撰文丨王聪 编辑丨王多鱼 排版丨水成文 晚发性阿尔茨海默病 （Late-Onset Alzheimer's Disease, LOAD） 是指 65 岁之后发病的阿尔茨海默病 （AD） ，占所有阿尔茨海默病的 90% 以上。全基因组关联研究 （GWAS） 已确定了多个 与 LOAD 发病 风险增加相关的基因多态性，许多与 LOAD 风险相关的等位基因通过影响 小胶质细胞 （microglia，MG） 的先天免疫反应和脂质代谢来改变疾病的发生机制。 2025 年 6 月 9 日，西达赛奈医疗中心的研究人员在 Nature 子刊 Nature Aging 上发表了题为： Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer's disease in 5xFAD mice 的研究论文。 该研究显示，在小胶质细胞中增强 ACE 表达，能够保护阿尔茨海默病小鼠模型的大脑，表明了 表达 ACE 的小胶质细胞可能作为一种治疗阿尔茨海默病的新型细胞疗法。 血管紧张素转换酶 （ACE） 是一种在 全基因组关联研究 ...

Core Viewpoint - The production of Manzoutan capsules, used for treating Alzheimer's disease, has been halted due to the expiration of its drug registration certificate, with the company awaiting approval from the drug regulatory authority [1][8]. Company Summary - Green Valley Pharmaceutical Technology has confirmed the closure of its office and production areas related to Manzoutan capsules, citing the expiration of the drug registration certificate and the ongoing wait for regulatory approval [1][8]. - The company previously acknowledged the difficulties patients faced in obtaining the medication and expressed regret over the potential impact of drug interruptions on patients' conditions [8]. Market Summary - The market price of Manzoutan capsules has surged approximately 40% in recent months, with prices on e-commerce platforms ranging from 428 yuan to 534.5 yuan per box, and some pharmacies listing prices as high as 5000 yuan per box [4]. - Reports indicate that many patients are struggling to find the medication, with numerous complaints about stock shortages and price hikes on social media [5][4]. Regulatory Summary - The approval status of Manzoutan capsules is currently pending, having entered the review queue on October 25, 2024. The situation of halting production due to expired licenses is considered rare in the industry [8][9]. - Manzoutan capsules were conditionally approved for market entry in China in November 2019, marking it as the first new drug for Alzheimer's disease approved globally since 2003 [8][9]. Clinical Summary - Concerns regarding the efficacy and safety of Manzoutan capsules persist, as the drug was approved under conditions requiring further research on its pharmacological mechanisms and long-term safety [9]. - The three-phase clinical trial for Manzoutan lasted only 36 weeks, which is deemed insufficient for a chronic degenerative disease like Alzheimer's, typically requiring longer observation periods to confirm sustained cognitive improvement [9].

Core Viewpoint - The company, Green Valley Pharmaceutical Technology, has announced the suspension of production for the mannitol sodium capsule product line due to the expiration of its drug registration certificate, currently awaiting approval from the drug regulatory authority [1] Group 1: Company Actions and Responses - Green Valley Pharmaceutical Technology has halted the production of mannitol sodium capsules and will close related office and production areas [1] - Employees affected by the suspension will receive wages at the minimum wage standard set by Shanghai, with social security and housing funds being paid normally [1] - The company has committed to restoring original salary standards once its operational conditions improve and it regains the ability to pay [1] Group 2: Product Background and Market Impact - Mannitol sodium capsules, developed in collaboration with Ocean University of China and the Shanghai Institute of Materia Medica, are used for mild to moderate Alzheimer's disease to improve cognitive function [1] - Since its launch in November 2019, the drug has benefited over 500,000 patients, with projected sales exceeding 2.1 million boxes in 2024 [1] - There is currently a shortage of mannitol sodium across the country, with prices on online platforms fluctuating daily [1] - The company has received over 9,300 requests from Alzheimer's patients for purchasing the drug through its hotline and online platforms [1] Group 3: Clinical Research and Development - The mechanism of action of mannitol sodium was published in a cover article in "Cell Research" in 2019, and further validation studies were published in 2024 [2] - An international Phase III clinical trial was initiated in 2020 but was abruptly halted in May 2022 due to increased dropout rates and funding issues [2] - Domestic post-marketing clinical research has involved 3,300 patients, with mid-term analysis showing 16% of patients exhibiting stable or improved efficacy indicators [3] - The final results of the post-marketing study are expected to be presented at an international academic conference in the second half of 2025 [3] Group 4: Industry Context - Alzheimer's disease remains a significant challenge in the medical field, with few new drugs approved since 2003, primarily focusing on symptom improvement [3] - Major pharmaceutical companies, including Eli Lilly, Takeda, Merck, Pfizer, and Roche, have entered the market, but no groundbreaking drugs have emerged yet [3] - The strategy for treating Alzheimer's is diversifying, with a growing number of clinical trials focusing on neuroinflammation rather than solely relying on amyloid-beta [3]

Core Viewpoint - The company, Green Valley Pharmaceutical Technology, has halted the production of its controversial drug, Glycyrrhizin Sodium Capsules, which is intended for the treatment of mild to moderate Alzheimer's disease, due to severe operational pressures and cash flow issues [2][4][6]. Group 1: Product and Regulatory Status - Glycyrrhizin Sodium Capsules received conditional approval from the National Medical Products Administration in November 2019, with requirements for further studies on carcinogenicity and pharmacological mechanisms [2]. - The drug's international Phase III clinical trial, which aimed to recruit 2,046 participants across China, the U.S., and Europe, was stopped in May 2022 due to factors such as the pandemic and funding issues [2][4]. - The company announced on May 30, 2025, that it would cease operations related to the Glycyrrhizin Sodium product line, pending the approval of its drug registration certificate [2][3]. Group 2: Industry Context and Challenges - Alzheimer's disease presents a significant challenge for the medical community, with global pharmaceutical companies investing hundreds of billions of dollars in research, yet most have failed to produce effective treatments [4]. - The company previously conducted post-marketing clinical research on Glycyrrhizin Sodium, involving 3,300 patients across China, with results expected to be presented at an international academic conference in the second half of 2025 [5]. - The ongoing operational difficulties and cash flow constraints have left the future of this controversial drug uncertain [6].

绿谷深陷经营困局，现金流极度紧张。 绿谷医药科技（下称"绿谷"）的甘露特钠胶囊，来到了产品周期的转折点。 第一财经今日获悉，绿谷已经停产甘露特钠胶囊，公司将关闭相关办公区、生产区。 2025年5月30日，绿谷发布内部通知，宣布甘露特钠胶囊产品线的相关岗位停工停产。绿谷对第一财经 反馈称，这是因为甘露特钠的药品注册证到期，目前正在等待药监局审批结果。 制药企业一般在许可批件到期的六个月前就会提前延续申请。许可证过期而尚未获得新一轮审批通过， 以至于企业停工停产的情况并不常见。 绿谷方面称，其近期面临严重经营压力，现金流极度紧张。 阿尔茨海默病是一种中枢神经系统的退行性病变，它的发病机制复杂，病程漫长，影响众多的全球及中 国患者。对于面临老龄化的中国社会、患者和家庭，阿尔茨海默病带来沉重的经济负担。 阿尔茨海默病也是医学界公认的难题。全球制药企业为延缓和治疗阿尔茨海默病前赴后继，罗氏、武 田、默沙东、辉瑞等企业为此共计投入了成百上千亿美元的资金，绝大多数公司铩羽而归。最近二十年 来，全球获批上市的新药寥寥无几，且大部分已上市药品以改善临床症状为主。 绿谷曾在国内对甘露特钠开展了上市后临床研究，覆盖全国各地3300 ...

Core Viewpoint - Alzheimer's disease (AD) is a destructive neurodegenerative disorder characterized by gradual cognitive decline, necessitating therapies that can slow or halt its progression [2][6]. Group 1: Current Treatments and Limitations - Currently, only a few FDA-approved monoclonal antibodies targeting amyloid-beta (Aβ) are available for early-stage Alzheimer's treatment, such as Lecanemab and Donanemab, which show efficacy in reducing amyloid burden but have limited impact on disease progression [2]. - The focus on Aβ alone is insufficient to address the progressive nature of Alzheimer's disease [2]. Group 2: Gene Therapy as a Promising Strategy - Gene therapy that enhances intrinsic neuroprotective pathways presents a promising new strategy to slow neurodegenerative changes and prevent further cognitive decline [3][6]. - Caveolin-1 (Cav-1), a membrane scaffolding protein, regulates various growth-promoting and survival signaling pathways, indicating its potential in Alzheimer's treatment [6]. Group 3: Research Findings - A recent study from the University of California, San Diego, demonstrated that delivering Cav-1 via AAV9 to symptomatic Alzheimer's mouse models can mitigate cognitive loss and pathological transcriptome changes [4][5]. - The study involved administering SynCav1 to symptomatic Alzheimer's mouse models (PSAPP and APPKI) and showed that it maintained hippocampal-dependent memory abilities [7][8]. - Transcriptomic analysis indicated that the profiles of PSAPP-SynCav1 mice were similar to those of age-matched wild-type mice, with downregulation of neurodegenerative pathways and upregulation of synaptic and cognitive-related pathways [8][10]. Group 4: Mechanisms of Action - The delivery of SynCav1 to the hippocampus during the symptomatic stage protected learning and memory abilities, with increased expression levels of p-CaMKII and p-CREB in primary cortical neurons, suggesting enhanced neuronal and synaptic activity [10]. - Activity-dependent neuroprotective protein (ADNP) was identified as a potential mediator of SynCav1's neuroprotective effects, retaining PAC1R, a known regulator of ADNP expression [11][12].

Core Viewpoint - The drug Gantoret Sodium Capsule (brand name: Jiuyi) for Alzheimer's disease has become scarce, leading to widespread concern about the difficulties patients face in obtaining medication [2][4][5] Group 1: Supply Issues - Since 2025, Gantoret Sodium Capsule has faced prescription difficulties in hospitals and supply shortages on online platforms [4][5] - The manufacturer, Green Valley Pharmaceutical Technology, acknowledged the supply issues and is in communication with relevant authorities to address the situation [2][4] - Reports indicate that the drug's market price has increased by approximately 40% in recent months, with some pharmacies listing prices as high as 5000 yuan per box [5][6] Group 2: Market Dynamics - The drug was first approved for conditional listing in November 2019 and officially launched in December 2019, allowing patients to purchase it with a doctor's prescription [4][6] - The initial price of the drug was set at 895 yuan per box, but it was later included in the national medical insurance directory, reducing the price to 296 yuan per box [6][7] - The current monthly cost for patients using Gantoret Sodium is approximately 1184 yuan, significantly lower than the combined cost of traditional treatments [6][7] Group 3: Disease Context - Alzheimer's disease is a major neurodegenerative condition affecting over 55 million people globally, with China having the highest number of patients [8] - The treatment options for Alzheimer's disease are limited, with Gantoret Sodium being one of the few drugs that can improve cognitive function without worsening the condition [8][9] - The drug was conditionally approved due to the urgent need for treatment options, despite some initial concerns regarding long-term safety data [9]

Core Viewpoint - The innovative drug Mannothe Sodium (brand name: Jiuyiqi) developed by Green Valley (Shanghai) Pharmaceutical Technology Co., Ltd. has received strong recommendations and high evidence quality rating in the "Alzheimer's Disease Multidimensional Rehabilitation Intervention Chinese Expert Consensus (2025)" [1][2] Group 1: Drug Efficacy and Recommendations - Mannothe Sodium is recognized as the first oligosaccharide drug targeting the gut-brain axis for Alzheimer's treatment, showing significant improvement in cognitive function and daily living abilities for mild to moderate Alzheimer's patients [2][3] - The drug has been recommended for its ability to improve cognitive function and daily living abilities in patients, with long-term use potentially delaying disease progression [2][3] - The consensus document includes 23 consensus opinions across four areas: prevention, treatment, rehabilitation, and care, emphasizing the drug's clinical relevance and evidence transparency [1][2] Group 2: Clinical Research and Safety - Two post-marketing clinical studies (GV-971-PMS-A and GV-971-PMS-B) involving 3,300 patients over two years indicate that patients treated with Mannothe Sodium showed significant cognitive and daily living improvements compared to baseline [3] - The drug demonstrated a safety profile without potential risks when used in elderly patients with common comorbidities and concurrent medications [3] - The final data results from these studies are expected to be presented at international academic conferences later this year [3] Group 3: Company Background - Green Valley Pharmaceutical Technology focuses on innovative cognitive health solutions, particularly in the treatment of cognitive disorders such as Alzheimer's disease, vascular dementia, and Parkinson's disease [8] - The company aims to enhance human cognitive health through research on the gut-brain axis and artificial intelligence, establishing a cognitive health industry ecosystem [8] - Mannothe Sodium has broken a 17-year drought of new drug approvals in the field and was included in the national medical insurance directory in 2021 [8]

Financial Data and Key Metrics Changes - For Q1 2025, the operating loss decreased to $3.7 million from $4.4 million in Q1 2024, attributed to initial net product revenues from ZUNVEL and recognized licensing revenue of $2.6 million from CMS [9][10] - The net loss for Q1 2025 was $2 million or $0.13 per share, a decrease from a loss of $5 million or $0.87 per share in the same quarter last year, driven by increased interest income and favorable changes in derivative liabilities [10][11] - As of March 31, 2025, the company had approximately $45.5 million in unrestricted cash and cash equivalents, maintaining a debt-free balance sheet [11][12] Business Line Data and Key Metrics Changes - The first quarter of 2025 marked the first recorded revenue for ZUNVEL, with initial net product revenues of $347,000 in the last two weeks of March [4][10] - The company anticipates modest royalty revenue from the CMS deal in 2026, with additional business development deals expected to generate revenues in 2026 [5][6] Market Data and Key Metrics Changes - ZUNVEL became reimbursable by Medicare as of April 1, 2025, which is critical for long-term care access [14] - Approximately 66% of top-tier long-term care targets have been engaged by the sales team, with about 1,400 unique homes reached [15] Company Strategy and Development Direction - The company aims to establish ZUNVEL as a core therapy in the long-term care segment, focusing on building a prescription base with gerontology groups [8][19] - The management is optimistic about the commercial launch and plans to continue expanding access and awareness in the coming months [19][20] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the early uptake of ZUNVEL, noting positive feedback from healthcare professionals and a strong demand for the product [14][21] - The company is focused on executing its strategic priorities and believes it can achieve a positive cash flow position in year three if it executes according to plan [8][12] Other Important Information - The company has received multiple abstracts accepted for presentation at the upcoming AAIC meeting, indicating ongoing research and validation of ZUNVEL [8][19] - Management reiterated that they are not providing revenue guidance at this time but expect to maintain expense guidance in the range of $38 million to $42 million for 2025 [12] Q&A Session Summary Question: Can you provide details on commercial metrics and repeat prescribers? - Management indicated that more than half of the 100 unique accounts that placed orders have already reordered, showing early signs of clinical adoption [31][32] Question: What is the length of time patients have been on therapy? - Patients have been on therapy since April 1, with some on the drug for up to six weeks, and management anticipates patients may remain on the drug for life as long as it is effective and tolerated [29][30] Question: What are the prior authorization requirements for ZUNVEL? - The prior authorization process has been relatively simple, with many plans requiring minimal documentation, which is encouraging for early adoption [33][34] Question: What is the company's strategy for commercial plans beyond Medicare? - The company plans to pursue commercial contracts after establishing a foothold in Medicare and Medicaid, as the long-term care segment primarily relies on Medicare [42][43] Question: How is the company addressing potential pricing pressures? - Management does not anticipate significant impacts from recent U.S. policy developments on pricing power, as they expect consistency in the Alzheimer's category [84][86]

Core Insights - The second "Hong Kong World Youth Science Conference" and the 2025 "Hong Kong Innovation and Technology Forum" were held in Hong Kong, featuring Nobel laureates and academicians from around the world, including the notable couple Edward and May-Britt Moser, who won the Nobel Prize in Physiology or Medicine in 2014 for their discovery of grid cells in the brain [1] Group 1: Discovery of Grid Cells - The Mosers discovered grid cells, which are crucial for the brain's spatial navigation system, functioning similarly to a GPS [2][3] - Grid cells create a geometric pattern in the brain, forming a grid-like structure that helps in spatial awareness and navigation [2][3] Group 2: Implications for Brain Science - The discovery of grid cells is significant as it reveals that the brain has an internal map that is not solely reliant on sensory input but is generated internally [3][4] - This internal navigation system is universal across humans and animals, but its effectiveness depends on how individuals anchor this map to stable external landmarks [6] Group 3: Alzheimer's Disease Research - The research on grid cells has opened new avenues for understanding neurodegenerative diseases, particularly Alzheimer's disease, which is characterized by early degeneration in the entorhinal cortex where grid cells are located [7][9] - The Mosers emphasize the need to focus on specific brain regions like the entorhinal cortex to understand the mechanisms behind Alzheimer's disease and develop potential treatments [10] Group 4: Cultural and Educational Exchange - The Mosers have engaged in significant collaborations with Chinese researchers, highlighting the importance of integrating Eastern and Western medical knowledge [12][13] - Their experiences in China have led to fruitful academic exchanges, including the development of innovative microscopy technology by a talented student from Peking University [14][15] Group 5: Gender Equality in Science - May-Britt Moser discusses the challenges of gender bias in science, advocating for a focus on individual capabilities rather than gender [17][18]