GABARAP

饮食/热量限制（Dietary/Caloric Restriction）能延缓衰老并非新闻。自古以来，人们便意识到了限制饮食或热量的重要性。《黄帝内经》中有这样一句养生之道：食饮有节，起居有常，不妄作劳，故能形与神俱，而尽终其天年，度百岁乃去。东晋时期著名医生葛洪曾言，不欲极饥而食，食不过饱。现在人们最常提到的“饭吃八分饱”的说法，也与其有着异曲同工之处。饮食/热量限制（DR/CR），是指在满足必需营养素（如必需氨基酸、维生素、必需脂肪酸等）摄取的情况下，减少能量摄入。从现代科学来看，饮食限制能延寿并非“空穴来风”，目前已在多物种中观察到其抗衰老、延寿命的作用，包括酵母、啮齿动物、非人类灵长动物，甚至人类身上。在现实生活中，衰老往往伴随着“认知能力下降”现象的发生。于是，研究者开始思考，既然饮食限制能够延缓物种的衰老，是否也同样能起到保护大脑的作用呢？最近，来自美国巴克衰老研究所的研究团队回答了上述问题，并从细胞学机制层面找到了饮食限制能延长寿命和保护大脑的关键一环——mtd/OXR1基因。具体来说，在饮食限制的条件下，mtd/OXR1可以维持逆转录酶，从而保护神经健康和延缓大脑衰老。该研究发表在Nature Communications上。https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-023-44343-3研究者早已观察到，人耐氧化性能蛋白（OXR1）基因具有着重要作用——如果基因发生变异，会导致小脑萎缩、张力减退、语言发育迟缓和癫痫发作等一系列疾病。相反，在肌萎缩侧索硬化症（ALS）的小鼠模型中，OXR1基因的过表达则能够提高存活率。那么，在神经缺陷和过早死亡的发生过程中，OXR1基因是否发挥了保护作用？又是如何发挥的呢？为了回答这一问题，研究者扫首先描了160种具有不同遗传背景的果蝇，并在自由进食（AL）和DR（约正常饮食的10%）的条件下进行喂养。在测试了果蝇寿命后，定位到了5个与“DR诱导的长寿”显著相关的基因，它们均具有特定的遗传变异。但在上述5个基因中，仅仅铁氧还原蛋白（Fdxh）和mustard（mtd）有人类同源基因，分别对应着铁氧还原蛋白2和OXR1。对比发现，由Act5c-GS-Gal4驱动的全身mtdRNA干扰会导致DR特异性的寿命缩短，而FdxhRNA干扰则无法诱导该现象。也就是说，mtd表达在DR介导的长寿过程中发挥着重要作用。于是，在这两个基因中，研究者选择了与人类和小鼠OXR1相对应的基因mtd，而后续研究将基于mtd深入展开。DR条件下延长的寿命需要基于mtd的表达有意思的是，研究者在果蝇的头部观察到，DR条件下的mtd mRNA表达量增加了7倍。如果能一直坚持DR，整个生命周期中的mtd表达均显著增加。也就是说，饮食限制能够增加果蝇神经元中mtd的表达。但与之相反，当采用组成型活性elav-Gal4驱动神经元mtd mRNA干扰后，无论是采用何种饮食模式，甚至DR，均会诱导果蝇发育缺陷的发生以及严重的寿命缩短。Mtd/OXR1中的TLDc结构域发挥着保护神经的作用。于是，研究者进一步在不携带mtd等位基因的果蝇神经元中过表达了缩减的人OXR1基因（hOXR1OE），观察到果蝇“找回了”丢失的寿命和DR反应。由此可见，神经元mtd的表达是DR介导的寿命延长过程中必不可少的一环，如果将其敲除则会诱发严重的发育缺陷以及寿命缩短。敲除mtd基因会导致寿命的缩短利用公开的ChIP-seq数据，研究者找到了DR中调节mtd表达的关键点——Traffic Jam（TJ）。具体来说，ChIP-seq数据显示基因座上存在CCCTC结合因子（CTCF）和TJ的重要结合信号。其中，诱导性神经元ctcfRNA干扰增加了mtd的表达，而tjRNA干扰则导致DR条件下所有mtd转录表达的降低以及寿命的缩短。事实上，饮食限制主要限制了整体蛋白质摄入量，进一步的验证显示，蛋白质限制诱导的mtd增加受到TJ的调控，从而延长了果蝇的寿命；但在正常饮食条件下，mtd表达则会受到CTCF的影响而被抑制。不过，这些效应只影响变异位点和TJ/CTCF结合位点下游的较短转录本。研究者解释道，体内营养相关成分的增加并非好事儿，反而可能会带来一定的健康损害，比如逆转录酶失调，甚至进一步缩短了寿命。在“向下”找到了影响mtd表达的关键因素之后，接下来“向上”探索mtd影响寿命的具体机制。这个过程究竟是如何实现的呢？研究者分析了与人OXR1共表达模式相似的前50个基因的基因本体（GO）术语，并对人成纤维细胞的OXR1和囊泡转运细胞器标记物进行了共同染色，包括溶酶体、核内体、高尔基体、内质网和线粒体。进一步的实验观察到，OXR1染色与内体标志物RAB7高度重叠。这时候，如果对神经元mtdRNA进行干扰，会发现果蝇体内Atg8a-II水平有所增加，即自噬体形成的标志物增加。研究者解释道，由于内吞蛋白和脂质的不当运输，内体中逆运复合体（retromer）功能障碍会导致溶酶体功能障碍，以及自噬体形成的增加。因此，可以推测，OXR1具有维持逆运复合体功能的作用。果不其然，当研究者对果蝇体内的神经元mtdRNA和tjRNA进行干扰时，逆运复合体蛋白水平被显著降低了，证明上述推测是正确的。事实上，对于健康的神经元来说，逆运复合体的维持是必不可少的；相反，当缺失逆运复合体蛋白时，则会诱导神经退行性疾病的发生。所以，mtd基因之所以能发挥抗衰和保护神经的作用，是因为它参与了逆运复合体功能的维持。mtd与逆运复合体之间的相互作用最后一步，回归人体——mtd/OXR1表达是否能够发挥防止神经退行性疾病和阿尔茨海默症发生的作用呢？利用人类组学数据集，研究者观察到，在丰度水平与OXR1基因呈正相关的蛋白质和受年龄影响的基因中，有83个基因存在重叠。进一步对数据集重叠基因进行KEGG通路分析，结果显示，与年龄相关的神经退行性疾病（包括阿尔茨海默症、亨廷顿氏症、帕金森病等）均出现了显著的富集。此外，研究者观察到，低水平的OXR1、VPS35、SNX5和RAB7A与阿尔茨海默症的诊断、记忆力和病理评分低下有关，而这些都是人OXR1和逆运复合体相关蛋白。相反，如果过表达了OXR1或逆运复合体，则能够挽救与阿尔茨海默症以及tau病理相关的表型。正如先前提到的那样，逆运复合体功能障碍与年龄相关性退行性神经疾病（比如阿尔茨海默症）之间有着紧密联系，尤其是在疾病进展的转运和突触功能的维持。鉴于OXR1与逆运复合体之间的关系，OXR1及其蛋白网络是减缓人类和果蝇衰老和与年龄相关的神经退行性疾病的关键调节剂。综上所述，本研究发现了一个重要基因mtd/OXR1——在间歇性禁食或者卡路里限制等营养限制的策略中，mtd/OXR1基因水平会有所提高，进一步激活了逆运复合体功能，发挥出维持神经元功能、延缓大脑衰老以及寿命延长等多种作用，对大脑健康产生正向影响。本研究的共同通讯作者Kenneth Wilson还强调了另一个观点“饮食会影响人体内所有的过程”。所以，只要你努力坚持健康饮食方式，身体是不会“辜负”你的，而且这种影响会比你想象得更大。总结来说，吃得少，活得久，脑更灵。春节想必大家一定吃了不少吧，从今天开始可以加入“少吃”行列了哦参考资料：[1]Wilson, K.A., Bar, S., Dammer, E.B. et al. OXR1 maintains the retromer to delay brain aging under dietary restriction. Nat Commun 15, 467 (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-023-44343-3撰文 | Swagpp编辑 | Swagpp版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。点击下方「阅读原文」 立刻下载梅斯医学APP！

Pictured: Unhappy woman with her head in her hands in front of her baby's stroller/iStock, AndreyPopov Despite launching with just days left in 2023, Sage Therapeutics’ postpartum depression therapy Zurzuvae (zuranolone) made $1.6 million in sales, the Massachusetts-based biotech reported in Wednesday’ s fourth-quarter and full-year earnings results. CEO Barry Greene in an investor call said that Zurzuvae launched in mid-December 2023, “giving us about 10 days in 2023 where women with [postpartum depression (PPD)] in need of treatment could access” the drug. In that short amount of time, Sage was able to deliver approximately 120 prescriptions of Zurzuvae at the end of the fourth quarter. In the U.S., Sage is looking at a market of around 500,000 women who experience PPD after giving birth each year. “It’s early but I do believe that Zurzuvae is the key to unlock the blockbuster potential of PPD, enabling us to help many women suffering from postpartum depression,” Greene said during the call, adding that the company expects the market to grow even further as the industry and healthcare system increasingly recognize PPD as an urgent and serious medical condition. Greene also reported “encouraging developments across the treatment landscape,” including a specialty distribution network that delivers Zurzuvae to patients’ homes, ongoing conversations that lower PPD stigma as well as patients themselves advocating for Zurzuvae. “We’re early in launch days, and there are aspects of launch we certainly need to optimize, but the initial response and uptake are highly encouraging,” Greene said. Zurzuvae is an orally available neuroactive steroid that works by binding to the GABA-A receptor, modulating its response to the inhibitory neurotransmitter GABA. Sage is developing and commercializing Zurzuvae in partnership with Biogen, with which is splits the revenues. Approved in August 2023, Zurzuvae is the first pill cleared for PPD. At the time, however, Zurzuvae missed out on the FDA’s greenlight for major depressive disorder, which would have given it access to a much larger market. Following that FDA rejection, Sage’s shares tanked and the company reduced its workforce by 40% weeks later. Sage appears to have recouped some of its losses since then, but it has yet to fully recover. During the fourth quarter of 2023, the biotech reported a net product revenue of nearly $1.99 million, down from nearly $2.87 million during the same period the prior year. Sage’s net revenue in the quarter sat just below $78 million, driven heavily by a $75 million license and milestone boost from Biogen. By the end of December 2023, Sage had over $753 million in cash, cash equivalents and marketable securities, down from the nearly $1.3 billion it had in 2022. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

ZURZUVAE, the first and only oral, once-daily, 14-day treatment course, has shown to provide rapid improvements in depressive symptoms at Day 15 and as early as Day 3 for women with PPD Patient support program, ZURZUVAE For You, and financial assistance available to eligible women with PPD prescribed ZURZUVAE Patients will receive prescriptions directly at home via specialty pharmacy distribution model CAMBRIDGE, Mass., Dec. 14, 2023 (GLOBE NEWSWIRE) -- Biogen Inc. (Nasdaq: BIIB) and Sage Therapeutics, Inc. (Nasdaq: SAGE) announced ZURZUVAE™ (zuranolone) 50 mg (two 25 mg capsules per day) CIV is now available by prescription for the treatment of postpartum depression (PPD) for adults in the United States, with product already at specialty pharmacies and delivered to patients. ZURZUVAE is the first and only oral, 14-day treatment course for adults with PPD that can provide rapid improvements in depressive symptoms at Day 15 and as early as Day 3. “For women with PPD, delayed improvement in depressive symptoms can significantly worsen outcomes. Having an option like ZURZUVAE that can work at Day 15 and improve symptoms in as early as three days has the potential to make a profound difference in the lives of women with PPD,” said Dr. Kristina Deligiannidis, a principal investigator in the ZURZUVAE clinical development program and Professor, The Feinstein Institutes for Medical Research in Manhasset, New York. “This milestone is hopefully a catalyst for more systemic change for women with PPD including a much-needed increase in screening, diagnosis and treatment across physician specialties.” “After having a baby, the post-birth follow-up appointment is usually the first time a woman has the opportunity to talk about how she is feeling. It shouldn’t matter if it takes place with her midwife, OBGYN or family practitioner – it’s critical we use these conversations to proactively discuss her mental health and take action to support women in need,” said Dr. Quinn Peeper, Obstetrician/Gynecologist at City Crescent Physicians in New Orleans. “A treatment like ZURZUVAE provides us with a new option to help address the needs of women with PPD.” Biogen and Sage are prioritizing access through active discussions with national, regional and government payors to advocate for broad and equitable access to ZURZUVAE for women with PPD with minimal restrictions. While coverage decisions by insurers across all payor segments can take time, Biogen and Sage are focused on helping women who are prescribed ZURZUVAE gain access as quickly as possible. The companies also launched a patient support program, ZURZUVAE For You, which provides educational resources, help with understanding insurance coverage, and assistance navigating the prescription fulfillment process. The program also includes financial assistance, such as a copay assistance program, and product at no cost for eligible patients. The companies are partnering with several of the leading national specialty pharmacies and ZURZUVAE will be shipped directly to women with PPD who are prescribed the treatment. “It’s critical that as a society we recognize PPD is a serious medical condition. I have witnessed the devastating impact untreated PPD can have on women, only heightened by the fact that Black and Brown women and those living in a lower socioeconomic status are disproportionately impacted,” said Wendy N. Davis, Ph.D., PMH-C, Executive Director at Postpartum Support International. “PPD should not be treated as an afterthought. We need to embrace the care of women and increase access to effective care. Treatments like ZURZUVAE are a signal of hope that we're one step closer to prioritizing maternal mental health.” PPD symptoms can be debilitating and are characterized by negative changes in mood and impaired function.1,2 PPD impacts women of all races, ethnicity, socio-economic status and community,3-5 though symptoms are more common among minority patient populations compared to white patients.3,4 Black and Brown women, women who live in rural areas, or those on Medicaid may be more likely to receive inadequate postpartum care, compared to individuals in urban areas or with private health insurance.5 Biogen and Sage are working with key stakeholders across states to help raise awareness of the importance of treating PPD rapidly and removing barriers to treatment. “We are committed to working with healthcare providers so women with PPD do not face this isolating condition alone,” said Alisha A. Alaimo, President of Biogen’s North America Organization. “We are proud to offer the first oral therapy indicated specifically for women with PPD and we hope this milestone adds to the growing efforts, federally and among health organizations, to improve maternal mental health care.” “We are immensely proud of the feedback following the approval of ZURZUVAE from those on the front lines who are advocating for and delivering maternal mental healthcare, as well as their commitment to making an impact collaboratively,” said Chris Benecchi, Chief Business Officer at Sage Therapeutics. “Innovations are only impactful if people can access them, and we will continue supporting the goal of broad and equitable access. Our support programs aim, where possible, to help women with PPD who are prescribed ZURZUVAE to have little to no copay, and to provide product at no cost for eligible patients with no insurance, as we believe that lack of insurance or financial means should not be a barrier to treatment access.” For more information on ZURZUVAE and the patient support program, ZURZUVAE For You, HCPs and their patients can visit ZURZUVAE.com or call 844-987-9882. Indication and Important Safety Information What is ZURZUVAE?ZURZUVAE is a prescription medicine used to treat adults with postpartum depression (PPD). It is not known if ZURZUVAE is safe and effective in children. IMPORTANT SAFETY INFORMATION What is the most important information I should know about ZURZUVAE? ZURZUVAE may cause serious side effects, including: Decreased ability to drive or do other dangerous activities. ZURZUVAE may decrease your awareness and alertness, which can affect your ability to drive safely or safely do other dangerous activities Do not drive, operate machinery, or do other dangerous activities until at least 12 hours after taking each dose during your 14-day treatment course of ZURZUVAEYou may not be able to tell on your own if you can drive safely or tell how much ZURZUVAE is affecting you Decreased awareness and alertness [central nervous system (CNS) depressant effects]. ZURZUVAE may cause sleepiness, drowsiness, slow thinking, dizziness, confusion, and trouble walking Because of these symptoms, you may be at a higher risk for falls during treatment with ZURZUVAETaking alcohol, other medicines that cause CNS depressant effects, or opioids while taking ZURZUVAE can make these symptoms worse and may also cause trouble breathingTell your healthcare provider if you develop any of these symptoms, or if they get worse during treatment with ZURZUVAE. Your healthcare provider may decrease your dose or stop ZURZUVAE treatment if you develop these symptoms ZURZUVAE is a federal controlled substance (C-IV) because it contains zuranolone, which can be abused or lead to dependence. Keep ZURZUVAE in a safe place to protect it from theft. Do not sell or give away ZURZUVAE, because it may harm others and is against the law. Before taking ZURZUVAE, tell your healthcare provider about all of your medical conditions, including if you: drink alcoholhave abused or been dependent on prescription medicines, street drugs, or alcoholhave liver or kidney problemsare pregnant or plan to become pregnant. ZURZUVAE may harm your unborn babyare breastfeeding or plan to breastfeed. ZURZUVAE passes into breast milk, and it is not known if it can harm your baby. Talk to your healthcare provider about the risks and benefits of breastfeeding and about the best way to feed your baby during treatment with ZURZUVAE Females who are able to become pregnant: Tell your healthcare provider right away if you become pregnant during treatment with ZURZUVAE.You should use effective birth control (contraception) during treatment with ZURZUVAE and for 1 week after the final doseThere is a pregnancy registry for females who are exposed to ZURZUVAE during pregnancy. The purpose of the registry is to collect information about the health of females exposed to ZURZUVAE and their baby. If you become pregnant during treatment with ZURZUVAE, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visit online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ZURZUVAE and some medicines may interact with each other and cause serious side effects. ZURZUVAE may affect the way other medicines work, and other medicines may affect the way ZURZUVAE works. Especially tell your healthcare provider if you take antidepressants, opioids, or CNS depressants such as benzodiazepines. What should I avoid while taking ZURZUVAE? Do not drive a car, operate machinery, or do other dangerous activities until at least 12 hours after taking each dose of ZURZUVAE because ZURZUVAE may make you feel sleepy, confused, or dizzyDo not drink alcohol or take other medicines that make you sleepy or dizzy while taking ZURZUVAE without talking to your healthcare provider See “What is the most important information I should know about ZURZUVAE?” ZURZUVAE may cause serious side effects, including: See “What is the most important information I should know about ZURZUVAE?” Increased risk of suicidal thoughts or actions. ZURZUVAE and other antidepressant medicines may increase the risk of suicidal thoughts and actions in people 24 years of age and younger. ZURZUVAE is not for use in children How can I watch for and try to prevent suicidal thoughts and actions? Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changedTell your healthcare provider right away if you have any new or sudden changes in mood, behavior, thoughts, or feelingsKeep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms Tell your healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you: attempts to commit suicidethoughts about suicide or dyingnew or worse depressionfeeling very agitated or restlesstrouble sleeping (insomnia)new or worse anxietypanic attacksnew or worse irritabilityacting aggressive, being angry, or violentan extreme increase in activity and talking (mania)acting on dangerous impulsesother unusual changes in behavior or mood The most common side effects of ZURZUVAE include: Sleepiness or drowsiness, dizziness, common cold, diarrhea, feeling tired, weak, or having no energy, and urinary tract infection These are not all of the possible side effects of ZURZUVAE. Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see full Prescribing Information, including Boxed Warning and Medication Guide. About ZURZUVAETM (zuranolone)ZURZUVAE is a once-daily, oral, 14-day medicine for the treatment of adults with postpartum depression (PPD). ZURZUVAE is a neuroactive steroid (NAS) GABA-A receptor positive allosteric modulator (PAM). The GABA system is the major inhibitory signaling pathway of the brain and central nervous system and contributes to regulating brain function. About BiogenFounded in 1978, Biogen is a leading global biotechnology company that has pioneered multiple breakthrough innovations including a broad portfolio of medicines to treat multiple sclerosis, the first approved treatment for spinal muscular atrophy, two co-developed treatments to address a defining pathology of Alzheimer’s disease, the first treatment to target a genetic form of ALS, the first oral treatment approved for postpartum depression, and the first approved treatment for Friedreich’s ataxia. Biogen is advancing a pipeline of potential novel therapies across neurology, neuropsychiatry, specialized immunology and rare diseases and remains acutely focused on its purpose of serving humanity through science while advancing a healthier, more sustainable and equitable world. We routinely post information that may be important to investors on our website at www.biogen.com. Follow us on social media - Facebook, LinkedIn, X, YouTube. About Sage Therapeutics Sage Therapeutics is a biopharmaceutical company fearlessly leading the way to create a world with better brain health. Our mission is to pioneer solutions to deliver life-changing brain health medicines, so every person can thrive. For more information, please visit www.sagerx.com. Biogen Safe Harbor This news release contains forward-looking statements, relating to the potential, benefits, safety and efficacy of ZURZUVAE; the potential of Biogen’s commercial business and pipeline programs, including ZURZUVAE; the anticipated benefits and potential of Biogen’s collaboration arrangement with Sage; and risks and uncertainties associated with drug development and commercialization. These forward-looking statements may be accompanied by words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “intend,” “may,” “plan,” “potential,” “possible,” “will,” “would” and other words and terms of similar meaning. Drug development and commercialization involve a high degree of risk and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical trials may not be indicative of full results or results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including without limitation, uncertainty of success in the development and potential commercialization of ZURZUVAE for PPD; unexpected concerns may arise from additional data, analysis or results of clinical studies of zuranolone; regulatory authorities may require additional information or further studies, or may fail or refuse to approve or may delay approval of Biogen’s drug candidates; the occurrence of adverse safety events; the risks of other unexpected hurdles, costs or delays; failure to protect and enforce data, intellectual property and other proprietary rights and uncertainties relating to intellectual property claims and challenges; product liability claims; third party collaboration risks; and the direct and indirect impact of COVID-19 on our business, results of operations and financial condition. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from Biogen’s expectations in any forward-looking statement. Investors should consider this cautionary statement as well as the risk factors identified in Biogen’s most recent annual or quarterly report and in other reports Biogen has filed with the U.S. Securities and Exchange Commission. These statements speak only as of the date of this news release. Biogen does not undertake any obligation to publicly update any forward-looking statements. Sage Therapeutics Safe Harbor Various statements in this release concern Sage's future expectations, plans and prospects, including without limitation our statements regarding: our plans for commercializing ZURZUVAE in the treatment of women with PPD; our expectations as to our patient support programs for ZURZUVAE; our goals and plans with respect to access and reimbursement coverage for women with PPD who are prescribed ZURZUVAE; statements regarding the unmet need in the treatment of PPD; our belief in the potential clinical benefit of ZURZUVAE in the treatment of PPD; and the mission and goals for our business. These statements constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. These forward-looking statements are neither promises nor guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond our control, which could cause actual results to differ materially from those contemplated in these forward-looking statements, including the risks that: our commercialization efforts in the U.S. with respect to ZURZUVAE for the treatment of women with PPD may not be successful, and we may be unable to generate revenues at the levels or on the timing we expect or at levels or on the timing necessary to support our goals; the number of women with PPD, the unmet need for additional treatment options, and the potential market for ZURZUVAE in this indication may be significantly smaller than we expect; ZURZUVAE may not achieve the clinical benefit, clinical use or market acceptance we expect in the treatment of women with PPD; we may not achieve broad access or reimbursement coverage with minimal restrictions for ZURZUVAE in the treatment of women with PPD; we may encounter reimbursement-related or other market-related issues that impact the success of our commercialization efforts or access to ZURZUVAE in the treatment of women with PPD; we may encounter adverse events related to ZURZUVAE at any stage that negatively impact commercialization; the need to align with our collaborators may hamper or delay our commercialization efforts or increase our costs; our business may be adversely affected and our costs may increase if any of our key collaborators fails to perform its obligations or terminates our collaboration; our ongoing efforts and activities to successfully develop products in addition to ZURZUVAE may not be successful; as well as those risks more fully discussed in the section entitled "Risk Factors" in our most recent quarterly report, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We explicitly disclaim any obligation to update any forward-looking statements. References: Thurgood S, et al. Am J Clin Med. 2009;6:17-22.National Institutes of Mental Health. https://www-nimh-nih-gov.libproxy1.nus.edu.sg/health/publications/perinatal-depression. Accessed March 22, 2023.Cannon C, Nasrallah HA. Ann Clin Psychiatry. 2019;31 (2):138-143.Bauman BL, et al. MMWR Morb Mortal Wkly Rep. 2020;69(19):575-581.Interrante JD, et al. JAMA Health Forum. 2022;3(10):e223292. ZUR-US-0739 12/2023 MEDIA CONTACTS:BiogenJack Cox+1 781 464 3260public.affairs@biogen.comSage TherapeuticsMatthew Henson+1 917 930 7147Matthew.Henson@sagerx.comINVESTOR CONTACTS:BiogenChuck Triano+1 781 464 2442IR@biogen.com Sage TherapeuticsAshley Kaplowitz+1 786 252 1419Ashley.Kaplowitz@sagerx.com