Fezolinetant

//   • 女性健康不仅是生殖健康，还包括可能对女性产生不同影响或影响更为突出的常见健康问题。 • 子宫内膜异位症和更年期健康领域具有很大的未满足需求，新药开发的方向都是寻求非激素类或者更安全的新型激素药物。 • 女性的生理差异影响到部分药物，尤其是心血管代谢药物的疗效和安全性。 世界经济论坛（World Economic Forum）和麦肯锡健康促进研究院（McKinsey Health Institution）近期发布的一项分析显示，相对于男性，女性处在健康不佳状态的事件要多出25%；另一方面，过去40年来，30%的药品召回与女性相关的安全风险有关。解决这一显著未满足需求可能会在2040年每年为全球贡献超过1万亿美元的GDP，并创造新的市场机会。 女性健康不仅仅是生殖健康。麦肯锡的定义更为广泛，不仅涵盖了与女性生殖或其他女性生理特征相关的特定疾病，还包括可能对女性产生不同影响或影响更为突出的常见健康问题。 大多数药企已经涉足了女性健康领域。麦肯锡的分析显示，全球排名前20的制药公司中，大多数超过60%的收入来自于治疗那些影响女性的疾病的产品，其中相当部分用于治疗自身免疫疾病、精神障碍、骨质疏松、心血管疾病和女性相关癌症。 然而，女性健康方面的药物研发仍然显著不足。除去肿瘤，女性健康相关疾病的新药开发投入仅占药企全部临床开发费用的1%，且资产集中在生殖、妇科疾病和妇科感染方面。麦肯锡认为，在孕产期健康、子宫内膜异位症和更年期健康这三个领域上，具有非常大的发展潜力。 急需更安全的新型药物 子宫内膜异位症影响了约1.7亿全球女性，带来严重的疼痛和生育问题。目前的治疗方法包括采用NASID短期镇痛，口服避孕药或孕激素，以及一些二线治疗如GnRH激动剂和左炔诺孕酮宫内缓释系统（LNG-IUS）。 围绝经期相关症状包括潮热、夜间盗汗、情绪波动以及增加骨质疏松和心血管疾病的风险。标准治疗方法是激素替代疗法（HRT）。 这两类显著影响女性健康的疾病都涉及激素变化，因此长期以来都是以激素疗法为主要治疗手段，但是激素疗法会带来一些副作用，比如GnRH激动剂会导致雌激素缺乏症、排卵抑制，而HRT与乳腺癌、心脏病发作、中风和血栓等风险相关。因此这两类疾病药物开发的共同方向都是寻求非激素类或者更安全的新型激素药物，改善患者的生活质量。 然而，涉足这一领域药物开发的公司有限。 2018年，FDA批准艾伯维的GnRH拮抗剂Orilissa（elagolix）用于子宫内膜异位症疼痛，成为十年来首个用于该适应症的口服疗法。然而，这一新型激素药物仍然会带来骨丢失的问题。另一款GnRH拮抗剂linzagolix正在开展相同适应症的3期研究，这款在研药物的国内权益为葆正医药所有。 在非激素药物的开发上，和其瑞从拜耳引进的PRL单抗目前正在国内外开展2期研究。去年10月，发布了研究的中期积极结果。此前拜耳曾尝试开发P2X3 受体拮抗剂 eliapixant用于子宫内膜异位症，但因安全性问题而放弃。 围绝经期相关研发的重点近年来转向针对潮热的非激素治疗。2023年FDA批准了安斯泰来的Veozah（fezolinetant），使其成为首款获批用于围绝经期潮热症状的NK3受体拮抗剂。不过，由于潜在的肝损伤风险，接受该药治疗的患者需要检测肝功能，上市后销售额也不如预期。 拜耳已经向FDA提交了NK1/3受体拮抗剂elinzanetant的上市申请。打击NK1受体可能在理论上提供比仅靶向NK3的Veozah更好的肝脏安全性。拜耳认为，靶向NK1受体理论上可提供比仅靶向NK3的药物更好的肝脏安全性。 药物研发中的性别差异 一些研究发现，由于女性第二条X染色体在免疫反应中的积极作用，尤其是脂肪分布和代谢方面的生理差异，会影响到部分药物，尤其是心血管代谢药物的疗效和安全性。 比如，诺华发现，其心衰药物诺欣妥（沙库巴曲缬沙坦钠）对女性更为有效，原因是因为女性发生射血分数保留的心衰（HFpEF）的几率是男性的两倍。该公司在针对目标患者亚群开展临床试验后，成功拓展了适应症，使药物覆盖人群增加了超过200万名。 类似的例子还有优时比的西敏佳（培塞利珠单抗）。优时比发现，这一药物在胎盘和母乳中的量极少，因而于2024年获得FDA的批准允许孕妇使用，使相关患者可以在孕期继续治疗。 麦肯锡的分析显示，弥补性别差异对女性患者的治疗，可以提高女性患者的依从率，让更多女性患者获益，并防止相关伤残调整生命年（DALY）的损失，对整个医疗系统带来深远的影响。 编辑 | 姚嘉 yao.jia@PharmaDJ.com  总第2353期 访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com

Despite multiple ongoing programs in novel technologies such as cell and gene therapy, Astellas is trying to spend more energy on less risky modalities. In the last few years, Astellas has invested heavily in novel technologies that are not necessarily the most successful or popular in the industry. With multiple programs now nearing proof-of-concept readouts, yet still “not happy about the pace” of development, Astellas is shifting its focus more to later-stage opportunities, chief strategy officer Adam Pearson said.In 2019, Astellas made big investments in cell and gene therapies with its back-to-back acquisitions of Audentes Therapeutics and Xyphos Biosciences. And last year, the company tacked on collaborations with lentiviral vector delivery specialist Kelonia Therapeutics, allogeneic CAR-T biotech Poseida Therapeutics—which was just bought by Roche—and genomic medicine expert Sangamo Therapeutics.But after a few separate setbacks and an industrywide pullback among large pharmas, Astellas’ cell and gene programs remain in the early stages.“We’re not happy about the pace,” Pearson said on the sidelines of the J.P. Morgan Healthcare Conference in January. “We’d like to go faster, but we have to learn. These are modalities where the learning is part of [the process].”Astellas expects initial clinical readouts for a couple of candidates built on cell and gene technologies in the near future. AT845, an AAV gene replacement therapy designed for Pompe disease, could report data within a year, Pearson said. ASP7317, a regenerative cell therapy for moderate-to-severe geographic atrophy patients, is also “very close” to proof-of-concept results. In cancer cell therapy, Astellas is exploring different technologies, but Pearson said it’s too early to know which ones might work out.  For cell therapy, Astellas is focusing on solid tumors and regeneration of the back of the eye. For gene therapy, the Japanese pharma remains hopeful that it can eventually build a presence in neuromuscular disorders because these are the most amenable indications to genetic medicines, he added.“When we enter that market ourselves, it will be difficult to get everything right,” Pearson said. “But one thing we are trying to do is really study what our competitors do and what’s made a success of some of these products and what’s not. What’s helpful for us is that these products are no longer science fiction to doctors.”Despite multiple ongoing programs in cell and gene therapy, Astellas is trying to spend more energy on less risky modalities, the exec said.“We will shift our investment into more somewhat established modalities like bispecifics or immuno-stimulatory ADCs and targeted protein degradation,” Pearson said. “So probably the balance of our investment will be heavier in those areas which are a bit more derisked and where we understand how to make progress.”The company hopes to one day understand how ASP2138, a CLDN18.2xCD3 bispecific, could be different from the company’s newly FDA-approved monoclonal antibody Vyloy. In addition, forthcoming phase 1 data from ASP3082, which targets KRAS G12D mutations, will help Astellas see if its big bet on protein degradation is worthwhile. Astellas will soon have an efficacy readout from a multicohort phase 2 trial for the Pfizer-partnered ADC Padcev to help guide future development of the star drug after its groundbreaking success in bladder cancer.Although antibody-drug conjugates (ADCs) have attracted industry-wide interest and Astellas is one of the few players with a major product in the hot field, Pearson said the modality is not at the moment the focus of the company’s internal pipeline beyond Padcev.Still, if “there was the right, in late-stage, in-licensing opportunity that fitted,” the company might pursue it, Pearson said.That “late-stage” comment reflects a high-level strategy shift at Astellas as it conducts a pipeline review, which led to the recent discontinuation of an early CAR-T prospect aimed at CD20 B-cell lymphomas.“We will continue to go through a prioritization exercise where we will generally shift our resources to focus on slightly later-stage opportunities, whether they be still phase 2 at the moment or life-cycle management, and maybe have room for an in-licensed product to add to that, whilst maintaining kind of a vital level of research in the core areas,” Pearson said.Astellas’ primary focus areas are genetic regulation mostly in neuromuscular diseases, immuno-oncology, blindness and regeneration, and targeted protein degradation. When it comes to acquisitions or licensing, Astellas generally follows those more confined boundaries, even though it doesn’t rule out other opportunities, according to Pearson. The company did branch out recently into women’s health with its hot flash drug Veozah. However, shortly after the drug’s launch, Astellas lowered its peak sales expectations by half to a range of 150 billion Japanese yen to 250 billion Japanese yen ($1 billion to $1.6 billion).“We partly thought about Veozah as a one-off, exciting opportunity to bring a new class to treat an untreated population,” Pearson explained.“We’ve learned a lot from this experience, and we’re really doubling down on the areas where we’ve got this pipeline and a deeper portfolio already,” he added.Veozah, Vyloy and Padcev, together with the geographic atrophy med Izervay and the FLT3 inhibitor Xospata, form the strategic brands in Astellas’ in-market portfolio.The company is undergoing a four-year cost-cutting initiative, which aims to eventually achieve between 120 billion Japanese yen and 150 billion Japanese yen ($800 million to $1 billion) in annual cost savings by the end of its fiscal year 2027 when Pfizer-partnered old prostate cancer drug Xtandi is expected to lose market exclusivity in the U.S.