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她,值得更多关爱

华义文 华义文 来源:医药魔方
2019-03-08
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原文


你可曾知道,令你魂牵梦萦的她,也有难言之隐,也受病痛之苦,也需要你的关爱。都说女人能顶半边天,但在人类繁衍后代过程中,女性承担更多职责。也正因为如此,有些疾病是女性特有或是主要发病人群,这就需要医药行业中的你我他给予多一份关注和付出。

 

本文针对常见妇产科疾病,简单介绍一下新近批准或在研的药品与器械,希望有助于大家对女同胞们多一点了解。


01

引子

 

20世纪五六十年代震惊世界的“反应停”事件,不仅成就了弗朗西丝·凯尔西博士(Frances Kathleen Oldham Kelsey, Ph.D., M.D.)博士的英雄美名,也奠定了美国FDA在药品监管领域的全球领先地位,同时留给一万多个“海豹婴儿”及其家庭无限的痛苦。这一事件虽然过去了半个多世纪,但时至今日仍然被反复提及,时刻提醒着医药行业新产品研发过程中安全性研究的重要性,也告诫着医药产品监管部门科学严谨审评的意义。

 

不过,人们往往忽视了一点,那就是事件的起因:妊娠期呕吐(Nausea and Vomiting of Pregnancy,NVP),俗称孕吐或晨吐(Pregnancy or Morning Sickness),古人称为害喜。这是怀孕初期的孕妇所产生的恶心、呕吐等现象,通常在清晨起床时其症状最为严重。根据不同文献分析,全球约70%-80%孕妇经历孕吐,而妊娠剧吐(Hyperemesis Gravidarum)的比例约为1.1%。这个阶段有多难受,有过妊娠经历的女性深有体会,至于没有相关经历的人士可以咨询过来人。

 

当然,身为女性,一生中可能遭受的痛苦远不止如此。

 

02

大姨妈来了,别烦我

 

上初中那会儿,男生们发现女生们十分矫情,而且还有一项特权,那就是动不动就可以跟体育老师请假,可以旁观或者在教室里待着。后来男生们才渐渐了解到女生们每个月总有那么几天都有一个称为“大姨妈”的亲戚定期来访,而且给女生们带来很多不便。最为常见的表现是痛经(Dysmenorrhea,Menstrual Cramps),严重者可服用布洛芬、对乙酰氨基酚等止痛药或激素类避孕药缓解疼痛。还有一种表现则需要使用“想怎么动就怎么动的姨妈巾”,但如果流量过大,就可能是一种病症了。

 

月经过多

月经量每月超过80ml,就是月经过多。但是如何判断80ml是较为主观的,大概每1-2个小时就湿透一片大的卫生巾或卫生棉,就说明月经量偏多。根据不同文献统计,在育龄期女性中9%-30%有月经过多,发生率随年龄增长,在停经前到达峰值。

 

氨甲环酸,前段时间成为热门话题是因为关于在牙膏中添加此物是否合规的讨论。临床上,这是一种用于手术中止血的老药了,早在1962年就由日本女科学家冈本歌子(Utako Okamoto)发现。但是直到2009年11月才被美国FDA批准用于月经过多,该产品是来自全球知名妇产科制药公司瑞士辉凌制药(Ferring)的Lysteda。

 

除此之外,治疗女性相关病症似乎都离不开雌激素,月经过多同样如此。2012年3月,美国FDA批准拜耳Natazia用于治疗月经过多。本品一个疗程包括28片,包括

2片深黄色含3mg戊酸雌二醇

5片中红色含2mg戊酸雌二醇和2mg地诺孕素

17片浅黄色含2mg戊酸雌二醇和3mg地诺孕素

2片深红色含1mg戊酸雌二醇,以及

2片白色空白片

 

治疗手段不仅有药物,还有器械,例如Channel Medsystems开发Cerene冷冻疗法仪器。和现有子宫内膜切除仪器不同的是,该产品无需热源,也无需麻醉镇静,全程不到三分钟。在仪器探头达到子宫底部,二氧化氮释放从而使充气袋迅速膨胀并与子宫内膜接触。二氧化氮可以冷却目标组织,而充气袋可以避免对周围组织产生不必要的损伤。

 

2017年,Channel Medsystems迎来了收获,先是在3月完成美国的关键临床试验开始收集整理数据准备申报上市,很快在6月获得欧盟CE认证,用于已育女性绝经前月经过多。11月又与已经拥有20%股份的行业巨头波士顿科学(Boston Scientific)达成协议,一旦在2019年9月30日前获得美国FDA批准就以2.75亿美元收购剩余80%股份。然而就在辉煌的2017年即将画上圆满句号的时候,突然爆出公司质量副总裁涉嫌通过空壳公司贪污300万美元。尽管公司采取措施并声明不影响产品在美国的上市计划,但是波士顿科学认为受到欺诈宣布取消收购计划。在商谈无果后,Channel Medsystems于2018年9月12日起诉波士顿科学要求其履行先前达成的收购协议。开庭日期定在2019年4月15日。



03

生个娃,好辛苦啊

 

人世间最神奇的事情无疑是生命的孕育,繁衍生息、开枝散叶是生命的本能,子孙满堂是每个人所向往。然而,先别说“推干就湿,耗尽心血,看着他们平平安安成人,教他们堂堂正正做人,甚至指望他们克绍箕裘光大祖业”,纵然现代医学如此发达,光是十月怀胎、一朝分娩就已经让母亲在鬼门关走一遭了。

 

不孕不育

 

想要传承后代,首先是能够顺利怀孕。但是,在全球范围内有将近10%的适龄夫妇因各种原因正遭受不孕不育的困扰。而在中国,大约八对夫妇中会有一对在尝试怀孕一年之后仍然没有受孕。加上放开二胎政策后高龄夫妇备孕,我国的不孕不育率预计会从2017年的15.5%上升到2023年的18.1%。他们中许多人寄希望于体外受精(In Vitro Fertilization)这样的辅助生殖技术,俗称试管婴儿技术,是指将精子和卵子取出后在体外受精,形成受精卵,再将受精卵在体外继续培养一段时间,将所形成的胚胎移植入母体子宫的助孕技术。但受各种因素影响,试管婴儿并不总能成功。

 

致力于女性生殖健康的瑞士ObsEva公司开发的Nolasiban作为一款口服催产素受体拮抗剂,有望减少子宫收缩,增强子宫血流量,提高子宫内膜对胚胎植入的接受程度。ObsEva在2013年从德国默克获得全球权益。在已经结束的一项3期临床试验结果来看,显示相比安慰剂的成功率提高7-11%。虽然仅有区区10%左右,但是对于不孕不育症夫妇来说已经增加了很多希望。ObsEva已经于2018年11月在欧洲启动另一项3期临床试验,并计划在2019年底在欧洲提交上市申请。

 

Myovant正在开发的MVT-602是一种寡肽kisspeptin激动剂,可以在辅助生殖技术中用于治疗女性不孕。Kisspeptin是一种天然多肽,刺激促性腺激素释放激素(GnRH)释放。这种激素是青春期发育和维持正常生殖功能所必须,包括精子生成、卵泡成熟和排卵,以及女性雌激素和孕酮生成和男性睾酮生成。该项目正在进行2a期临床试验,预计在2019年上半年公布初步数据。其实这家致力于女性健康的Myovant公司为业界所津津乐道的不止是手上的项目,更多的是其背后的传奇色彩(见:2016最牛Biotech:成立4个月,IPO募资$2.18亿,估值$8.78亿)。


不过,虽然历经艰辛,但成功怀孕还只是第一步,在妊娠过程中还会经历很多坎坷。

 

子痫前期

又称先兆子痫,指妊娠24周后,出现水肿、高血压、蛋白尿,并兼有头痛、眩晕、呕吐、上腹不适、视力障碍或血压收缩压在160毫米汞柱(21.3kPa)以上。如果得不到及时有效干预,有可能发展为子痫甚至产妇死亡。综合各类文献报道,子痫前期的发病率在2%-10%之间。子痫前期加上子痫是造成产妇死亡的四大原因之一(其余为产后出血、感染和不安全引产),占比10%-20%。

 

美国AMAG制药公司正在开发一项治疗子痫前期的药物地高辛免疫抗原结合片段(羊源)DIF,该项目从另一家美国公司Velo Bio处获得。后者已经在2017年中期启动了2b/3a期临床试验,预计在2020年上半年公布数据并计划在2020年下半年向美国FDA提交上市申请。此前,美国FDA已经授予孤儿药和快速通道资格。

 

早产

人类正常妊娠周期是40周,而妊娠不满37孕周分娩即为早产。按照妊娠周期又可以将早产分为:

少于28周,极为早产,占比约5%

28-31周,重度早产,占比约15%

32-33周,中度早产,占比约20%

34-36周,轻微早产,占比约60%-70%

 

全球每年约有1500万早产儿,各个国家的早产率差异较大,范围5%-18%。其中北欧地区为5%,而撒哈拉沙漠以南非洲地区及部分亚洲国家超过15%以上。我国早产率约为7%,接近欧洲地区6.2%,甚至优于北美地区的10.6%。但即使如此,鉴于我国庞大人口基数和每年新生人口数,每年的早产儿绝对数仍然高达约120万,约为印度的三分之一,高居全球第二位。

 

美国AMAG制药公司的另一个产品Makena己酸羟孕酮注射液于2011年2月被美国FDA批准用于预防早产。本品原研是Hologic公司,后来辗转被AMAG获得。

 

瑞士ObsEva公司正在开发的OBE022是一种新型的口服前列腺素F2alpha(PGF2α)的受体拮抗剂,目前正在进行用于早产治疗的2a期临床试验。PGF2α收缩子宫肌层,造成羊水之前和生成期间代谢产物增加。PGF2α也上调酶引起宫颈扩张和膜破裂。OBE022通过特异性抑制PGF2α受体,并安全控制炎症,它不仅具有抑制子宫收缩也能防止早产导致宫颈变化。

 

在已经完成的2a期第一部分开放标记临床试验中发现,共9位有早产症状的孕妇中有8位在用药7天内没有分娩,只有1位在用药第2天分娩。目前已经在欧洲和亚洲部分国家启动2a期第二部分双盲临床试验。

 

怀胎十月,一朝分娩。新生命降临人间,全家人沉浸在添丁喜悦之中,这个时候焦点集中在新生儿上,但是不要忘记还需要持续关注产妇健康。

 

产后出血

 

《活着》 是中国当代文学一部重要作品,也是新中国电影史上难以忽略的重要作品。其中有一个情节是这样的:福贵的女儿凤霞难产,女婿万二喜找来了被关在牛棚里饿了三天的资深妇产科医生王医生。饿坏了的王医生将福贵买来的七个馒头一口气吃下,又喝了水,胀得无法动弹了。此刻,凤霞虽然用尽力气生下一个男孩,但出现产后大出血,面对这种紧急状况,一帮子抢班夺权的红卫兵护士手足无措,而经验丰富的王医生已经昏过去。可怜的凤霞,因为小时候一场高烧成为聋哑人,都没能发出呻吟就这样走完了这苦命的一生。

 

产后24小时内阴道失血量超过500ml即为产后出血,如果超过1000ml就是重症。前面提过,产后出血是产妇死亡的四大原因之一。全球产后出血的发病率约占分娩总数的2%。产后出血导致产妇死亡率占分娩总数的千分之一,绝大多数发生在欠发达地区,而发达地区控制在十万分之一。

 

正因为在欠发达地区产后出血造成产妇死亡的风险极高,因此便于运输储存的药物十分重要。世卫组织联合美国默克和瑞士辉凌开展了一项热稳定卡贝缩宫素的研究,其中热稳定卡贝缩宫素由辉凌免费提供。这种药品不需要冰箱保存,在30摄氏度和75%相对湿度条件下可以保存3年。由于欠发达地区也集中在温湿度较高地区,医疗条件落后,因此这种药品对于该地区降低产妇死于产后出血大有裨益。

 

前文提到的老药氨甲环酸也同样适用于治疗产后出血,机理其实是一回事。只不过,由于产后出血属于急症,因此剂型采用的是注射剂,而前文提到用于月经过多则采用片剂经口服用。

 

除了采用药物进行止血治疗,美国Alydia公司在研发一款器械。该产品利用真空产生负压,促使子宫迅速收缩,自然关闭血管开口,从而达到快速止血的效果。在已经完成的初步试验中,10位产妇都能在数分钟内迅速有效控制产后出血。2018年9月,公司完成1000万美元B轮融资用以关键临床试验支持向美国FDA提出510(K)申请。该试验计划在美国招募107位产妇。


产后抑郁

虽说孩子诞生是一件开心的事情,但是大约70%-80%的新妈妈都会在分娩后有情绪波动,这种现象称为“Baby Blue”(婴儿忧郁症),一般维持数小时到数天,可自行消退,多加安抚即可,无须治疗。另有10%-15%新妈妈会患上产后抑郁,主要表现为情绪低落、了无生趣、健忘、焦虑、失眠以及易发怒,持续时间有数周甚至几个月,这就需要采取治疗措施了。严重者会患上精神疾病,甚至导致自杀,就必须住院治疗,这个比例大约是0.1%-0.2%。

 

其实,用于治疗抑郁的药物有不少,但通常临床试验都不会入组妊娠期或哺乳期女性。因此,这些药物在临床上使用也都是存在风险的。因此,如果有一款直接针对产后抑郁的药物,那对于受此折磨的新妈妈来说是非常有帮助的。

 

美国Sage Therapeutics公司专注于中枢神经系统疾病新药研发,有一个静脉给药项目Brexanolone用于治疗产后抑郁。Brexanolone是一种可同时作用于突触和突触外GABAA受体的变构调节剂。神经递质受体活动的变构调节能产生各种不同程度的所期望的活动,而不是完全激活或完全抑制。

 

该产品早在2016年9月就已经被FDA授予突破性疗法资格。2018年4月Sage向美国FDA提交了的新药上市申请,并且在同年11月被美国FDA两个咨询委员会以17:1压倒性通过支持其上市,不过需要另行提交一份包含安全使用保障措施的风险评估和应对策略方案(Risk Evaluation and Mitigation Strategies)。Sage很快就提交了这份方案,不过FDA需要更多时间审查这份方案,因此PDUFA日期从原先的2018年12月19日推迟到2019年3月19日。这会是给广大新妈妈的一份迟来的三八节礼物吗?让我们拭目以待。

 

性欲障碍

 

食、色,性也。但是人类的本能也可能会存在困难。男人常见的性功能障碍可以通过服用万艾可、希爱力、必利劲等耳熟能详的药物促进血液循环,提高性功能。女人却不一样。最常见的女性性功能障碍是性欲障碍,是对性幻想和性行为欲望的缺失。这是一种精神疾病,发病率约为10%。

 

2015年8月,美国FDA批准Addyi氟班色林用于治疗绝经前女性广泛性欲障碍。一时间引起热议,Addyi也被称为“女性伟哥”或“伟姐”。这个产品原本是勃林格殷格翰手中近乎烂尾的项目。Sprout公司2012年接手后以死缠烂打的劲头获得批准其上市,仅仅2个月后,Valeant以10亿美元收购Sprout。但是,Addyi是一款存在天然缺陷的药物,起效缓慢,甚至需要提前数周每日服用,明显不符合实际需求;加上眩晕、低血压、昏迷和嗜睡等不良反应,且不能与酒精同时服用,根本不受市场待见。原本以为大卖,销量实际上差强人意。甚至销售团队都被解散了。


正因如此,下一款“女性伟哥”更值得期待了。美国Palatin公司的Bremelanotide的PDUFA日期就在2019年3月23日。这是一种首创的黑皮质素4受体激动剂,具有一种新颖的作用机制,能够激活大脑内参与人体正常性欲和性欲唤醒反应的内源性黑皮质素通路。申请的剂型是一种预充式一次性自动注射笔,由女性患者进行自我皮下注射,相比口服剂型,显得不是那么浪漫。2017年2月,Palatin将北美权益转让给AMAG,同年9月将中国(包括大陆、台湾、香港、澳门)权益转让给复星医药,11月将韩国权益转让给KwangDong。


相比注射剂,人们可能还是更加期待口服剂型,毕竟方便许多,且没有挨一针的痛。美国S1生物制药公司的Lorexys是一种口服复方制剂,含有两种抗抑郁药安非拉酮和曲唑酮。S1设计的处方配比可以使得多巴胺、5-羟色胺和去甲肾上腺素保持平衡,而这正是在人体内调节性抑制和性兴奋的三种神经递质。目前正在推进2b期临床试验,后续将以505(b)(2)途径申请上市。

 

避孕


虽然孕育生命是一个神奇的过程,但并不是在任何时候都期盼着新生命的,尤其是要得到男女双方共同认可。然而在以往,是否使用避孕套的决定权,更多掌握在男性手上。考虑到使用感、获取途径或生育目的,即使有避孕套,女性也往往也没有办法阻止性行为带来的不断怀孕的结果。而避孕药的诞生给女性提供了更多的选择权,不必纠结男性愿不愿意使用,女性自己掌握主动权。

 

在过去半个世纪,人类已经发明了很多种避孕药。除了常见的口服药片,还有注射剂、埋植剂、阴道环、避孕贴等。女性可以根据自己的生活喜好自主选择适合自己的避孕方式。

 

德国制药巨头拜耳研发的新型长效宫内节育器Kyleena在2016年先后获得美国FDA和欧盟EMA批准上市。Kyleena是一种新的低剂量左炔诺孕酮宫内缓释系统(LNG-IUS),可随时取出,在取出后女性可快速恢复正常生育能力。Kyleena是一个小型、柔性、塑料材质的T形设备,含有19.5mg的合成激素左炔诺孕酮。Kyleena尺寸为28毫米 x 30毫米,置管直径为3.8毫米。Kyleena一旦放置于子宫内后,能够持续释放低剂量的左炔诺孕酮,可提供长达5年的避孕效果。

 

对于美国Agile公司来说,2017年12月原本是收获的季节,然而等来的是美国FDA的完全回复函。该回复函中指出Agile公司开发的低剂量激素复方避孕贴Twirla黏附力检测方法存在缺陷,对第三方生产商Corium审计中发现观察项,以及对体内黏附性欲临床试验结果之间的关系存在疑问。在与FDA下属骨科生殖和泌尿药物咨询委员会商讨之后,公司决定开展与另一款上市避孕贴产品Xulane进行关于黏附力的非劣对比研究,预计在2019年第一季度完成试验,并在上半年再度提交上市申请。Twirla采用Agile公司专有Skinfusion技术在七天中递送乙炔雌二醇和左炔诺孕酮。该产品每周一贴,共三周,另一周无须使用贴剂,可以提高使用者顺应性。

 

Annovera是一种阴道避孕药环,形状是一个柔软的硅橡胶环状物,直径约5.715厘米,环内含醋酸烯诺孕酮(Segesterone Acetate)和乙炔雌二醇。使用时放置在阴道:放置21天、取出7天,可避孕28天。放置期间,Annovera所含的激素会通过环壁按一定速率释放,被阴道粘膜吸收,发挥避孕作用。妇女可自己放置和取出,每个Annovera可重复使用1年。该产品在2018年8月被美国FDA批准上市。

 

除了最为常见的激素类避孕药,还有一些非激素类产品已经批准上市或正在为之努力。

 

乌利司他(Ulipristal)是一种选择性孕酮受体调节剂,对孕酮受体有拮抗和部分激动作用。它与人体内孕酮受体结合从而阻止孕酮与孕酮受体的结合。2009年和2010年先后被欧盟EMA和美国FDA批准30mg规格上市用于120小时(5天)内无保护性交或避孕失败的紧急避孕。另有5mg规格批准用于治疗子宫肌瘤。

 

美国Evofem公司开发的Amphora是一种多功能阴道pH调节剂,含有左旋乳酸、柠檬酸和重酒石酸钾。公司开发成凝胶剂,可以将阴道pH调节到正常范围3.5到4.5之间,从而保持酸性环境,这可以抵御精子以及病毒和细菌病原体,但是对健康菌群无害。早在2015年,公司就提交过新药上市申请,但是在2016年4月收到美国FDA开具的完全回复函,指出在美国和俄罗斯的队列研究中存在差异。在重新进行临床试验后,如果顺利,公司计划在2019年第二季度提交新药上市申请。本品还在开发用于细菌性阴道病和淋病等妇科疾病。

 

除了药,也有器械。Femasys开发的一款女性永久避孕系统FemBloc,无须麻醉或植入。这其实是一种生物聚合物,可以使人体自身在输卵管中启动伤口修复从而形成伤疤组织,实现永久关闭输卵管。在早期人体试验中,没有发现明显不良反应,并已经开始一项500位受试者的关键试验,目前已经完成100位受试者试验。

 

04

更年期大妈不是好惹的

 

月经到来,意味着女性开始发育,也伴随着各种苦恼,逐渐具备生育能力。而停经则意味着女性生育期的结束。虽然月经褪去是一种自然生理现象,但是也会给女性带来诸多不适,影响生活质量。这些症状包括潮热伴随盗汗、睡眠紊乱、关节疼痛以及泌尿生殖系统症状,包括性欲低下、性交困难和膀胱失禁。引起上述症状的主要原因是雌激素水平变化,而造成这一变化的原因便是卵巢老化。约85%绝经后女性都会出现至少一种停经症状。这就是常说的更年期犯了。

 

血管舒缩症状

 

停经会导致中重度血管舒缩症状,通俗来说就是更年期女性因自身激素水平下降而导致的更年期症状,通常表现为潮热和盗汗。随着卵巢停止产生激素,循环雌激素水平降低,会经常发引发血管舒缩症状,以及睡眠和情绪紊乱和泌尿生殖系统问题。潮热(包括盗汗)是最常见的症状,80%的女性受此影响,其可使人衰弱,并在绝经后持续数年。

 

既然是激素水平下降导致的症状,那直接补充激素就是一个不错的办法。辉瑞的Duavee(雌激素和巴多昔芬结合物)于2013年10月被美国FDA批准上市。2018年10月美国FDA批准TherapeuticsMD公司的Bijuva上市,该产品由1毫克雌二醇和100毫克黄体酮构成复方胶囊。这是FDA批准的第一款生物相同(bio-identical)的组合激素替代疗法,即在分子上与女性体内产生的激素相同。

 

不过直接采用激素替代疗法,会产生一定不良反应。如Bijuva最常见的不良反应(≥3%)包括乳房胀痛、头痛、阴道出血、阴道溢液和骨盆疼痛。已经批准上市的非激素疗法有2013年7月Noven制药的Brisdelle(7.5mg低剂量甲磺酸帕罗西汀),而10mg等以上规格则被批准用于治疗抑郁症。

 

Fervent制药在开发的非激素疗法并不是新化合物,而是从众多老药中寻找安全性得到充分认知的活性成分,即氢溴酸右美沙芬。该项目FP-101已经完成2A期临床试验,最终将通过505(b)(2)途径申请上市。

 

KNDy神经元可以增加卵巢的雌激素合成并在温度调节中发挥作用。当更年期卵巢不能合成足够的雌激素时,KNDy神经元会释放出更多的信号。这些信号将同时影响女性体温调节,进而因其潮热的发生。比利时Ogeda公司开发的G蛋白偶联受体(GPCR)即NK3受体拮抗剂Fezolinetant可以通过直接作用于神经元来减少KNDy的调节活动。该公司在2017年被安斯泰来整体收购。目前,Fezolinetant已经完成2b期临床试验,在大部分队列中四项终点全部达到。目前正在准备3期临床试验。

 

英国KaNDy公司已经完成第三轮融资,获得2500万英镑用于NT-814的临床试验。该产品同时作用于NK1和NK3受体,用于改善包括潮热、睡眠和情绪问题在内的多种绝经期症状。目前在进行2b期临床试验,预计于2019年底获得初步数据。

 

应该说制药公司对这个疾病的关注还是比较多的,其实此前批准的药物还有不少,在此不一一列举了。

 

绝经期泌尿生殖综合征


又称外阴阴道萎缩(vulvovaginal atrophy,VVA),是阴道组织雌激素减少引起的一种常见的慢性进行性病症,症状包括阴道干燥、刺激、瘙痒、疼痛、灼烧、尿频尿急以及性交困难等。该病症在女性一生任何阶段都有可能出现,但更常见于绝经后,绝经后的发病率约为50%,而且其中50%-60%患者并未选择就医,也只有25%患者会获得相应治疗。由于绝经期外阴阴道萎缩与生理、组织和解剖学相关,因此和血管舒缩症状(潮红、盗汗)不同的是,如果不采取治疗干预,外阴阴道萎缩是不会消退的。

 

不过,既然同血管舒缩症状一样都是由激素水平下降导致的症状,那直接补充激素同样是一个不错的办法。2018年5月美国FDA批准TherapeuticsMD公司的Imvexxy上市,这是一种雌二醇阴道插入物,用于治疗绝经引起的外阴阴道萎缩症状之一的中重度性交困难。

 

普拉睾酮(脱氢异雄酮,DHEA)主要由肾上腺皮质和卵巢产生,是绝经后女性性腺外激素的重要前体。DHEA及其硫酸盐转化为雌酚酮或睾酮,睾酮随即在性腺外组织内(如大脑、骨骼和脂肪)演变为雌二醇或双氢睾酮。2016年11月,美国FDA批准Endoceutics的Intrarosa上市,这是一种普拉睾酮阴道插入物,用于绝经期因雌激素水平下降引起外阴阴道萎缩导致中度至重度性交疼痛的治疗。

 

奥培米芬片(Ospemifene)由日本盐野义公司开发,并在美国(Osphena,2013年2月;2019年1月)和欧盟(Senshio,2015年1月)批准上市,用于治疗绝经引起外阴阴道萎缩的症状,包括中重度性交困难和中重度阴道干燥。其中北美市场权益后被Duchesnay收购。

 

绝经后骨质疏松


骨质疏松是骨强度显著下降的一种骨病,后果是骨折风险上升。根据世卫组织,全球30%的50岁以上女性患有骨质疏松。造成老年女性骨质疏松的主要原因是绝经后雌激素缺失。我国老年人骨质疏松的发病率约为15.7%,男女比例约1.0:1.61。

 

目前市场上治疗骨质疏松的药物主要分成四类:1)抑制吸收,即抑制成骨细胞的二磷酸盐类药物,如诺华的唑来膦酸;2)选择性雌激素受体调节剂,如礼来的雷洛昔芬,以及前文提到的辉瑞的Duavee(雌激素和巴多昔芬结合物);3)促骨合成的甲状旁腺素类似物,如礼来的特立帕肽;以及4)单抗药物,如安进的RANKL受体激动剂地诺单抗。

 

目前的研发重点也集中在后面两类药物。如2017年4月被美国FDA批准的Abaloparatide也是一种甲状旁腺激素相关蛋白[PTHrP(1-34)]类似物,能与甲状旁腺受体1结合,从而起到调节代谢,促进骨骼形成的作用。Abaloparatide最初由Ipsen研发,后转让给Radius Health。

 

而安进与UCB联合开发的Romosozumab是一种靶向抑制骨形成信号通路的单抗药物,可抑制骨硬化蛋白(sclerostin)的活性,从而加速骨形成,同时可减少骨吸收。本品已经在2019年1月8日获得日本PMDA批准上市。虽然美国FDA在2017年拒绝批准其上市,为此安进和UCB补充研究重新提交申请。2019年1月16日宣布FDA下属骨科生殖和泌尿药物咨询委员会在以压倒性优势投票通过支持本品上市。欧盟EMA也正在审评之中。随着本品陆续在主要国家批准上市,安进在骨质疏松领域的地位得到进一步巩固。


 

05

广告说洗洗更健康,男人问为啥啊?

 

女阴阴道念珠菌病

 

念珠菌阴道炎或女阴念珠菌感染,大多数是由白念珠菌引起。约70%-79%成年女性一生中会出现至少一次,且50%女性会复发。如果每年患病三次及以上就称为复发性女阴阴道念珠菌病(RVVC),影响约5%-8%女性。疾病多发生在育龄期女性,在妊娠最后三个月也是较为常见的,而到了绝经期后就减少。

 

Ibrexafungerp是结构独特的葡聚糖合成酶抑制剂,被世卫组织认可为全新类别三萜抗真菌药。本品原本由Scynexis和美国默克联合开发,后被默克放弃并由Scynexis继续开发用于多种真菌感染治疗和预防。目前用于治疗女阴阴道念珠菌病的临床试验处于3期,计划在2020年提交上市申请。

 

美国Mycovia 公司的VT-1161是一种真菌CYP51抑制剂,可以阻断真菌细胞膜重要成分麦角固醇的产生,目前正在开展3期临床试验,预计2020年下半年完成。

 

细菌性阴道病


细菌性阴道病是阴道炎最常见的原因,治疗一个月后的复发率约20%-40%;这也是育龄期女性阴道溢液最常见的原因,占全部病例的40%-50%。细菌性阴道病发病与正常阴道菌群变化有关,如从乳酸菌变为包括兼性厌氧菌在内的多种细菌,新菌落产生挥发性胺,以及阴道pH上升到4.5以上(正常范围4.0-4.5)。

 

美国Symbiomix公司的塞克硝唑是一种强效5-硝基咪唑抗生素,于2017年9月被美国FDA批准上市,用于治疗成年女性的细菌性阴道病。这是唯一一款治疗细菌性阴道病的单剂口服疗法。

 

前文提到过美国Evofem公司开发的Amphora凝胶是一种多功能阴道pH调节剂,可以将阴道pH调节到正常范围内。除了可以抵御精子,也可以消灭细菌病原体。目前也在开发用于细菌性阴道病。

 

美国Starpharma开发的VivaGel BV是一种非抗生素水性阴道凝胶,用于治疗细菌性阴道病和预防复发性细菌性阴道病。本品已经在欧洲和澳大利亚批准上市,不过美国FDA在2018年12月提出需要更多临床数据。

 

上述五个抗菌药品种都获得了FDA的QIDP认证资格。


06

啥才是真正的老窝?

子宫肌瘤


这是子宫平滑肌增生形成的良性肿瘤,较为常见,基本上都发生在育龄期女性,发病率为20%-40%,风险随年龄增长,到停经时达到峰值。一部分子宫肌瘤没有症状,所以也不会被诊断出来。子宫肌瘤通常会引起经期疼痛、非经期阴道出血、不孕、贫血等。另外,对于症状性子宫肌瘤,最常见的治疗手段是子宫切除术。

 

前文提到的乌利司他30mg规格已经被欧盟EMA和美国FDA批准上市用于紧急避孕。乌利司他作为一种选择性孕激素受体调制器而发挥作用,其直接作用于三个目标组织,即子宫内膜、子宫肌瘤和脑下垂体的孕酮受体,该化合物以5mg规格也被欧盟EMA批准用于治疗子宫肌瘤。不过由于有几位患者因用药产生严重肝损伤,因此EMA药物警戒风险评估委员会经过审慎调查,建议对其用药进行限制,采取措施来降低该药肝损伤风险,包括禁用于已知肝脏问题患者,在治疗前中后进行肝功能检测,以及告知患者相关肝损伤风险。正因为存在上述安全性问题,虽然选择以治疗子宫肌瘤患者的子宫异常出血症状申请上市,不过还是在2018年8月被美国FDA拒绝。

 

武田开发的Relugolix在2019年1月8日被日本PMDA批准上市,用于子宫肌瘤的治疗和症状缓解,包括月经过多、下腹痛、腰痛和贫血。Relugolix是一种促性腺激素释放激素(GnRH)受体拮抗剂,能够迅速降低女性雌激素和孕激素。需要特别提一下的是本品在日本及特定亚洲国家以为的权益属于Myovant。Myovant已经在全球范围内开展治疗子宫肌瘤相关月经过多和子宫内膜异位症相关疼痛3期临床试验各两项。

 

前文提过的同样致力于女性生殖健康的瑞士ObsEva公司也有一个GnRH受体拮抗剂Linzagolix,目前正在进行关于子宫肌瘤相关月经过多的3期临床试验,以及完成了关于子宫内膜异位症相关疼痛的2b期临床试验。

 

子宫内膜异位症

内膜细胞本该生长在子宫腔内,但由于子宫腔通过输卵管与卵巢、盆腔相通,因此使得内膜细胞可经由输卵管进入卵巢、盆腔及子宫邻近区域异位生长,这就形成子宫内膜异位症。该病症在育龄期女性中的发病率约为10%-15%。其中70%患者有慢性盆腔疼痛;30% - 50%的患者会引起不孕。此外,子宫内膜异位症患者罹患卵巢癌的风险也会增加30%-66%。子宫内膜异位症确诊周期较长,从症状出现到确诊平均需要7.5年。

 

2018 年 7 月 23 日,美国FDA批准艾伯维的Elagolix用于治疗因子宫内膜异位症导致的疼痛。Elagolix是一种口服GnRH拮抗剂,通过抑制脑垂体促性腺释放激素受体,最终降低血循环中性腺激素水平。此外,本品治疗子宫肌瘤的3期临床试验也正在进行中。

 

07

癌症,众疾之皇

 

乳腺癌

在全球范围内,乳腺癌是女性中最常见的癌症,2018年新增病例超过200万例。中国女性乳腺癌发病率在184个国家中居第160位,死亡率居第177位,均处于全球较低水平。但由于我国人口基数庞大,女性乳腺癌发病例数和死亡例数分别占全球发病和死亡的11.2%和9.2%,在世界范围位居前列。

 

女性乳腺癌分别位居我国女性恶性肿瘤发病率和死亡率的第1位和第5位。2018年发布的数据是约27.89万例,占女性恶性肿瘤发病的16.51%;而2019年发布的数据是新增病例约为30.4万,占女性恶性肿瘤发病的17.10%,呈现上升的趋势。

 

近几年美国FDA已经批准了多款乳腺癌靶向药物,如辉瑞的PARP抑制剂Talazoparib和三款CDK4/6抑制剂,分别是辉瑞的Palbociclib,诺华的Ribociclib和礼来的Abemaciclib,以及早些年罗氏不断升级产品曲妥珠单抗(Herceptin)、帕妥珠单抗(Perjeta)和曲妥珠单抗-美坦新偶联物(Kadcyla)。而美国MacroGenics公司的Margetuximab在2018年1月获得了美国FDA授予快速通道资格对于曾接受过曲妥珠单抗和帕妥珠单抗治疗无效的转移性HER2乳腺癌患者,该药物的关键性3期临床试验达到主要终点,预计2019年内向FDA提交上市申请。本品中国权益已经被再鼎获得。

此外,还有3项最值得关注的治疗乳腺癌新药3期临床试验:分别是的曲妥珠单抗-Deruxtecan、Alpelisib和Ipatasertib。


上述药物基本上都是用于HER2阳性乳腺癌。而占乳腺癌的12%-20%的三阴乳腺癌一直在期待治疗手段实现突破。

 

原本在2019年1月, Immunomedics的抗体药物偶联物Sacituzumab govitecan预计会被美国FDA批准用于治疗转移性三阴性乳腺癌(mTNBC),然而等来的却是一封完全回复函。缺陷不是临床有效性或安全性,而是CMC药学方面的原因。Sacituzumab govitecan是由靶向TROP-2抗原的人源化IgG1抗体与化疗药物伊立替康(一种拓扑异构酶I抑制剂)的代谢活性产物SN-38偶联而成。TROP-2是一种在90%以上的TNBC中表达的细胞表面糖蛋白。本品曾被美国FDA授予突破性疗法资格。

 

值得一提的是,罗氏PD-L1产品Tecentriq联合白蛋白紫杉醇(Abraxane)一线治疗PD-L1阳性局部晚期或转移性TNBC也获得FDA优先审查资格,PDUFA日期是在2019年3月12日。如果获批,Tecentriq与Abraxane组合将成为治疗PD-L1阳性转移性TNBC的首个癌症免疫治疗方案。


卵巢癌


全球每年新增卵巢癌病例接近30万,死亡人数突破15万。我国女性癌症死亡患者排第十位是卵巢癌,但发病前十位中没有卵巢癌。尽管我国卵巢癌发病率相对较低,但庞大的人口基数仍然使得我国的卵巢癌负担巨大。2015年我国新增病例约52100例,死亡22500例;而同期美国分别是21290例和14180例。从这些数字中可见这种癌症的凶险程度。

 

近几年被美国FDA批准上市适用于卵巢癌治疗的药物有三款PARP抑制剂,分别是阿斯利康的Olaparib、Clovis的Rucaparib和Tesaro的Niraparib,其中最后一个药物是首个在用药之前不需进行BRCA或其它生物标志物检测的PARP抑制剂。此外,还有罗氏的贝伐珠单抗(Avastin)。Niraparib包括香港在内的中国权益已经被再鼎获得,2018年10月已经在香港批准上市,而2019年1月在大陆的上市申请已经获得受理且授予了优先审查资格。


2019年3月1日,ImmunoGen宣布Mirvetuximab Soravtansin的3期临床试验未能达到主要终点:无进展生存期。Mirvetuximab Soravtansine是一款靶向FRα(叶酸受体α)的抗体偶联药物(ADC),其将能与FRα结合的人源化单克隆抗体和能够产生细胞毒性的小分子通过二硫键连接起来,属于ADC领域FRα靶点的全球首创(first-in-class)。FRα是一种在卵巢癌中过度表达的蛋白质,在大部分(80-96%)上皮性卵巢癌呈持续高水平表达,而在正常卵巢上皮中并没有表达,应该是一个很理想的治疗卵巢癌的靶点。然而,早在2013年卫材的Farletuzumab也折戟于3项临床试验,原因同样是未达到无进展生存期的主要终点。

 

子宫内膜癌

子宫内膜癌在全球女性癌症患者中处于第5位,在西方国家处于第3位。在我国女性癌症发病率处于第9位,占比有上升趋势,但死亡率排名在十位开外。子宫内膜癌完全可以治愈,主要治疗手段是子宫切除术。80%以上患者可以存活5年以上。

 

但是专门适用于子宫内膜癌的药物却很少。除了几十年前批准上市甲地孕酮用于辅助治疗,就只有2017年5月美国FDA批准帕博利珠单抗(Keytruda)用于微卫星不稳定或错配修复缺陷的不可切除或转移性实体瘤患者。2018年8月,帕博利珠单抗联合乐伐替尼治疗晚期或转移性非微卫星不稳定高或错配修复完整的子宫内膜癌获得 FDA 突破性疗法认定。

 

美国Checkpoint Therapeutics公司也有一个PD-L1单抗药物CK-301,在2019年1月宣布在开展的有关CK-301的多中心临床试验已经进入到队列扩展研究阶段并开始入组微卫星不稳定高或微卫星稳定子宫内膜癌患者。前期初步数据表明CK-301在规定剂量下安全且耐受良好的,治疗相关不良事件与市售PD-1/PD-L1抗体一致。

 

宫颈癌

在全球范围内,宫颈癌在女性癌症中排第四位,2018年新增病例超过50万例。在我国,宫颈癌在女性癌症发病率排第6位,而死亡率排第8位。宫颈癌主要是由人乳头状瘤病毒(HPV)感染引起。默沙东的九价宫颈癌疫苗可以防御90%由HPV引起的宫颈癌。虽然我国已经以极高效率批准默沙东的九价宫颈癌疫苗进口上市,但是由于产能严重跟不上国内巨大需求,时至今日仍然一剂难求(见:年终盘点:2018年制药圈十大热词)。

 

人们除了热烈期盼更多更好的宫颈癌疫苗,也希望能够有治疗性产品问世。由美国Advaxis公司开发的AXAL(AXALIMOGENE FILOLISBAC)是一种靶向单核细胞增生性李斯特菌(Listeria monocytogenes,Lm)的免疫疗法,将减毒的活性李斯特菌进行基因改造,产生抗癌T细胞对抗癌症抗原,同时破坏肿瘤微环境保护免疫攻击的自然防御而攻击HPV相关癌症。本项目被美国FDA授予快速通道资格和孤儿药认证。这个被众人寄予厚望的项目却经历波折。先是2018年3月因为在与阿斯利康IMFINZI联合用药的1/2期试验时发生受试者死亡,而被FDA叫停。2019年1月又因为药学研究(CMC)相关问题被FDA暂停3期临床试验招募患者。后续如何,大家默默祈祷吧。

 

08

害喜?害惨了!

 

或许读到这里,你还在疑惑。本文最开始提到的孕吐,既然沙利度胺被证明是对胎儿有害而不能使用,那孕妇面对痛苦的孕吐是不是就束手无措了呢?当然不是,除了补充维生素、指压按摩和针灸之外,生活习惯上注意少食多餐、高碳水、低脂肪以及适当摄入姜制品等措施之外,2013年4月美国FDA批准了Duchesnay公司的Diclegis(多西拉敏+维生素B6)专门用于治疗妊娠期恶心呕吐。

 

其实早在1956年美国FDA就批准含有双环胺+多西拉敏+维生素B6的三合一药物,商品名Bendectin。由于发现双环胺并无益处,因此在1976年开始改为多西拉敏+维生素B6二合一药物。从20世纪60 年代后期及整个 70 年代,很多研究报道对该产品的安全性产生质疑,特别是怀疑会引起出生缺陷。由于“反应停”事件阴霾久久不能散去,在美国人心中产生巨大阴影,加上主流媒体也进行相关报道,律师事务所发起宣传运动,导致生产商面临成百上千起诉讼。终于,生产商无力应对,在1983年宣布产品撤市,就此美国市场上没有任何一个药物是专门用于治疗孕吐。然而,流行病学研究发现产品撤市后的多年期间,因孕吐住院病例翻番,但出生缺陷基本保持稳定。

 

30年后,美国FDA 对 Diclegis 的批准是基于一项随机、安慰剂对照临床试验的安全性及有效性数据,同时也考虑了多西拉敏+维生素B6复方药物不具有致畸作用的广泛数据,但是FDA 将继续仔细监测 Diclegis 上市后的使用数据。


09

她,值得更多关爱

 

以上20种病症和对症药物只做了简单列举,但其实很容易就发现,原来有那么多病症可能肆虐你身边的她。或许现在可以更加深刻了解她的痛是难言之隐,同时是不是更加体会到:

 

她,值得更多关爱!

 

特别声明:本篇不适用于求医问药。如有相关疑惑,请前往正规医疗机构咨询。


机器翻译

Do you ever know that she has something to say, she has something to say, she is in pain, she needs your care.They say women can hold half the sky, but in the course of human reproduction, women assume more responsibility.Because of this, some diseases are unique to women or the main incidence of people, which requires you and me in the pharmaceutical industry he gave more attention and pay.

This article briefly introduces the newly approved or investigational drugs and devices for common gynecological and obstetrical diseases, hoping to help you learn more about female compatriots.

01

Quadrant

The "reaction stoppage" that shocked the world in the 1950s and 1960s not only became the hero of Dr. Frances Kathleen Oldham Kelsey, Ph.D., M.D., but also established the FDA's global lead in drug regulation, leaving more than 10,000 "seal babies" and their families with unlimited pain.Although this event has been mentioned repeatedly for more than half a century, it always reminds the pharmaceutical industry of the importance of safety research in the R & D process of new products, and also warns the significance of scientific and rigorous review by pharmaceutical product regulatory authorities.

However, people often ignore the point that the cause of the event is: Nausea and Vomiting of Pregnancy (NVP), commonly known as morning sickness or morning sickness, known as the ancients.This is the nausea of a pregnant woman in the first trimester.Vomiting, etc., is usually most severe when you get up in the morning.According to different literature analysis, about 70% -80% of pregnant women worldwide experience morning sickness, while the proportion of hyperemesis gravidarum is about 1.1%.How difficult this stage is, women who have had pregnancy experience, as for those who do not have the relevant experience can consult a person.

Of course, being a woman can be much more painful than that.

02

Auntie is here, leave me alone

When he was in junior high school, the boys found that the girls were very affectionate and had the privilege of taking time off from the gym teacher, watching or staying in the classroom.Later, the boys gradually learned that girls always have a few days a month called "aunt" a relative to visit regularly, and to the girls bring a lot of inconvenience.The most common manifestation is dysmenorrhea (Dysmenorrhea, Menstrual Cramps), and ibuprofen can be taken in severe cases.Pain relieving drugs such as paracetamol or hormonal contraceptives.There is also a performance that requires the use of an "aunt's towel, if you want to move", but if the flow is too large, it can be a disease.

Menorrhagia

Menstrual flow exceeds 80 ml per month, which is menorrhagia.However, how to judge 80ml is more subjective, about every 1-2 hours on the wet through a large sanitary napkin or tampon, it means more menstrual flow.According to different literature statistics, menorrhagia occurs in 9% -30% of women of childbearing age. The incidence increases with age and peaks before menopause.

Tranexamic acid, which became a hot topic some time ago, is due to a discussion about whether it is compliant to add it to toothpaste.Clinically, this is an old drug used to stop bleeding during surgery. It was discovered as early as 1962 by Japanese female scientist Utako Okamoto.However, it was not approved for menorrhagia until November 2009 by the US FDA, Lysteda from Ferring, a world-renowned obstetrics and gynecology pharmaceutical company.

In addition, estrogen seems to be essential for the treatment of female-related disorders, as is menorrhagia.In March 2012, the U.S. FDA approved Bayer Natazia for the treatment of menorrhagia.One course of this product includes 28 tablets, including

2 dark yellow tablets containing 3 mg estradiol valerate

Red contains 2 mg of estradiol valerate and 2 mg of dienogest in 5 tablets

17 Tablets light yellow containing 2 mg estradiol valerate and 3 mg dienogest

2 dark red tablets containing 1 mg estradiol valerate, and

2 white blank tablets

Treatments include not only drugs but also devices such as the Cerene cryotherapy instrument developed by Channel Medsystems.Unlike existing endometrial ablation devices, the product does not require heat or anesthesia for less than three minutes.When the probe reaches the bottom of the uterus, nitrogen dioxide is released so that the bag expands rapidly and comes into contact with the endometrium.Nitrogen dioxide can cool the target tissue, while the inflatable bag can avoid unnecessary damage to the surrounding tissue.

In 2017, Channel Medsystems received a harvest. First, in March, it completed the key clinical trials in the United States and began to collect and sort out data for application for marketing. Soon after, it received the EU CE mark in June for premenopausal menorrhagia in pregnant women.In November, it struck a deal with Boston Scientific, an industry giant that already has a 20% stake, to buy the remaining 80% for $275 million once it was approved by the U.S. FDA on September 30, 2019.But as the brilliant year of 2017 comes to a successful end, it suddenly comes to light that the company's vice president of quality is suspected of embezzling $3 million through shell companies.Although the company took action and said it did not affect its plans to launch the product in the United States, Boston Scientific believes it was fraudulently announced to cancel the acquisition.Channel Medsystems sued Boston Scientific on Sept. 12, 2018 for demanding that it fulfill a previously agreed acquisition agreement after negotiations failed.The court session is scheduled for April 15, 2019.

03

It's hard to have a baby

The most magical thing in the world is no doubt the birth and development of life.To open branches and scatter leaves is the instinct of life.However, let's not say "dry and wet, exhausted their efforts, look at them safe and sound adults, teach them to behave in a decent manner, and even expect them to shaoqiao bright ancestral industry," even though modern medicine is so developed, just in October pregnant.The first childbirth had already left her mother at the door.

Infertility

If you want to inherit your offspring, first of all you can get pregnant.However, nearly 10% of couples worldwide are suffering from infertility for various reasons.In China, about one in eight couples still do not conceive a year after trying to conceive.In addition, after the release of the two-child policy for elderly couples to prepare for pregnancy, the infertility rate in China is expected to rise from 15.5% in 2017 to 18.1% in 2023.Many of them hope that assisted reproductive technologies such as In Vitro Fertilization, commonly known as IVF technology, refer to in vitro fertilization in which sperm and eggs are removed to form fertilized eggs, which are then cultured in vitro for a period of time to transfer the formed embryos into the mother's uterus.However, due to various factors, IVF is not always successful.

Nolasiban, an oral oxytocin receptor antagonist developed by Swiss company ObsEva, which is dedicated to female reproductive health, is expected to reduce uterine contractions, enhance uterine blood flow, and improve endometrial acceptance of embryo implantation.ObsEva received global interest from Merck in Germany in 2013.The results of a completed phase 3 trial showed a 7-11% improvement in success compared to placebo.Although only about 10%, but for infertile couples has increased a lot of hope.ObsEva has initiated another Phase 3 clinical trial in Europe in November 2018 and plans to submit a marketing application in Europe by the end of 2019.

Myovant is developing MVT-602, an oligopeptide kisspeptin agonist that can be used in assisted reproductive technology to treat female infertility.Kisspeptin is a natural peptide that stimulates gonadotropin-releasing hormone (GnRH) release.This hormone is essential for pubertal development and normal reproductive function, including spermatogenesis.Follicular maturation and ovulation, as well as estrogen and progesterone production in women and testosterone production in men.The project is in phase 2a clinical trials and preliminary data are expected to be published in the first half of 2019.In fact, this Myovant company dedicated to women's health is not only the project in hand, but also the legendary color behind it.

However, despite the hardships, successful pregnancy is only the first step, in the course of pregnancy will experience many bumps.

Preeclampsia

Also known as pre-eclampsia, refers to 24 weeks after pregnancy, the occurrence of edema.Hypertension.Proteinuria and headache.Dizziness.Vomiting.Epigastric discomfort.Visual impairment or blood pressure systolic above 160 mm Hg (21.3 kPa).Without timely and effective intervention, there is a risk of developing eclampsia and even maternal death.According to various literature reports, the incidence of preeclampsia is between 2% and 10%.Preeclampsia plus eclampsia is one of the four leading causes of maternal death (the rest is postpartum hemorrhage.Infections and unsafe induction of labor), accounting for 10% – 20%.

AMAG Pharmaceuticals Inc. is developing DIF, a digoxin immunizing antigen-binding fragment (ovine) for the treatment of preeclampsia, from Velo Bio, another U.S. company.The latter has initiated a phase 2b/3a clinical trial in mid-2017 and is expected to release data in the first half of 2020 and plans to submit a marketing application to the US FDA in the second half of 2020.Earlier, the US Food and Drug Administration had granted orphan drugs and fast-track access.

Premature

In humans, the normal gestational period is 40 weeks, and delivery at less than 37 weeks of gestation is considered premature.According to the pregnancy cycle, premature delivery can be divided into:

Less than 28 weeks, extremely preterm, about 5%

28-31 weeks, severe preterm delivery, approximately 15%

32-33 weeks, moderate preterm delivery, approximately 20%

34-36 weeks, slight premature delivery, accounting for about 60% -70%

There are approximately 15 million premature infants worldwide each year, with a wide range of preterm birth rates from 5% to 18% across countries.Of these, 5% are in northern Europe, while more than 15% are in sub-Saharan Africa and some Asian countries.The rate of premature delivery in China is about 7%, close to 6.2% in Europe, even better than 10.6% in North America.But even so, given China's large population base and the annual number of new born population, the absolute number of premature infants per year is still as high as about 1.2 million, about a third of India, ranking second in the world.

Makena Hydroxyprogesterone Caproate Injection, another product of AMAG Pharmaceuticals, was approved by the U.S. FDA in February 2011 for the prevention of preterm labor.The originator of this product was Hologic, which was later acquired by AMAG.

OBE022, being developed by Swiss company ObsEva, is a novel oral prostaglandin F2alpha (PGF2α) receptor antagonist that is currently in phase 2a clinical trials for the treatment of preterm labor.PGF2α contracts the myometrium, causing an increase in metabolites before and during amniotic fluid formation.PGF2α also upregulates the enzyme causing cervical dilatation and membrane rupture.By specifically inhibiting the PGF2 alpha receptor and safely controlling inflammation, OBE022 not only inhibits uterine contractions but also prevents cervical changes resulting from preterm labor.

In the completed Phase 2a, Part 1, open-label clinical trial, 8 of 9 women with symptoms of preterm labor did not deliver within 7 days of treatment, and only 1 did so on Day 2.Phase 2a, part II, double-blind clinical trial has been initiated in some countries in Europe and Asia.

In October, a baby is delivered.New life arrives, the whole family is immersed in the joy of Tim Ding, this time focusing on the newborn, but do not forget the need to continue to pay attention to maternal health.

Postpartum hemorrhage

"Alive" is an important work in Chinese contemporary literature, and it is also an important work in the history of new Chinese film.One of the plot is this: Fugui's daughter Feng Xia dystocia, son-in-law Wan Erxi to be kept in a barn hungry for three days of senior obstetrician and gynecologist Dr. Wang.The hungry Doctor Wang ate the seven steamed buns bought by Fugui in one breath and drank the water again.At this moment, although Fengxia gave birth to a boy, but there was a massive postpartum hemorrhage, in the face of this emergency situation, a group of red guard nurses grabbed power, and experienced Dr. Wang has fainted.Poor Fengxia, because a high fever became deaf and dumb when he was a child, he could not make a groan and finished his life.

Postpartum hemorrhage is defined as vaginal blood loss of more than 500 ml within 24 hours after delivery.As mentioned earlier, postpartum hemorrhage is one of the four major causes of maternal death.The global incidence of postpartum hemorrhage accounts for about 2% of all deliveries.Postpartum haemorrhage accounts for 1 in 1,000 births, mostly in less developed regions, and 1 in 100,000 in developed regions.

Because of the high risk of maternal death from postpartum hemorrhage in underdeveloped regions, it is important to facilitate the transport and storage of drugs.Who conducted a study of heat-stable carbetocin, which was provided free of charge by the company, in conjunction with Merck, USA, and Pfizer, Switzerland.The drug does not need to be stored in a refrigerator and can be stored at 30 degrees Celsius and 75 percent relative humidity for 3 years.Because less developed areas are also concentrated in areas with high temperature and humidity, and medical conditions are backward, this drug is of great benefit in reducing maternal death from postpartum hemorrhage in this area.

The older drug mentioned above, tranexamic acid, is also suitable for the treatment of postpartum hemorrhage. The mechanism is one thing.However, since postpartum haemorrhage is an emergency, the dosage form is given as an injectable form, whereas for menorrhagia, tablets are given orally.

In addition to the use of drugs for hemostatic therapy, American company Alydia is developing a device.This product uses vacuum to generate negative pressure, prompting the uterus to rapidly contract and naturally close the vascular opening, so as to achieve the effect of rapid hemostasis.In the pilot study, 10 women were able to control postpartum hemorrhage quickly and effectively within minutes.In September 2018, the company completed $10 million round B financing to support 510 (K) applications to the U.S. Food and Drug Administration.The trial plans to recruit 107 women in the United States.

Postpartum depression

Although the birth of a child is a happy thing, but about 70% -80% of new mothers will have mood swings after childbirth, this phenomenon is called "Baby Blue" (infantile depression), generally for several hours to several days, can be self-resolving, more reassurance, no treatment.Another 10-15% of new mothers will suffer from postpartum depression, mainly manifested as depressed mood.No fun.Forgetfulness.Anxiety.Insomnia and irritability, lasting weeks or even months, require treatment.Severe cases can lead to mental illness, even suicide, requiring hospitalization, which is about 0.1% -0.2%.

In fact, there are many drugs used to treat depression, but usually clinical trials will not enroll pregnant or lactating women.Therefore, these drugs are also risky in clinical use.So, if there is a drug that directly targets postpartum depression, it is very helpful for the new mother who suffers from it.

Sage Therapeutics, Inc., USA, specializes in the development of new drugs for central nervous system diseases and has an intravenous drug delivery program, Brexanolone, for the treatment of postpartum depression.Brexanolone is an allosteric modulator that acts on both synaptic and extrasynaptic GABAA receptors.Allosteric modulation of neurotransmitter receptor activity can produce various degrees of desired activity, rather than complete activation or complete inhibition.

The product was granted Breakthrough Therapy by the FDA as early as September 2016.The new drug marketing application submitted by Sage to the US FDA in April 2018 was overwhelmingly approved by two US FDA advisory committees in November of the same year to support its marketing. However, it is necessary to submit a separate Risk Evaluation and Mitigation Strategies including safety and security measures.Sage quickly submitted the plan, but the FDA needed more time to review the plan, so the PDUFA date was postponed from December 19, 2018 to March 19, 2019.Will this be a late 38 holiday gift for new moms?Let's wait and see.

Sexual desire disorder

Food.Color, sex too.But human instincts can also be difficult.Common sexual dysfunction in men can be treated with VIAGRA.Cialis.Bi Li Jin and other well-known drugs to promote blood circulation, improve sexual function.Women are different.The most common female sexual dysfunction is sexual desire disorder, which is the absence of sexual fantasies and sexual desire.It is a psychiatric disorder with an incidence of about 10%.

In August 2015, the US FDA approved Addyi flibanserin for the treatment of widespread sexual desire disorder in premenopausal women.For a time, Addyi was also known as "Viagra Female" or "Wei Jie."The product was originally Boehringer Ingelheim's near-final project.Sprout won approval in 2012 for a $1 billion deal just two months after taking over.However, Addyi is a naturally defective drug that has a slow onset of action and even requires several weeks of daily dosing, clearly not meeting actual needs.Plus vertigo.Low blood pressure.Coma and somnolence and other adverse reactions, and can not be taken with alcohol, not at all by the market.It was supposed to be a big sale, but the sales were actually poor.Even the sales team was disbanded.

That's why the next Viagra for women is all the more exciting.The PDUFA date of Bremelanotide of Palatin, Inc. (USA) was March 23, 2019.This is a pioneering melanocortin 4 receptor agonist with a novel mechanism of action that activates endogenous melanocortin pathways in the brain involved in normal sexual desire and arousal responses to sexual desire in humans.The proposed formulation is a prefilled disposable autoinjector that is self-injected subcutaneously by female patients and is less romantic than the oral formulation.In February 2017, Palatin transferred North American interests to AMAG, and in September of the same year, China (including the mainland.Taiwan.Hong Kong.Macao) equity transfer to Fosun Pharma, and Korea equity transfer to Kwang Dong in November.

People may still be looking forward to oral dosage forms more than injections, which are much more convenient after all, without the pain of a shot.Lorexys from S1 Biopharmaceuticals, USA is an oral combination containing two antidepressants, bupropion and trazodone.S1 is designed to make dopamine.Serotonin and norepinephrine balance, and these are the three neurotransmitters that regulate sexual inhibition and arousal in humans.Phase 2b clinical trials are currently being advanced and a subsequent marketing application will be filed via the 505 (b) (2) route.

Contraception

Although life is a miraculous process, it is not always expected to be new, especially if both men and women agree.In the past, however, the right to decide whether to use condoms was more in the hands of men.Considering the sense of use.Access or fertility purposes, even with condoms, women often have no way to prevent the ongoing pregnancy consequences of sex.The birth of the pill for women to provide more options, do not have to worry about whether men would like to use, women own initiative.

Over the past half century, humans have invented many kinds of birth control pills.In addition to the common oral tablets, there are injections.Implanting agent.Vaginal ring.Contraceptive stickers, etc.Women can choose their own appropriate contraceptive method according to their life preferences.

Kyleena, a new long-acting intrauterine device developed by German pharmaceutical giant Bayer, was approved by US FDA and EU EMA in 2016.Kyleena is a new low-dose levonorgestrel-releasing intrauterine system (LNG-IUS) that can be removed at any time, and women can quickly return to normal fertility after removal.Kyleena is a small.Flexible.A plastic T-shaped device containing 19.5 mg of the synthetic hormone levonorgestrel.Kyleena is 28 mm x 30 mm in size and 3.8 mm in diameter.Once placed in the womb, Kyleena delivers a sustained release of low doses of levonorgestrel, providing up to 5 years of contraceptive effectiveness.

For Agile, December 2017 was originally the harvest season, however, a complete response from the US FDA is awaiting.In the reply letter, it was pointed out that the Twirla adhesion test method developed by Agile Corporation for low-dose hormonal combination contraceptive patch was defective, and that there was doubt about the relationship between the observation items found in the audit on the third-party manufacturer Corium and the results of clinical trials on in vivo adhesive desire.After discussion with FDA's Orthopedic Advisory Committee on Reproductive and Urological Drugs, the company decided to conduct a non-inferiority study on adhesion with another marketed contraceptive patch product, Xulane. It is expected to complete the trial in the first quarter of 2019 and submit the marketing application again in the first half of this year.Twirla uses Agile's proprietary Skinfusion technology to deliver ethinyl estradiol and levonorgestrel over seven days.The product is applied once a week for three weeks, and no patch is needed for another week, which can improve the compliance of users.

Annovera is a vaginal contraceptive ring shaped like a soft silicone rubber ring with a diameter of about 5.715 centimeters and contains a combination of seconorgestrel acetate and ethinyl estradiol.Place in vagina during use: Place for 21 days.Explanted for 7 days and can use contraception for 28 days.During placement, the hormones contained in ANNOVERA are released through the ring wall at a rate that is absorbed by the vaginal mucosa and exerts a contraceptive effect.Women may place and remove each Annovera by themselves for 1 year.The product was approved by FDA in August 2018.

In addition to the most common hormonal contraceptives, there are some non-hormonal products that have been approved or are being tried for.

Ulipristal is a selective progesterone receptor modulator with antagonistic and partial agonistic effects on progesterone receptors.It binds to progesterone receptors in the human body and thus prevents progesterone from binding to progesterone receptors.In 2009 and 2010, it was approved by the European Union EMA and the US FDA for use in emergency contraception with unprotected intercourse or contraceptive failure within 120 hours (5 days).Another 5 mg strength is approved for the treatment of uterine fibroids.

Amphora, developed by Evofem USA, is a multifunctional vaginal pH regulator that contains L-lactic acid.Citric acid and potassium bitartrate.Developed as a gel that adjusts vaginal pH to a normal range of 3.5 to 4.5, the company maintains an acidic environment that protects against sperm and viral and bacterial pathogens, but not against healthy flora.As early as 2015, the company submitted a new drug marketing application, but in April 2016 received a complete reply letter from the US FDA, pointing out that there are differences in the cohort study in the United States and Russia.If successful, the company plans to submit a new drug application in the second quarter of 2019, after the trial is resumed.It is also being developed for use in gynecologic conditions such as bacterial vaginosis and gonorrhea.

In addition to drugs, there are also devices.Femasys develops a female permanent contraceptive system called FemBloc that does not require anesthesia or implants.This is actually a biopolymer that allows the body itself to initiate wound repair in the fallopian tube to form scar tissue and permanently close the fallopian tube.In early human trials, no significant adverse effects were observed and a 500-subject pivotal trial has been initiated and 100 subjects have been completed.

04

Menopausal aunt is not a good one

The onset of menstruation means that women begin to develop and gradually become fertile with all kinds of distress.Menopause, on the other hand, means the end of the female reproductive period.Although menstruation fading is a natural physiological phenomenon, but it can also bring a lot of discomfort to women, affecting the quality of life.These symptoms include hot flashes with night sweats.Sleep disturbance.Joint pain and genitourinary symptoms, including low libido.Dyspareunia and bladder incontinence.The main cause of these symptoms is changes in estrogen levels, and the cause is aging of the ovaries.About 85% of postmenopausal women experience at least one symptom of menopause.This is what is often called menopause.

Vasomotor symptoms

Menopause can lead to moderate to severe vasomotor symptoms, which are commonly referred to as menopausal symptoms in menopausal women due to decreased levels of their own hormones, usually manifested as hot flashes and night sweats.As the ovaries stop producing hormones, circulating estrogen levels fall, often triggering vasomotor symptoms, as well as sleep and mood disorders and genitourinary problems.Hot flashes (including night sweats) are the most common symptom, affecting 80% of women, and can be debilitating and persist for years after menopause.

Since it is a symptom of a drop in hormone levels, it is a good idea to take hormones directly.Pfizer's Duavee (estrogen and bazedoxifene conjugate) was approved by the U.S. FDA in October 2013.In October 2018, the U.S. Food and Drug Administration approved Bijuva from Therapeutics MD, a compound capsule composed of 1 mg estradiol and 100 mg progesterone.This is the first FDA-approved bio-identical combination hormone replacement therapy that is molecularly identical to the hormones produced in women.

However, the use of hormone replacement therapy may cause adverse effects.For example, the most common adverse reactions (≥ 3%) of Bijuva include breast tenderness.Headache.Vaginal bleeding.Vaginal discharge and pelvic pain.Non-hormonal therapies that have been approved for marketing include Noven Pharmaceuticals' Brisdelle (7.5 mg low dose paroxetine mesylate) in July 2013, while strengths such as 10 mg are approved for the treatment of depression.

Fervent Pharmaceuticals is developing a non-hormonal therapy that is not a new compound, but rather an active ingredient with a well-recognized safety profile from numerous older drugs, namely dextromethorphan hydrobromide.The project FP-101 has completed Phase 2A clinical trials and will eventually be marketed via the 505 (b) (2) route.

KNDy neurons increase estrogen synthesis in the ovary and play a role in thermoregulation.When the ovaries fail to synthesize enough estrogen during menopause, KNDy neurons release more signals.These signals will also affect female thermoregulation, which in turn is due to the occurrence of hot flashes.The NK3 receptor antagonist Fezolinetant, developed by Belgian company Ogeda, can reduce the regulatory activity of KNDy by directly acting on neurons.The company was acquired by Astellas in 2017.Currently, fezolinetant has completed a phase 2b clinical trial in which all four endpoints are met in most cohorts.Phase 3 clinical trials are currently being prepared.

KaNDy, UK, has completed a third round of funding and received £25 million for the NT-814 clinical trial.The product acts on both NK1 and NK3 receptors and is used to ameliorate conditions including hot flashes.Multiple menopausal symptoms including sleep and mood problems.Phase 2b clinical trials are currently ongoing and preliminary data are expected to be available by the end of 2019.

It should be said that pharmaceutical companies pay more attention to this disease. In fact, there are still many previously approved drugs, which are not listed here.

Menopausal genitourinary syndrome

Also known as vulvovaginal atrophy (VVA), is a common chronic progressive condition caused by decreased vaginal tissue estrogen, symptoms include vaginal dryness.Irritation.Itching.Pain.Burn.Frequent urination, urgency and dyspareunia.The condition is likely to appear at any stage of a woman's life, but it is more common after menopause, where the incidence is about 50%, of which 50% -60% of patients do not choose to see a doctor, and only 25% of patients will receive appropriate treatment.Vulvovaginal atrophy due to menopause and physiology.Histologically and anatomically related and therefore associated with vasomotor symptoms (flushing.The difference is that vulvovaginal atrophy does not resolve without therapeutic intervention.

However, since vasomotor symptoms, like those of vasomotor symptoms, are caused by a drop in hormone levels, it is also a good idea to take hormones directly.In May 2018, the U.S. FDA approved TherapeuticsMD's Imvexxy, an estradiol vaginal insert for the treatment of moderate to severe dyspareunia, one of the symptoms of vulvovaginal atrophy caused by menopause.

Prasterone (dehydroisoandrosterone, DHEA) is mainly produced by the adrenal cortex and ovaries and is an important precursor of extragonadal hormones in postmenopausal women.DHEA and its sulfates are converted to estrone or testosterone, which is then incorporated into extragonadal tissues (e.g., the brain.Bone and fat) evolve to estradiol or dihydrotestosterone.In November 2016, the US FDA approved Endoceutics' Intrarosa, a prasterone vaginal insert for the treatment of moderate to severe dyspareunia due to vulvovaginal atrophy caused by decreased estrogen levels during menopause.

Ospemifene tablets (Ospemifene) were developed by the Japanese company, Yasano, and are available in the United States (Osphena, February 2013.January 2019) and the European Union (Senshio, January 2015) approved for the treatment of symptoms of vulvovaginal atrophy due to menopause, including moderate to severe dyspareunia and moderate to severe vaginal dryness.The North American market was later bought by Duchesnay.

Postmenopausal osteoporosis

Osteoporosis is a bone disease in which bone strength is significantly reduced, with the consequence of an increased risk of fracture.According to WHO, 30% of women over the age of 50 suffer from osteoporosis worldwide.The main cause of osteoporosis in elderly women is the absence of estrogen after menopause.The incidence of osteoporosis in the elderly in China is about 15.7%, and the male to female ratio is about 1.0:1.61.

Drugs currently marketed for the treatment of osteoporosis fall into four main classes: 1) antiresorptive, ie, bisphosphonates that inhibit osteoblasts, such as Zoledronic acid from Novartis.2) Selective estrogen receptor modulators, such as raloxifene from Lilly, and Pfizer's Duavee (estrogen and bazedoxifene conjugate) as previously mentioned.3) Bone synthesizing parathyroid hormone analogues such as Lilly's teriparatide.And 4) Monoclonal antibody drugs, such as Amgen's RANKL receptor agonist denosumab.

The current research and development focus is also on the latter two types of drugs.For example, Abaloparatide, which was approved by the US FDA in April 2017, is also a parathyroid hormone-related protein [PTHrP (1-34)] analog that binds to parathyroid receptor 1, thereby regulating metabolism and promoting bone formation.Abaloparatide was originally developed by Ipsen and later transferred to Radius Health.

Romosozumab, developed by Amgen in conjunction with UCB, is a monoclonal antibody that targets the bone formation signaling pathway and inhibits the activity of sclerostin, thereby accelerating bone formation and reducing bone resorption.This product has been approved for marketing by PMDA in Japan on January 8, 2019.Although the US Food and Drug Administration (FDA) declined to approve its launch in 2017, Amgen and UCB have resubmitted their applications for the study.January 16, 2019 announced that the FDA's Advisory Committee on Reproductive and Urological Drugs in Orthopaedics voted overwhelmingly to support the launch of the product.The EU EMA is also under review.Amgen's position in the field of osteoporosis has been further consolidated as the product has been approved for marketing in major countries.

05

Advertisement says washing is healthier, why do men ask?

Vaginal candidiasis of the vulva

Candida vaginitis or vulvovaginal candidiasis, most of which are caused by Candida albicans.About 70% -79% of adult women will experience at least one episode in their lifetime and 50% will relapse.Recurrent vulvovaginal candidiasis (RVVC), which affects about 5 to 8 percent of women, occurs three or more times a year.Most of the disease occurs in women of childbearing age, in the last trimester of pregnancy is also more common, and to reduce after menopause.

Ibrexafungerp is a structurally unique glucan synthase inhibitor recognized by WHO as a novel class of triterpenoid antifungal agents.Originally developed jointly by Scynexis and Merck, the product was abandoned by Merck and continued to be developed by Scynexis for the treatment and prevention of various fungal infections.Current clinical trials for vulvovaginal candidiasis are in phase 3 and a marketing application is planned for 2020.

VT-1161 from Mycovia, Inc., a fungal CYP51 inhibitor that blocks the production of ergosterol, an important component of fungal membranes, is currently in phase 3 clinical trials and is expected to be completed in the second half of 2020.

Bacterial vaginosis

Bacterial vaginosis is the most common cause of vaginitis, with a recurrence rate of about 20% to 40% after one month of treatment.This is also the most common cause of vaginal discharge in women of childbearing age, accounting for 40% -50% of all cases.The onset of bacterial vaginosis is associated with changes in the normal vaginal flora, such as a change from lactic acid bacteria to a variety of bacteria including facultative anaerobes, the production of volatile amines by new colonies, and a rise in vaginal pH above 4.5 (normal range 4.0-4.5).

Secnidazole from Symbiomix, USA is a potent 5-nitroimidazole antibiotic approved by the US FDA in September 2017 for the treatment of bacterial vaginosis in adult women.This is the only single-dose oral therapy for bacterial vaginosis.

(p) Amphora gel, developed by Evofem, is a multifunctional vaginal pH regulator that adjusts vaginal pH to within normal limits.In addition to protecting against sperm, it can also eliminate bacterial pathogens.It is also being developed for bacterial vaginosis.

VivaGel BV, developed by Starpharma, USA, is a non-antibiotic aqueous vaginal gel for the treatment of bacterial vaginosis and prevention of recurrent bacterial vaginosis.The product has been approved in Europe and Australia, but in December 2018 the US Food and Drug Administration said more clinical data were needed.

All five antibacterial drugs have obtained FDA's QIDP certification.

06

What is the real lair?

Uterine fibroids

This is a relatively common, benign tumor of uterine smooth muscle proliferation that occurs in women of childbearing age, with an incidence of 20% to 40%. The risk increases with age and peaks at menopause.Some uterine fibroids have no symptoms, so they won't be diagnosed.Uterine fibroids usually cause menstrual pain.Non-menstrual vaginal bleeding.Infertility.Anemia, etc.In addition, the most common treatment for symptomatic uterine fibroids is hysterectomy.

The aforementioned 30 mg strength of ulipristal has been approved by the European Union EMA and the US FDA for emergency contraception.Ulipristal acts as a selective progesterone receptor modulator that acts directly on three target tissues, the endometrium.Progesterone receptors in uterine fibroids and the pituitary gland. The compound is also approved by the European Union's EMA for the treatment of uterine fibroids at a dose of 5 mg.However, since several patients had severe liver injury due to medication, the EMA Pharmacovigilance Risk Assessment Committee, after careful investigation, recommended that its medication be restricted and that measures be taken to reduce the risk of liver injury with the drug, including contraindication in patients with known liver problems, liver function tests before, during and after treatment, and informing patients about the risk of liver injury.Because of the above safety concerns, although the application for marketing of the treatment of uterine fibroids in patients with abnormal uterine bleeding symptoms was selected, it was still rejected by the US FDA in August 2018.

Relugolix developed by Takeda was approved by PMDA in Japan on January 8, 2019 for the treatment and symptom relief of uterine fibroids, including menorrhagia.Lower abdominal pain.Low back pain and anemia.Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist that rapidly reduces estrogen and progesterone in women.It should be noted that the rights and interests of this product in Japan and specific Asian countries belong to Myovant.Myovant has conducted two phase 3 clinical trials worldwide for the treatment of menorrhagia associated with uterine fibroids and pain associated with endometriosis.

The Swiss company ObsEva, which is also committed to female reproductive health mentioned above, also has a GnRH receptor antagonist, Linzagolix, which is currently undergoing phase 3 clinical trials on uterine fibroid-related menorrhagia and has completed phase 2b clinical trials on endometriosis-related pain.

Endometriosis

Endometrial cells are supposed to grow in the uterine cavity, but because the uterine cavity passes through the fallopian tubes and ovaries.The pelvis communicates, thus allowing the endometrial cells to enter the ovary via the fallopian tube.Endometriosis develops when the pelvis and adjacent areas of the uterus grow ectopically.The incidence of this condition in women of childbearing age is about 10% -15%.Seventy percent of these patients have chronic pelvic pain.30% - 50% of patients will cause infertility.In addition, women with endometriosis have a 30% to 66% increased risk of developing ovarian cancer.Endometriosis is diagnosed over a long period of time, taking an average of 7.5 years from symptom onset to diagnosis.

On July 23, 2018, the US FDA approved Elagolix for the treatment of pain due to endometriosis.Elagolix is an oral GnRH antagonist that ultimately lowers circulating gonadal hormone levels by inhibiting pituitary gonadotropin-releasing hormone receptors.In addition, phase 3 clinical trials of this product in the treatment of uterine fibroids are also ongoing.

07

Cancer, The Emperor of Disease

Breast cancer

Worldwide, breast cancer is the most common cancer in women, with more than 2 million new cases in 2018.The incidence rate of female breast cancer in China ranks 160th among 184 countries, and the mortality rate ranks 177th, which is at the global low level.However, due to the large population base in China, the incidence and death of female breast cancer accounted for 11.2% and 9.2% of the global incidence and death, respectively, ranking among the top in the world.

Female breast cancer ranks first and fifth in the incidence and mortality of female malignancies in China, respectively.The data released in 2018 is about 278,900 cases, accounting for 16.51% of female malignant tumor incidence.The data released in 2019 is about 304,000 new cases, accounting for 17.10% of female malignant tumors, showing an upward trend.

In recent years, the US FDA has approved a number of breast cancer targeted drugs, such as Pfizer's PARP inhibitor Talazoparib and three CDK4/6 inhibitors, Pfizer's Palbociclib, Novartis' Ribociclib and Lilly's Abemaciclib, and earlier Roche's continually upgraded product, Trastuzumab (Herceptin). Pertuzumab (Perjeta) and Trastuzumab-Metanaxine Conjugate (Kadcyla).However, in January 2018, MacroGenics' Margetuximab was granted fast-track qualification by the US FDA. For patients with metastatic HER2 breast cancer who have failed to respond to trastuzumab and pertuzumab, the pivotal phase 3 clinical trial of this drug has reached the primary endpoint. It is expected to submit a marketing application to the FDA in 2019.The Chinese rights and interests of this product have been reinstated.

In addition, there are three Phase 3 clinical trials of new drugs for breast cancer that are of most interest: Trastuzumab-Deruxtecan.Alpelisib and Ipatasertib.

These drugs are essentially used in HER2-positive breast cancer.Triple-negative breast cancer, which accounts for 12% -20% of breast cancers, has been expecting breakthroughs in treatment.

Originally in January 2019, Immunomedics' antibody drug conjugate, sacituzumab govitecan, is expected to be approved by the US FDA for the treatment of metastatic triple-negative breast cancer (mTNBC), but a complete response letter was received.The defect is not the clinical efficacy or safety, but the reason of CMC pharmacy.Sacituzumab govitecan is a humanized IgG1 antibody targeting the TROP-2 antigen conjugated to SN-38, the metabolically active product of the chemotherapeutic drug irinotecan, a topoisomerase I inhibitor.TROP-2 is a cell surface glycoprotein expressed in more than 90% of TNBC.This product has been granted breakthrough therapy by the US FDA.

It is worth mentioning that Roche PD-L1 product Tecentriq in combination with albumin paclitaxel (Abraxane) for the first-line treatment of PD-L1 positive locally advanced or metastatic TNBC has also received the priority review from the FDA, PDUFA on March 12, 2019.If approved, the combination of TECENTRIQ with ABRAXANE will be the first cancer immunotherapy regimen for the treatment of PD-L1 positive metastatic TNBC.

Ovarian cancer

Nearly 300,000 new cases of ovarian cancer are diagnosed each year worldwide, with more than 150,000 deaths.Ovarian cancer is the tenth leading cause of female cancer deaths in China, but there is no ovarian cancer in the top ten.Although the incidence of ovarian cancer in China is relatively low, the huge population base still makes the burden of ovarian cancer in China huge.In 2015, there were about 52100 new cases and 22500 deaths in China.This compares with 21,290 and 14,180 in the United States, respectively.These figures show the extent of the cancer.

Three PARP inhibitors have been approved by the US Food and Drug Administration for the treatment of ovarian cancer in recent years.Rucaparib from Clovis and Niraparib from Tesaro, the last of which is the first PARP inhibitor not to be tested for BRCA or other biomarkers prior to dosing.In addition, there is Roche's bevacizumab (Avastin).The Chinese interest in niraparib, including Hong Kong, has been re-approved and approved in Hong Kong in October 2018, while the listing application in China in January 2019 has been accepted and granted priority review.

On March 1, 2019, ImmunoGen announced that the Phase III clinical trial of Mirvetuximab Soravtansin failed to reach the primary endpoint: progression-free survival. Mirvetuximab Soravtansine is an antibody-conjugated drug (ADC) that targets FRα (folate receptor alpha). It combines a humanized monoclonal antibody that binds to FRα and a small molecule capable of producing cytotoxicity through a disulfide bond, and belongs to the world's first-in-class of the FRα target in the ADC field. FRα is a kind of Over-expressed proteins in ovarian cancer are expressed at a high level in most (80-96%) epithelial ovarian cancer, but not in normal ovarian epithelium, and should be an ideal target for the treatment of ovarian cancer. However, in 2013 Eisai's farletuzumab also collapsed in three clinical trials, again because the primary endpoint of progression-free survival was not met.

Endometrial cancer

Endometrial cancer ranks fifth among female cancer patients worldwide and third in Western countries.In China, the incidence of female cancer is in the 9th place, and the proportion has an upward trend, but the death rate ranks in the 10th place.Endometrial cancer is completely curable and the mainstay of treatment is hysterectomy.More than 80% of patients survive more than 5 years.

However, few drugs are indicated for endometrial cancer.In addition to the approval of megestrol acetate for adjuvant therapy decades ago, only in May 2017, the US FDA approved the use of Pabolizumab (Keytruda) in patients with unresectable or metastatic solid tumors with microsatellite instability or mismatch repair deficiency.In August 2018, Pabolizumab in combination with Lenvatinib received FDA Breakthrough Therapy designation for the treatment of advanced or metastatic non-microsatellite unstable high or mismatch repair intact endometrial cancer.

Checkpoint Therapeutics, Inc. also has a PD-L1 monoclonal antibody, CK-301, and announced in January 2019 that the ongoing multicenter clinical trial of CK-301 has entered the cohort expansion phase and started enrolling patients with microsatellite unstable high or microsatellite stable endometrial cancer.Preliminary data showed that CK-301 was safe and well tolerated at the specified dose, and treatment-related adverse events were consistent with those of commercially available PD-1/PD-L1 antibody.

Cervical cancer

Worldwide, cervical cancer ranks fourth among female cancers, with more than 500,000 new cases in 2018.In China, cervical cancer ranks sixth in female cancer incidence and eighth in mortality.Cervical cancer is mainly caused by human papilloma virus (HPV) infection.Merck's nine-valent cervical cancer vaccine protects 90 percent of cervical cancers caused by HPV.Although China has approved the import and marketing of the 9-valent cervical cancer vaccine from Merck with extremely high efficiency, it is still difficult to obtain a dose today due to the fact that the production capacity is seriously unable to keep up with the huge domestic demand (see: year-end inventory: the top ten hot words in the pharmaceutical circle in 2018).

In addition to eagerly hoping for more and better cervical cancer vaccines, people also hope to have therapeutic products.AXAL (AXALIMOGENE FILOLISBAC), developed by Advaxis, USA, is an immunotherapy targeting Listeria monocytogenes (Lm), which genetically modifies the attenuated active Listeria to produce anticancer T cells against cancer antigens while destroying the natural defense of tumor microenvironmental protection immune attack and attacking HPV-related cancers.This project was granted fast track qualification and orphan drug certification by the US FDA.This highly anticipated project has experienced a twist.It was first halted by the FDA in March 2018 due to the death of a subject in a Phase 1/2 trial with AstraZeneca's IMFINZI.In January 2019, the FDA suspended enrollment of patients in Phase 3 clinical trials due to issues related to pharmaceutical research (CMC).Then, let's pray in silence.

08

Happy?Damn it!

Maybe if you read this, you're still wondering.Since thalidomide has been shown to be harmful to the fetus and cannot be used, is it impossible for pregnant women to face the painful morning sickness?Of course not, except for vitamins.In addition to acupressure and acupuncture, life habits pay attention to eating small meals.High carbon water.In addition to measures such as low fat and proper intake of ginger products, in April 2013, the US FDA approved Duchesnay's Diclegis (doxylamine + vitamin B6) specifically for the treatment of nausea and vomiting during pregnancy.

In fact, as early as 1956, the US FDA approved a three-in-one drug containing dicyclomine + doxylamine + vitamin B6, trade name Bendectin.Since dicyclomine was found to be of no benefit, it was changed to doxylamine + vitamin B6 as a two-in-one drug in 1976.From the late 1960s and through the 1970s, a lot of research reports have questioned the safety of the product, especially the suspicion of causing birth defects.Law firms have launched a propaganda campaign that has led to hundreds of lawsuits against producers, as the haze from the "stop-reaction" affair has long failed to dissipate, creating a huge shadow in the hearts of Americans and leading media reports.Eventually, manufacturers were unable to cope, and in 1983 announced the withdrawal of the product, for which no drug in the US market was specifically designed to treat morning sickness.However, epidemiological studies have found that hospital admissions for emesis have doubled over the years since the product was withdrawn from the market, but birth defects have remained largely stable.

After 30 years, the U.S. FDA's approval of Diclegis was based on a random.Safety and efficacy data from placebo-controlled clinical trials have also considered extensive data on the non-teratogenic effects of the combination of doxylamine and vitamin B6, but the FDA will continue to carefully monitor the post-marketing use of Diclegis.

09

She deserves more care

The above 20 diseases and symptomatic drugs are only briefly listed, but it is actually easy to find that there are so many diseases that may rage her around you.Maybe now you can understand more deeply that her pain is unspeakable, and at the same time you know more:

She deserves more care!

Special statement: This article is not applicable to medical consultation.If you have any questions, please consult a regular medical institution.

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