Applied Therapeutics, Inc.

Current paediatric standard-of-care for galactosemia is a lactose-free diet. Image credit: Shutterstock / Photoongraphy. Nearly three months after an experimental treatment for classic galactosemia was rejected by the US Food and Drug Administration (FDA), there has been little progress in developing therapies to help patients with the genetic disorder. On Rare Disease Day, 28 February, a clinical expert in galactosemia explains why commercial therapies are not anticipated anytime soon and reasons behind a frozen trial landscape. What is galactosemia? Galactosemia is a rare genetic, metabolic disorder caused by a deficiency in the galactose-1-phosphate uridyltransferase (GALT). This means patients cannot break down galactose, causing a buildup of the sugar alcohol galactitol. It is purported that this build-up is toxic and responsible for the progressive neurological element of the disease. The current standard-of-care is a galactose-free diet – no pharmaceutical intervention is currently available. “Like lots of the inherited metal diseases, this is an enzyme deficiency. And so actually, at a biochemical level, we know exactly what the problem is,” says Dr Robin Lachmann, consultant in inherited metabolic disease at University College London’s National Hospital for Neurology and Neurosurgery. The issue, according to Dr Lachmann  – who is also chair of the scientific committee of the Recordati Rare Diseases Academy, is related to how current treatment modalities are not a fit for galactosemia. Enzyme replacement therapy has been successful for some lysosomal storage diseases, for example. But for galactosemia, where there’s a systemic lack of enzyme in cells, this approach cannot work. Lachmann adds: “The problem, if you’re not a lysosomal enzyme, is that we can inject it into the blood, but there’s no way for it to get into the cells throughout the body, including the brain. So actually, enzyme replacement therapy is only useful if there’s a way for the enzyme to get into the cell. So, beyond the lysosome, we can’t do that.” Then there’s the promise of cell and gene therapy. This modality has been particularly successful in haematological diseases such as sickle cell and haemophilia treatments approved in 2023 . “To get it to every cell in the body is difficult, and the brain is extremely difficult, because you have to inject it straight in. We can just about deliver it to the whole brain in a mouse, but we can’t do it in a human,” Lachmann explains. “That’s why the gene therapies that have been and continue to be disappointing [in this area], because we just don’t have the technology to get to the genes.” Clinical trial hurdles Higher promise from a scientific point of view, says Dr Lachmann, would be in personalised gene editing. This approach, however, has significant commercial barriers. Lachmann comments: “This isn’t the way with the pharma industry currently – developing individual treatments for individual treatments is not going to happen. It’s something that is done in a lab, not as part of a company.” Away from shortcomings in drug delivery technology, there is also the hurdle of patient heterogeneity. Similar to many rare diseases, the target population is small with large variance. Designing clinical trials with robust outcomes, therefore, is inherently tricky. Children and adults with galactosemia present on a wide-ranging spectrum of neurological symptoms, making it hard to assess the validity of clinical outcomes. US biotech Applied Therapeutics found that out first hand with its candidate govorestat. The experimental treatment failed a Phase III trial after failing to improve symptoms in children more than placebo. The endpoint was a composite of measures that looked at speech and listening skills, behaviour symptoms, and daily living activities. The FDA rejected approval of the therapy in December 2024, with Applied Therapeutics not issuing a public update about the drug since. Applied Therapeutics did not respond to multiple requests for comment from Pharmaceutical Technology . Lachmann says: “Companies overall, don’t want to do clinical trials in children. They want to do it in the adults and older patients who have a slowly progressive, very heterogeneous disease. And if you want clinically relevant outcomes, you’re going to have to invest in many years of treatment.” GlobalData’s Pharma Intelligence Center currently lists eight clinical trials with galactosemia as an indication. Govorest is the most clinically advanced candidate. Many of the other trials have been terminated, whilst completed studies – such as one evaluating arginine – have yielded unsuccessful results. The Galactosemia Foundation, a charity that advocates for new treatments, has previously stated: “The galactosemia community has gone more than a century with no approved treatment. The time for change is now.”

FDA和EMA等监管机构一直强调数据可靠性(DI)是药品生产质量管理规范合规的基石，ALCOA + +原则是其指导框架。依据FDA 2024年官方检查发现项引用和探讨最常见的不合规情况，本文将重点关注DI问题和长期存在的挑战，并就如何在2025年强化DI合规提供一些见解。 1. 管控与SOP存在缺陷 即使存在SOP，但往往不够详细，无法用来指导GMP数据和记录相关的活动，并且难以以一致的方式遵循或重复执行。根据FDA 2024年的数据，涵盖药品、生物制品和医疗器械等产品领域，发现项超过50%的引用都与规程不完善有关，一些具体引用包括： (1)21 CFR 820.100(a)：“未充分制定纠正和预防措施（CAPA）程序。” (2)21 CFR 820.198 (a)：“未充分建立由正式指定部门接收、审查和评估投诉的程序。” (3)21 CFR 211.22 (d)：“质量控制部门的职责和程序未以书面形式完全遵循。” (4)21 CFR 211.100 (a)：“未能制定充分的书面生产和工艺控制程序，以确保药品具有其声称或标明的特性、规格、纯度和质量。” 从DI的角度进一步审视同一时期的警告信，某些问题反复出现，其中就包括规程管控问题。监管机构不断强调：“在整个cGMP数据的生命周期中，包括数据的创建、修改、处理、维护、存档、检索、传递以及记录保存期结束后的销毁，DI都至关重要。” 在具体案例中，FDA检察官发现存在不充分的审计追踪审核说明，导致不同员工之间的审核存在不一致性。 Indoco Remedies被发现缺乏适当的程序控制，包括：“色谱分析程序种未要求审核所有审计追踪数据。在检查期间，贵公司人员不知道在分析过程中需要审查Empower信息中心的数据。” 许多公司在数据安全方面也存在不足，常见的被引用问题包括： 1) 不确定如何在正确的时间确认合适角色的访问权限，包括用户角色变更时。 2) 不确定在系统中可能拥有较高权限时，如何确认其活动。 Unexo Lifesciences被发现关键系统访问控制存在缺陷。“QC分析师能篡改内部和第三方合同实验室出具的CoA上的结果、日期和供应商印章审批图像，包括在多个成分CoA上复制印章审批的手段。” 3) 端到端备份和恢复过程的程序不完善。 Applied Therapeutics在对数据应用适当控制或充分维护数据备份方面存在难题。部分整改措施包括Applied Therapeutics创建 “一份数据流程图，清晰展示收集到的数据的流向和存储方式，以确保源数据在现场和申办方处均得以保存”，以及 “电子数据（即使存储在第三方系统中）也将得到适当备份并保存于申办方处”。 2.  验证缺陷 2024年，软件（包括网络或云解决方案）验证不足仍是一个问题，2025年的关注点可能会转向人工智能AI的合理使用及相关验证要求。2024年的一些关键问题如下： (1) 21 CFR 820.70 (i)：“作为生产、质量体系一部分使用的软件，未根据既定方案针对其预期用途进行充分验证。” Rolence未对用于便携式X光系统最终测试的X光质量控制软件应用程序进行验证。 (2) 21 CFR 211.68 (b)：“未对计算机相关公式系统记录或数据的输入和输出进行准确性检查。” 与211.68 (b)相关的引用约占所有引用的7%。这表明，企业要么缺乏管理计算机化系统和保护数据的适当规程，要么现有的规程起不了作用。 3. 系统管理清单有漏洞 经常被提及的系统管理清单漏洞包括： (1) 管理清单过期或不完整，导致数据和记录不受控制。 (2) 已停用的系统未得到妥善跟踪，但仍包含与GxP相关的数据。 在查阅警告信和483时，虽然与计算机化系统管理相关的缺陷并不总是一眼就能看出来是个大问题，但它可能会导致DI漏洞。当检察官提到 “对数据记录和报告中的不准确度进行全面调查” 时，应包括详细的调查方案、方法，以及对评估所涵盖的所有实验室、生产操作和系统的总结。 对于Viatris而言，如果不知道数据在哪里，也不确定其是否可靠，那又怎么能进行适当的控制呢？这是毋庸置疑的问题。 4. 记录或数据缺失以及记录缺少关键 ALCOA++属性 记录缺失仍然是个问题，许多公司在维护原始记录方面仍存在重大问题，这里仅列举部分公司：Viatris、Micro Orgo Chem以及碧迪公司（Becton, Dickinson, and Company）。 违背ALCOA++原则的情况包括： (1) 活动归属不当或无归属：角色未明确区分，使用通用账户导致难以确定究竟是谁完成了 GMP活动。 (2) 清晰度差或无法辨认：记录存在涂改或修改痕迹，但未记录修改原因，或者审计追踪被无故禁用。 (3) 准确性存疑：在无独立监督的情况下进行不受控制的数据转换和手动计算。 (4) 数据转换错误：未经核实的转换操作影响了数据准确性。在使用转换工具时，没有版本控制或编码控制。 5. 物理和逻辑安全问题 与物理记录相关的治理和控制仍然是个问题。江苏恒瑞医药在检查期间被指出了诸多问题，其中就包括：“严重的质量保证缺陷，例如在车辆下方的袋子里和附近垃圾桶中发现被丢弃的原始cGMP记录，而且生产经理可以在未经QA发放的情况下，随意获取空白生产批次记录和其他cGMP文件。” 与逻辑控制相关的另一个问题是通用账户的滥用。通常，这些通用账户由供应商使用，但正确的使用方式应该是由服务或应用程序本身使用，并且仅限于特定活动。通用账户通常不与具体的用户姓名关联，而且不应允许用户将其用作临时账户。如何降低DI风险？ 为了在这些问题/挑战演变成导致违规引用的问题之前更好地应对，管理团队、信息技术部门、质量部门以及所有数据相关方必须采取积极措施，几条建议如下： (1) 加强员工培训：确保所有员工都能理解ALCOA++原则的重要性及其实际应用。 (2) 定期修订SOP：定期审查和更新规程，纳入审计追踪、备份和恢复以及系统和数据生命周期管理的详细说明。 (3) 定期进行审计和评估：开展内部DI审计和现场巡查，以发现并解决漏洞。 (4) 利用技术手段：实施符合GxP的系统，简化审计追踪审核、数据安全异常报告和生命周期管理流程。 (5) 维护集中式清单：使用经验证的工具管理系统清单，确保对已停用的系统进行适当的监控。 Ref:21CFR Part 211；https://erasciences.com 药事纵横投稿须知：稿费已上调，欢迎投稿

NEW YORK, Feb. 11, 2025 /PRNewswire/ -- Levi & Korsinsky, LLP notifies investors in Applied Therapeutics, Inc. ("Applied Therapeutics" or the "Company") (NASDAQ: APLT) of a class action securities lawsuit. CLASS DEFINITION: The lawsuit seeks to recover losses on behalf of Applied Therapeutics investors who were adversely affected by alleged securities fraud between January 3, 2024 and December 2, 2024. Follow the link below to get more information and be contacted by a member of our team: APLT investors may also contact Joseph E. Levi, Esq. via email at [email protected] or by telephone at (212) 363-7500. CASE DETAILS: According to the complaint, on November 27, 2024, Applied Therapeutics issued a press release announcing that it had received a Complete Response Letter (CRL) for the New Drug Application (NDA) for govorestat, the Company's lead drug candidate. The CRL indicated that the FDA completed its review of the application and determined that it was unable to approve the NDA in its current form citing deficiencies in the clinical application. Following this news, the price of Applied Therapeutics' common stock declined dramatically. From a closing market price of $10.21 per share on November 26, 2024, Applied Therapeutics' stock price fell to $8.57 per share on November 27, 2024 before falling further to $2.03 on November 29, 2024 and $1.75 per share on December 2, 2024, a total decline of more than 80%. After market hours on December 2, 2024, Applied Therapeutics disclosed it received a "warning letter" from the FDA referring to the clinical trial issues underlying the CRL. Applied Therapeutics' disclosure of the "warning letter" prompted a further decline in the stock price as investors discovered the seriousness and severity of the Company's clinical trial errors. From a closing market price of $1.75 per share on December 2, 2024, Applied Therapeutics' stock price fell to $1.69 per share on December 3, 2024 before falling further to $1.38 per share on December 4, 2024 and $1.29 per share on December 5, 2024. WHAT'S NEXT? If you suffered a loss in Applied Therapeutics during the relevant time frame, you have until February 18, 2025 to request that the Court appoint you as lead plaintiff. Your ability to share in any recovery doesn't require that you serve as a lead plaintiff. NO COST TO YOU: If you are a class member, you may be entitled to compensation without payment of any out-of-pocket costs or fees. There is no cost or obligation to participate. WHY LEVI & KORSINSKY: Over the past 20 years, the team at Levi & Korsinsky has secured hundreds of millions of dollars for aggrieved shareholders and built a track record of winning high-stakes cases. Our firm has extensive expertise representing investors in complex securities litigation and a team of over 70 employees to serve our clients. For seven years in a row, Levi & Korsinsky has ranked in ISS Securities Class Action Services' Top 50 Report as one of the top securities litigation firms in the United States. CONTACT: Levi & Korsinsky, LLP Joseph E. Levi, Esq. Ed Korsinsky, Esq. 33 Whitehall Street, 17th Floor New York, NY 10004 [email protected] Tel: (212) 363-7500 Fax: (212) 363-7171 SOURCE Levi & Korsinsky, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED