Relugolix/Estradiol/Norethindrone Acetate

氨基观察-创新药组原创出品 作者 | 武月 时至今日，痛经依然没有对症的药物可用。 尽管在社会观念中，痛经被视为女性的寻常之痛。很多女性选择忍一忍或是止痛药来熬过经期疼痛，也很少有人为此特地就医。 然而，痛经并非总是无害的，这种隐忍有可能埋藏着极大隐患。 痛经，尤其严重的痛经，很可能是一种病——子宫内膜异位症。子宫内膜异位症远不止痛经那么简单，不仅可以侵袭周围组织和其他器官，导致复杂的症状，还容易在治疗后反复发作，直到绝经后才能缓解，给患者带来无尽的痛苦折磨，甚至被叫做“不死的癌症”。 在这背后，原因固然是多方面的。比如，错误的、固化的社会观念；比如无论患者还是医护人员，对子宫内膜异位症均缺乏早诊断、早治疗的意识；最重要的是，由于缺钱、缺数据等种种原因，药企鲜少踏足这一领域，这也导致临床上一直缺乏有效治疗手段。 子宫内膜异位症的处境，或许也只是万千疾病中的冰山一角，这也是科技进步昌明下的阴暗面。 而这种错综复杂的局面，也很难在一夕之间得到彻底扭转。 但是，我们依然保持期待。当越来越多女性意识到不舒服需要被看见，当子宫内膜异位症逐步得到重视，新的变化就将孕育而生。 / 01 / “不死的癌症” 子宫内膜异位症，是一种由子宫内膜脱离正常位置生长而引起的疾病。 简单来说，子宫内膜细胞原本是“居住”在宫腔内黏膜层上，在雌、孕激素的调控下发生周期性的改变。它可能会定期脱落，混迹于经血排出体外，也可能会成为受精卵发育的温床。 但是，部分“叛逆”的子宫内膜逃离了宫腔，在盆腔腹膜、卵巢、子宫表面以及宫骶韧带等部位“安营扎寨”，引发一系列不适症状以及不良后果。 作为内异症最主要的临床表现，痛经，就是身体发出的求救信号。 当然，子宫内膜异位症远不止痛经那么简单，不仅可以侵袭周围组织和其他器官，导致复杂的症状，还容易在治疗后反复发作，直到绝经后才能缓解。这种野蛮生长、难以根治的特性，以及它带给患者的痛苦折磨，让其被叫做“不死的癌症”。 作为一种复杂的疾病，子宫内膜异位症影响着全球许多妇女。有流行病学调查显示：约10%的生育期女性患有子宫内膜异位症，世界范围内的患病人数可能接近甚至超过2亿，亚洲的发病人数超过其他各大洲的总和。 真实的数据可能会更高。世界卫生组织的子宫内膜异位症专题中提到，一些地区的公众和部分医务人员缺乏对子宫内膜异位症早诊断、早治疗的意识，很多人都以为痛经、盆腔痛是必须忍耐的正常过程，因此耽误了及早就医和诊疗。 患者层面也是如此，对痛经重视不足，也是导致内异症延迟确诊的重要原因。 此外，内异症的延迟确诊，也与其缺乏有效的无创性诊断方法有关。以往临床上，通常只能借助腹腔镜手术直接观察子宫内的组织来诊断。这种方式虽被视为内异症诊断的“金标准”，但却会造成创伤，成本太大。 此外，超声检查虽然也是内异症的主要检查手段，但其准确度有限；另一种诊断方式是妇科查体（双合诊、三合诊），能够根据病变的位置准确识别内异症，尤其是深部浸润型内异症。 然而，查体的结果与医师的经验、检查技巧有很大关系，并非所有医生都能熟练掌握。 / 02 / 研究负循环 时至今日，尚没有彻底治愈子宫内膜异位症的办法，所有的治疗手段大都是为了控制或缓解症状。最常见的就是服用止痛药，以及激素类避孕药物等抑制病灶发展，严重的情况可能要转向手术，切除子宫内膜异位症引起的病变，甚至完全切除子宫。 通常情况下，患者规模庞大、治疗手段匮乏，意味着商业化前景广阔，往往会吸引药企的研发布局。但这一点，在子宫内膜异位症这里，似乎并不成立。 一方面，在任何条件下，开发药物都不是一件容易的事。尤其是当对疾病没有很好的了解时，这个过程会更加困难。 至今，子宫内膜异位症的发病机制尚未明确。 医学界有一些理论能部分解释子宫内膜异位症的发生，最流行的理论是1927年Sampson 提出的种植学说。该学说认为是宫腔内的子宫内膜漂流到其他部位并种植了下来，形成了内异症的病灶。 围经期的腹腔镜检查发现，90%的女性都有经血逆行的现象，但发生子宫内膜异位症的只是很少一部分人。这意味着除了内膜的迁移之外，或许还有其他因素参与了病灶的形成，如基因突变、免疫功能改变、内分泌信号异常等。 换句话说，即便有些理论看起来很合理，也仍然无法解释很多问题，这使得子宫内膜异位症的成因至今尚未明晰，自然也难以根据病因采取相应的预防治疗措施。 另一方面，信息赤字，是相关药物研发匮乏的关键原因。 研究人员有时会使用生物库——从组织、血液和DNA样本中收集医学和生物数据——来识别疾病的分子标志物，或开发有效的诊断方法。如果由政府资助的项目收集，数据通常会发布或提供给科学家，为药物研究提供了起点。 但是，按照贝勒医学院妇产科副教授兼临床医生Baburek和Joseph Nassif的说法，这种资源在子宫内膜异位症中十分有限。当然，改变正在发生，美国正在试图为所有患有子宫内膜异位症的患者做一个数据库。 事实上，这种信息不足根深蒂固。90年代末，FDA还建议将育龄妇女排除在参加第1阶段和第2阶段临床试验之外，即使她们使用的是避孕药具。这些政策是为了应对药物沙利度胺引起的出生缺陷而制定的。 1993年的一项法律要求将妇女和少数民族纳入美国国家卫生研究院资助的临床研究中，但是阻止妇女参与试验的效果，一直延续到今天。 2022年的一项研究发现，在2016年至2019年期间，美国进行的药物和医疗设备第1至第3阶段试验的参与者中，女性占41%。与女性在心脏病和精神障碍等一些疾病中占总患者人口的比例相比，女性参与临床的代表性远不足。 这些研究差距以及它们可能造成的临床信息、资源不足，最终使女孩、妇女处于“巨大劣势”。 这让事情陷入了一个负循环，尽管这种疾病很普遍，但人们对它了解甚少。 / 03 / 药企的撤退 当然，一切的根源或许还要指向，钱。子宫内膜异位症研究资金非常不足，药企也很少涉足这一领域。 事实上，与其他药物研发领域相比，女性健康仍然资金不足。对美国国立卫生研究院支持的研究的分析发现，主要影响男性的疾病获得了更多的资金。主要影响获得投资的妇女的疾病通常在肿瘤学领域，如乳腺癌和卵巢癌以及生殖医学。 硅谷银行的数据则显示，2019年，美国和欧洲在3225笔生物制药交易中投资了1220亿美元，这其中，只有13亿美元投资于女性健康生物制药公司。 缺乏资金，是导致生物技术公司停止研究候选药物或优先考虑其他项目的主要原因。 与此同时，庞大的未满足的临床需求，与最终的商业回报不成正比，也极大地影响着药企的投入热情。 最初被批准用于治疗前列腺癌的激素疗法Lupron Depot，在美国被批准用于控制与子宫内膜异位症相关的疼痛。 过去十年里，FDA还批准了另外两种用于子宫内膜异位症疼痛管理的产品：2018年的艾伯维的Orilissa，以及2022年的辉瑞和合作伙伴Myovant Sciences的Myfembree。 然而，这些药物的价格很高，Orilissa和Myfembree每月按各自的标价计算超过1000美元。它们也无法从根源解决疾病，且由于有可能降低骨密度，最多只能使用两年。 正因此，Orilissa和Myfembree的销售额并不理想。其中，Orilissa在获批三年后，艾伯维还曾试图出售该药物所在的妇女保健单位，但交易并未实现。这款药物的销售额也不再单独报告，而是与艾伯维财报中的“其他关键产品”一起汇总。 艾伯维上一次报告Orilissa的净收入是在2021财年，当时其在美国的销售额是1.39亿美元。 即使是大药企，出于回报的考虑也不得不转而追求其他领域：拜耳曾是妇女健康领域的主要参与者，去年它表示将把重点从妇女健康转移到免疫学、罕见疾病和神经学。 拜耳长期以来一直在销售一种名为Visanne的激素药物，用于治疗子宫内膜异位症相关疼痛。其还与美国和英国的研究人员合作，帮助识别了可能与子宫内膜异位症相关的炎症基因。拜耳发言人表示，虽然这一发现似乎指向了可能的非激素药物靶点，但进一步的研究“最终并没有推进开发”。 根据路透社的报道，原因是拜耳在女性健康领域的总体工作，“没有达到预期”。 / 04 / 总结 子宫内膜异位症的处境，或许也只是万千疾病中的冰山一角。 毕竟，人体是神秘而又复杂的组织，而相关疾病机制、临床数据的缺失，更是让我们对众多疾病的认识依然匮乏，这也是科技进步昌明下的阴暗面。 加上固有、错误的疾病社会认知，也会进一步阻碍新的变化发生。 但是，我们仍要保持期待。挫折和风险一直都是新药研发路上的常客，这并不会改变新药向前的趋势。开创性的研究往往是技术触发点，导致了新药研究的爆炸式增长。 无论子宫内膜异位症还是其他亟需新的治疗手段的疾病，都在等待这样一个触发点。 PS：欢迎扫描下方二维码，添加氨基君微信号交流。

Ally Schott felt lonely when she was diagnosed with endometriosis at the age of 12. With few treatment options and limited information to go on, she and her family had to become self-taught medical researchers.Even the diagnosis was the result of Schotts mother connecting the dots between the pain her daughter was experiencing and the symptoms described by women in a patient organization she had found.That's ultimately what convinced my parents that this is what I was dealing with seeing and reading about the experience of others, and recognizing that I was going through something similar, Schott said.In some ways, Schotts case is rare. Her diagnosis came early, unlike some women who dont learn they have endometriosis for a decade or more due to lack of disease awareness, misdiagnosis or even bias that assumes severe menstrual pain is normal.It's very, very easy to dismiss someone's discomfort if you believe something is meant to be uncomfortable, said Somer Baburek, CEO and co-founder of Hera Biotech, a biotechnology company developing a nonsurgical tool to diagnose endometriosis.Caused by the growth of uterine tissue outside of the uterus, endometriosis typically affects people who menstruate, but it can occur in post-menopausal women, too. The disease is characterized by chronic pelvic pain, especially during menstruation, but can also cause problems across other parts of the body. It is usually identified through a surgical procedure called a laparoscopy, as ultrasounds cant always image the abnormal tissue growth.Although physicians understanding of the disease has improved, endometriosis root causes remain debated even as it affects some 10% of women and girls globally.[Endometriosis research] has been very underfunded and so, despite the prevalence of this disease, it's not very well understood at all, said Marina R. Walther-Antonio, an assistant professor of surgery at the Mayo Clinic in Minnesota and a microbiome researcher.When Schott received her diagnosis, there was little she could do about it a reality that frustrated her and her family. I just felt like I finally had the answer, and that if we had the answer to what was wrong, there would be a solution, she said. Even since, only two new drugs for endometriosis-related pain have been approved in the U.S.That pattern is typical of diseases, like endometriosis, that primarily or only affect women. Insufficient funding of womens health research has stifled development of new products, resulting in prevalent conditions with hardly any available treatments. And while clinical trials are more inclusive than they were in the 1990s and earlier, studies are not always set up to tease out why or how disease symptoms may differ on the basis of biological sex.Information deficitsDevelopment of a drug is no easy feat for any condition. But the process is more difficult when the disorder isnt well understood, as with endometriosis.We're starting from multiple deficits, and one of them is an information deficit, said Heras Baburek. And I think that's something that all founders in women's health struggle from.For instance, researchers sometimes use biobanks collections of medical and biological data from tissue, blood and DNA samples to identify molecular markers of a disease, or develop effective diagnostics. If collected by a government-funded program, the data is often published or made available to scientists, providing a starting point for drug research.But such resources are more limited in endometriosis, according to Baburek and Joseph Nassif, an associate professor of obstetrics and gynecology at Baylor College of Medicine and a clinician. While such work has advanced further in other countries, the U.S. is just getting started.So now in the states, we're trying to do a database about all patients who have [endometriosis], Nassif said. We have banks for cancer and banks for other diseases. Once you have a lot of patients, we can study it better.With less of a foundation, drug developers taking aim at endometriosis, or other womens health conditions like polycystic ovary syndrome or premenstrual dysphoric disorder, can have a harder time starting out.When you're building the data story of your company, yours looks weaker than companies who are focused on indications outside of women's health, because they have access to all of those resources, Baburek said.Such information deficits have deep roots. Up until 30 years ago, the Food and Drug Administration recommended excluding women of childbearing age from participating in Phase 1 and 2 clinical trials, even if they were using contraception. The policies were made in response to birth defects caused by the drug thalidomide, which was prescribed to women to treat nausea in the 1950s and 1960s.A 1993 law mandated the inclusion of women and minorities in clinical research funded by the National Institutes of Health, but the effects of discouraging women from participating in trials have carried through to today.For example, a 2022 study found women made up 41% of participants in Phase 1 through Phase 3 trials for drugs and medical devices run between 2016 and 2019 in the U.S. Women were underrepresented compared to their estimated proportion of the overall patient population for a number of conditions, such as heart disease and psychiatric disorders.Those research gaps, and the knowledge deficits they can cause, ultimately put the lives of girls, women and their families at a huge disadvantage, Schott said.Federal efforts have tried to compensate. Most recently in February, the Biden administration committed to investing $100 million into womens health research. The FDA also recently updated draft guidance to ensure sponsors run more diverse clinical trials, supporting the Food and Drug Omnibus Reform Act of 2022, which requires specific documents and strategic plans.It's really important when you're going to try to understand the efficacy, tolerability and safety of a drug that you're testing it in the representative population of people who you anticipate actually using the product, said Katherine Seay, head of sales and operations at Clinical Trial Media, a patient recruitment and retention company.Limited optionsCompared to other areas of drug R&D, womens health remains underfunded. An analysis of NIH-backed research found that diseases largely affecting men received more funding. The conditions primarily affecting women that do get investment are typically within oncology, such as breast and ovarian cancer, and reproductive medicine.Baburek didnt intend to make reproduction Heras focus, for instance. But the company only gained interest from investors when she mentioned the negative impact endometriosis can have on fertility. While our reproductive organs may be involved in some of these chronic conditions, our ability to reproduce shouldn't be the focus, Baburek said.Hera's struggle for attention isn't an anomaly. Despite its prevalence, endometriosis remains low on drugmaker radar screens.Women with the disease typically take birth control, other hormonal therapies and pain medication to manage symptoms and their menstrual cycles. They may also turn to surgery to either remove the lesions endometriosis causes or, in severe cases, remove their uterus entirely.When Schott was young, the drug Lupron Depot, a hormonal therapy initially approved for the treatment of prostate cancer, was cleared in the U.S. to manage pain associated with endometriosis. The drug can cause side effects similar to that of menopause and was a horrific experience for Schott, who was about 13 years old when it was prescribed to her.Within the past decade, two other products have been approved by the FDA for pain management with endometriosis: AbbVies Orilissa in 2018, and Pfizer and partner Myovant Sciences Myfembree in 2022.The drugs come with hefty price tags: Orilissa and Myfembree each cost over $1,000 per month at their respective list prices. They also dont address the diseases roots, and use is limited to a maximum of two years due to their potential to decrease bone density.Those options are not widely discussed or celebrated because they're not actually treating the disease, Baburek said. [They are] just quieting some of the symptoms that make your life unbearable, but then you get a whole host of other symptoms that also might make your life unbearable.Schott was prescribed Myfembree as an adult, but never took it because of its limitations and potential effects on bone density. She says she likely wouldn't take Orilissa for the same reasons.For the moment being, we have some ways to manage [endometriosis], whether medical or surgical, definitely with some percentage of success and failure either way, said Nassif. But definitely, we need a lot of research for the future.Endometriosis involves the outgrowth of womb lining tissue in the pelvis or abdomen.OGPhoto via Getty ImagesA bare pipelineNeither Orilissa nor Myfembree are big sellers and dont seem to rate high on their makers priority lists.Three years after Orilissas approval, AbbVie tried to sell the womens health unit the drug was housed in, but the deal never materialized. Sales of the drug are no longer reported individually and are instead lumped in with other key products in AbbVies earnings report. The last time AbbVie reported Orilissas net revenue was for its 2021 fiscal year, when it recorded $139 million in U.S.sales.AbbVie did not provide additional details about the drugs development or sales when contacted by BioPharma Dive.In 2022, Japan-based Sumitomo Pharma agreed to acquire Myfembree developer Myovant Sciences for $2.9 billion. The drug is now sold by Sumitomo in Europe, while Pfizer jointly markets it in the U.S. and Canada.Pfizer doesnt report net sales, but lists Myfembree revenue as contributing to alliance revenue in financial filings.Myfembree is marketed for endometriosis pain by Pfizer and partner Sumitomo PharmaPermission granted by Sumitomo Pharma AmericaThe two drugs dont face much competition. Womens health company ObsEva had licensed a compound known as linzagolix from the Japan-based biotechnology company Kissei Pharmaceutical. However, the company terminated the deal and withdrew an approval application after the FDA informed it of deficiencies in its submission.ObsEva shut down operations earlier this year, one of several companies in womens health that had to refocus its research efforts recently.Pharma company Bayer has long sold a hormonal drug called Visanne for endometriosis-related pain, but the company has not submitted it for U.S. approval in that indication.We focus our research efforts on innovative options in areas of high unmet medical need, a Bayer spokesperson said in comments to BioPharma Dive. We regularly review our research and development portfolio to prioritize the advancement of the most promising projects.Working with researchers in the U.S. and U.K., Bayer also helped identify an inflammation gene that may be linked to endometriosis. While the discovery seemed to point to a possible non-hormonal drug target, further research did not end up moving forward into development, according to a Bayer spokesperson.Last year, Bayer shifted its focus away from womens health altogether. While new R&D could still yield womens health products, a Bayer executive told Reuters that the companys work in the field overall had fallen short of expectations.Elsewhere, Organon agreed in 2021 to acquire Forendo Pharma in a deal worth $75 million upfront, handing it a drug candidate targeting endometriotic lesions without affecting hormones. Other startups have emerged, including Gynica, FimmCyte and SLBST Pharma.Looking forwardWhile endometriosis research continues, Barburek argues that finding a non-hormonal target for treating the condition has to be a priority.We've got to mechanistically understand [endometriosis] so we know which levers to pull and which knobs to push, she said. So more research needs to go into the mechanistic side of it.There is some momentum. Alongside the $100 million the Biden administration pledged to womens health research, the Advanced Research Projects Agency for Health, or ARPA-H, also launched a sprint for womens health to fund health solutions for conditions that primarily or disproportionately affect women.Its not clear whether such efforts will remain a priority under President-elect Donald Trumps administration, however. Trump nominated Robert F. Kennedy Jr. to helm the Department of Health and Human Services, which oversees health agencies including the FDA. While Kennedy has made clear his views on vaccines and the pharmaceutical industry, his views on womens health research are less clear and his stance on abortion has been inconsistent.In a rally prior to the election, Trump said Kennedy is so into womens health, and would let him go wild on healthcare.Some experts worry state abortion bans might hinder recruitment into trials involving in vitro fertilization, or other conditions that might require documenting a womans medical history.I think, once you take that freedom of choice away from women and leave it in the hands of politicians, state or federal, it's not a great thing, Schott said. It's a devastating impact that's going to be further reaching than I think we even have the context to understand right now, and I do think that involves endometriosis.Amid such concerns, there is hope of progress in treating endometriosis. Yet, Baburek said, sustained interest and investment will require a concentrated effort to highlight, educate and draw attention to the issues or consequences of being a woman. '