ObsEva SA

氨基观察-创新药组原创出品作者 | 沙晓薇在全球，大概每10个育龄女性中就有1个饱受子宫内膜异位症的折磨——这是一种影响约1.9亿女性的高发疾病，90%的患者经历着间断性的盆腔疼痛，26%甚至面临不孕的阴影。然而，当Organon近日宣布其“明星候选药物”OG-6219在二期临床试验中宣告失败时，这个本应充满希望的领域再次被蒙上阴霾。OG-6219曾被寄予厚望，被Organon视为“重塑痛经治疗标准”的突破，但它的失败不仅让Organon的女性健康创新管线陷入危机，更揭示了子宫内膜异位症药物研发的深层困境：一个影响数亿人的市场，为何新药寥寥无几？痛经药物的春天究竟何时才能到来？/ 01 /需求巨大，供给稀缺痛经，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。理论上，子宫内膜异位症拥有巨大的治疗需求与商业空间，但现实却是新药稀缺，研发缓慢。究其原因，还是对该疾病的基础研究仍处在模糊的“边缘地带”。研究认为原发性痛经与前列腺素合成过度有关，但其发病涉及激素异常、免疫炎症、神经敏化等多重因素的影响，真正的致病机制尚未厘清。这直接导致了新药研发的步履维艰。患者个体差异大，激素、子宫结构、炎症状态等因素复杂交错，进一步增加了研究的复杂性。由于缺乏有效的动物模型和生物标志物，疾病的分型及治疗选择无法达到共识，这也使新机制药物的转化率长期维持在低水平。更糟糕的是，许多女性将痛经视为“正常生理现象”，不了解子宫内膜异位症的存在，错过了早期干预时机，进一步增加了治疗难度。当然，非甾体抗炎药（NSAIDs）如布洛芬和双氯芬酸，仍是首选用药，但却“治标不治本”，能缓解疼痛，却无法根除病灶。而布洛芬的低价和高可及性（一瓶仅需几美元），无形中抬高了新药的准入门槛：如果新药无法显著超越NSAIDs的短期疗效，就很难在审评或商业化中胜出。艾伯维的Orilissa和辉瑞的Myfembree就是活生生的例子，这两款针对GnRHR的拮抗剂虽早已获批，但1000美元/月的高价、骨密度降低的副作用以及肝毒性问题，让市场接受度大打折扣。而ObsEva开发的口服GnRH拮抗剂linzagolix也曾试图上市，后因审评问题撤回申请，公司最终于2024年初停止运营。更早前，拜耳也曾布局这一领域，其靶向孕激素/催乳素（ER/PR）药物Visanne于2010年首次在欧洲获批，用于治疗子宫内膜异位症引发的疼痛，尽管与GnRH激动剂相比有更优的耐受性，但整体销售未能形成突破性增长。随着市场增长迟缓，收益不佳，拜耳原计划开展的与GnRH拮抗剂Elagolix的联合疗法项目也早早中止。这些案例背后，是药企的理性计算：机制不明、治疗意识不足，加上NSAIDs的强势市场地位，让大公司如拜耳也不得不“知难而退”。子宫内膜异位症正陷入需求巨大、供给稀缺的悖论负循环之中。/ 02 /失意者Organon如今，失意者的名单要再增添一位，2021年被默沙东拆分出来的Organon。为了摆脱“老药依赖”的标签，其通过并购打造自己的创新管线。2021年，Organon收购Forendo Pharma，代价是7500万美元的预付款，并承担900万美元的债务，以及最高9亿美元的里程碑付款。通过此次收购，Organon获得了后者的主打候选药物O6-6219。OG-6219被Organon寄予厚望，Organon的研发主管兼首席医疗官将其誉为“我们最大的潜在机遇”的口服药物。这是一种口服17β-羟类固醇脱氢酶1型（HSD17B1）抑制剂，其作用原理是阻断雌二醇激素的合成与转化过程。由于子宫内膜异位症及其导致的痛经、慢性盆腔痛往往由雌激素驱动，该机制有望从源头缓解病灶炎症与疼痛反应。与现有治疗手段（如GnRHR拮抗剂）通过系统性抑制激素不同，OG-6219具有组织选择性，能在不显著影响全身激素水平的前提下，“精准”地降低子宫内膜异位症病灶中的雌激素活性。这种更温和且可持续的药物治疗，能够避免部分激素失活引起的副作用，比如骨质疏松、血脂异常等。显然，Organon希望靠这一新机制药物，来解锁巨大的子宫内膜异位症市场。I期和Ib期试验数据也令人鼓舞，在绝经后和绝经前女性中均显示安全性和耐受性良好，全身激素水平未受影响。可惜的是，新药研发向来九死一生，早期数据良好、后期翻车的案例比比皆是，OG-6219也没能逃过这一劫。7月2日，Organon公告OG-6219 II期试验未达主要终点，OG-6219在减轻子宫内膜异位症相关的总体盆腔疼痛方面，并未表现出优于安慰剂的疗效。Organon决定停止OG-6219的临床开发。这对于Organon的创新管线布局，无疑是一大打击。从2024年财报看，其女性健康管线本就薄弱，仅有OG-6219、OG-7191（针对多囊卵巢综合征）和OG-9489（非激素避孕）三个项目，后两者尚处临床前阶段。OG-6219的失败对Organon来说不仅是一个研发项目的损失，还是管线信心和市场预期的坍塌。从公司此次公告来看，目前暂无其他研发管线能够接棒OG-6219。尽管Organon表示会继续子宫内膜异位症女性患者探索新的治疗方案，但是，鉴于该领域研发难度高、临床转化周期长，短期内重塑有竞争力的产品线难度较大。Organon在子宫内膜异位症这一适应症上的探索也可能面临被动调整。这无疑让本就创新乏乏的子宫内膜异位症的前景，再度被阴霾笼罩。/ 03 /春天还要再等等当然，OG-6219的失败固然令人扼腕，但子宫内膜异位症的药物创新并未终结。随着女性健康在全球范围内受到越来越多关注，一些企业仍在坚持投入。目前，在研项目仍然以PR、GnRH通路为主，但也出现了少量尝试突破传统的探索方向。例如，以色列的Gynica聚焦内源性大麻素通路，开发靶向CB1/CB2受体的疗法；英国的Ananda Pharma探索CBD类化合物控制神经性疼痛；美国的FimmCyte则从炎症反应切入，试图绕过激素路径。国内方面，虽然尚未有新靶点突破，但相关研究仍在不断推进。目前已有动物模型中尝试通过阻断CGRP或TAM/CSF1R/NTRK治疗子宫内膜异位症，此外，已有中药如散结镇痛胶囊获批用于临床治疗。只不过，整体上这些探索仍停留在临床前或概念验证阶段，短时间还难以改写现有的治疗格局。市场格局的改写，或许还要等待一场真正的技术革命——或许是基因编辑、AI驱动的药物发现，或是多组学技术对疾病机制的彻底解密。更关键的是产业决心的考验，药企需平衡短期回报与长期投入，而投资者往往对高风险领域望而却步。Organon的失败提醒我们，痛经药物的春天不会自动降临，这需要科学家的执着、企业的勇气，以及社会对女性健康的重新认知：痛经不是“忍忍就过去”的小事，而是数亿女性亟待解决的医疗需求。或许，当更多资源涌入、更多跨界合作诞生时，我们终将迎来破冰之日。但在此之前，春天还要再等等。有时候，等待本身，就是一场耐心的革命。PS：欢迎扫描下方二维码，添加氨基君微信号交流。

A Swiss biotech has secured $65 million to launch a trio of mid-stage trials for two reproductive health drugs. ReproNovo announced the close of its Series A round on Wednesday. CEO Jean Marie Duvall co-founded the company with three other colleagues in 2021 with the goal of filling “critical gaps” in women’s health and reproductive medicine. The solution for those gaps? Duvall sees the potential in two candidates that originated at large pharma companies and were further developed at smaller biotechs before winding up in ReproNovo’s pipeline. ReproNovo’s lead candidate is an oral drug called leflutrozole, which came from Novartis originally and was acquired by Mereo BioPharma in 2015. ReproNovo struck a deal with Mereo in 2023 for the full global rights to leflutrozole, promising up to $64.3 million in potential milestones. While Mereo had been developing leflutrozole as a testosterone replacement therapy for obese men with a condition called hypogonadotropic hypogonadism, the company ultimately decided that the candidate should instead be developed for male infertility. “Low testosterone is increasing in young men, and this coincides with the whole broader decline in male reproductive health that we’re seeing and has been identified as a major health problem,” Duvall told Endpoints News. ReproNovo’s Series A round will be used in part to start a Phase 2 trial this year for leflutrozole, she said. ReproNovo is also planning two Phase 2 trials late this year or early next year for a second candidate called nolasiban. Nolasiban originated at Merck KGaA, and was licensed to ObsEva in 2013 before ReproNovo acquired the rights last year. ReproNovo plans on developing nolasiban to improve success rates in assisted reproductive technology (including IVF), and for a condition called adenomyosis, which is characterized by an overgrowth of endometrial tissue into the uterus. ObsEva reported a Phase 3 failure for nolasiban in 2019 in women undergoing embryo transfer following IVF. Duvall said ReproNovo plans on “reestablishing what we believe are the correct inclusion/exclusion criteria and how the drug will be used,” but declined to give further detail. One in six people are affected by infertility in their lifetime, according to the World Health Organization. Duvall said she’s seen recent momentum in the broader women’s health space, comparing the field to a wave that’s just starting to rise. “People are realizing there’s a real need in women’s health. There’s a real need in reproductive medicine,” she said.

ReproNovo has secured $65 million in a series A round to begin mid-stage testing of a pair of assets meant to address specific gaps in reproductive health.Its lead candidate, RPN-001 (leflutrozole), targets male infertility associated with low serum testosterone, a condition increasingly prevalent even among younger men, according to ReproNovo. The company has an exclusive global license agreement with Mereo BioPharma to develop and commercialise the oral therapy, which works by blocking the aromatase enzyme that converts testosterone to estradiol.Its second candidate, an oral drug called RPN-002 (nolasiban), is being developed as a potential "first-in-disease and first-in-class" treatment for adenomyosis — a condition where endometrial tissue grows into the uterine wall causing severe bleeding and pain — as well as improving embryo implantation success rates in assisted reproductive technology (ART). The company said it acquired exclusive rights, including all intellectual property and associated assets, related to nolasiban from ObsEva, which wound-down operations last year.The series A round was led by Jeito Capital and co-led by AXA IM Alts and founding investor M Ventures, with additional participation from Ysios Capital and ALSA Ventures.The investment comes as fertility issues affect approximately one in six people globally, according to Ksenija Pavletic, chief commercial officer at Jeito. Pavletic highlighted the ReproNovo team's "strong track record in this field, having brought a number of compounds successfully through clinical development and onto the market."ReproNovo — which was founded in 2021 — maintains headquarters in Lausanne, Switzerland, with its primary development operations in Copenhagen, Denmark, and an additional site in Barcelona, Spain.