarinic receptors. 8 The clinical significance of these in vitro data is unknown. VRAYLAR is developed jointly by AbbVie and Gedeon Richter Plc, with AbbVie responsible for commercialization in the U.S., Canada, Japan, Taiwan and certain Latin American countries (including Argentina , Bolivia , Brazil , Chile , Colombia , Ecuador , Mexico , Peru and Venezuela ). Visit www.vraylar.com for more information. VRAYLAR ® (cariprazine) Uses and Important Safety Information VRAYLAR is a prescription medicine used in adults: to treat schizophrenia for short-term (acute) treatment of manic or mixed episodes that happen with bipolar I disorder to treat depressive episodes that happen with bipolar I disorder (bipolar depression) along with antidepressant medicines to treat major depressive disorder What is the most important information I should know about VRAYLAR? Elderly people with dementia-related psychosis (having lost touch with reality due to confusion and memory loss) taking medicines like VRAYLAR are at an increased risk of death. VRAYLAR is not approved for treating patients with dementia-related psychosis. VRAYLAR and antidepressants may increase suicidal thoughts or actions in some children and young adults especially within the first few months of treatment or when the dose is changed. Depression and other mental illnesses are the most important causes of suicidal thoughts and actions. Patients on antidepressants and their families or caregivers should watch for new or worsening depression symptoms, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when VRAYLAR or the antidepressant is started or when the dose is changed. Report any change in these symptoms immediately to the doctor. VRAYLAR may cause serious side effects, including: Stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death Neuroleptic malignant syndrome (NMS): Call your healthcare provider or go to the nearest hospital emergency room right away if you have high fever, stiff muscles, confusion, increased sweating, or changes in breathing, heart rate, and blood pressure. These can be symptoms of a rare but potentially fatal side effect called NMS. VRAYLAR should be stopped if you have NMS. Uncontrolled body movements (tardive dyskinesia or TD): VRAYLAR may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking VRAYLAR. Tardive dyskinesia may also start after you stop taking VRAYLAR. Late-occurring side effects: VRAYLAR stays in your body for a long time. Some side effects may not happen right away and can start a few weeks after starting VRAYLAR, or if your dose increases. Your healthcare provider should monitor you for side effects for several weeks after starting or increasing dose of VRAYLAR. Problems with your metabolism, such as: High blood sugar and diabetes: Increases in blood sugar can happen in some people who take VRAYLAR. Extremely high blood sugar can lead to coma or death. Your healthcare provider should check your blood sugar before or soon after starting VRAYLAR and regularly during treatment. Tell your healthcare provider if you have symptoms such as feeling very thirsty, very hungry, or sick to your stomach, urinating more than usual, feeling weak, tired, confused, or your breath smells fruity. Increased fat levels (cholesterol and triglycerides) in your blood: Your healthcare provider should check fat levels in your blood before or soon after starting VRAYLAR and during treatment. Weight gain: Weight gain has been reported with VRAYLAR. You and your healthcare provider should check your weight before and regularly during treatment. Low white blood cell count: Low white blood cell counts have been reported with antipsychotic drugs, including VRAYLAR. This may increase your risk of infection. Very low white blood cell counts, which can be fatal, have been reported with other antipsychotics. Your healthcare provider may do blood tests during the first few months of treatment with VRAYLAR. Decreased blood pressure (orthostatic hypotension): You may feel lightheaded or faint when you rise too quickly from a sitting or lying position. Falls: VRAYLAR may make you sleepy or dizzy, may cause a decrease in blood pressure when changing position (orthostatic hypotension), and can slow thinking and motor skills, which may lead to falls that can cause fractures or other injuries. Seizures (convulsions) Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities: Do NOT drive, operate machinery, or do other dangerous activities until you know how VRAYLAR affects you. VRAYLAR may make you drowsy. Increased body temperature: Do not become too hot or dehydrated during VRAYLAR treatment. Do not exercise too much. In hot weather, stay inside in a cool place if possible. Stay out of the sun. Do not wear too much clothing or heavy clothing. Drink plenty of water. Difficulty swallowing that can cause food or liquid to get into your lungs Who should not take VRAYLAR? Do not take VRAYLAR if you are allergic to any of its ingredients. Get emergency medical help if you are having an allergic reaction (eg, rash, itching, hives, swelling of the tongue, lip, face or throat). What should I tell my healthcare provider before taking VRAYLAR? Tell your healthcare provider about any medical conditions and if you: have or have had heart problems or a stroke have or have had low or high blood pressure have or have had diabetes or high blood sugar in you or your family have or have had high levels of total cholesterol, LDL-cholesterol, or triglycerides; or low levels of HDL-cholesterol have or have had seizures (convulsions) have or have had kidney or liver problems have or have had low white blood cell count are pregnant or plan to become pregnant. VRAYLAR may harm your unborn baby. Taking VRAYLAR during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you take VRAYLAR during pregnancy. If you become pregnant or think you are pregnant during treatment, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or http://www.womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . are breastfeeding or plan to breastfeed. It is not known if VRAYLAR passes into breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with VRAYLAR. Tell your healthcare provider about all medicines that you take, including prescriptions, over-the-counter medicines, vitamins, and supplements. VRAYLAR may affect the way other medicines work, and other medicines may affect how VRAYLAR works. Do not start or stop any medicines while taking VRAYLAR without talking to your healthcare provider. What are the most common side effects of VRAYLAR? The most common side effects include difficulty moving or slow movements, tremors, uncontrolled body movements, restlessness and feeling like you need to move around, sleepiness, nausea, vomiting, indigestion, constipation, feeling tired, trouble sleeping, increased appetite, and dizziness. These are not all the possible side effects of VRAYLAR. Please see the full Prescribing Information , including Boxed Warnings, and Medication Guide . You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. If you are having difficulty paying for your medicine, AbbVie may be able to help. Visit AbbVie.com/myAbbVieAssist to learn more. About AbbVie in Mental Health AbbVie is driving the pursuit of better mental health. Over the last 30 years, the company's scientists and clinicians have worked to tackle the complexity of mental illness and today offer a portfolio of medicines and a pipeline of innovation that spans depression, anxiety, bipolar I disorder, and schizophrenia. To learn more about AbbVie's work to support individuals throughout their mental health journey, please visit www.abbvie. com or follow @abbvie on Twitter , Facebook , Instagram , YouTube and LinkedIn . About AbbVie AbbVie's mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women's health and gastroenterology, in addition to products and services across our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com . Follow @abbvie on Twitter , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statements Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, failure to realize the expected benefits from AbbVie's acquisition of Allergan plc ("Allergan"), failure to promptly and effectively integrate Allergan's businesses, competition from other products, challenges to intellectual property, difficulties inherent in the research and development process, adverse litigation or government action, changes to laws and regulations applicable to our industry and the impact of public health outbreaks, epidemics or pandemics, such as COVID-19. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2021 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law. US-VRAA-220055 References: Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States . JAMA Psychiatry . 2018;75(4):336-346. Trivedi MH, Rush AJ, Wisniewski SR, et al. Am J Psychiatry. 2006;163(1):28-40. National Institute of Mental Health (2022). Depression. Available at: https://www.nimh.nih.gov/health/topics/depression . Accessed December 2022 . Bains N, Abdijadid S. Major Depressive Disorder. [Updated 2022 Jun 1 ]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK559078/ . Accessed December 2022 . Friedrich MJ. Depression Is the Leading Cause of Disability Around the World . JAMA. 2017;317(15):1517. Greenberg P, Fournier AA, Sistsky T, et al. Pharmacoeconomics. 2021;39(6):653-65. Durgam S, Earley W, Guo H, et al. J Clin Psychiatry. 2016;77(3):371-8. VRAYLAR. Package insert. Allergan USA , Inc; 2022. Contacts US Media Mary Byun +1 (646) 709-4409 mary.byun@abbvie.com Global Media Mabel Martinez +1 (224) 306-4412 mabel.martinez@abbvie.com Investors Liz Shea +1 (847) 935-2211 liz.shea@abbvie.com SOURCE AbbVie