Fosdenopterin Hydrobromide

April 2, 2025 Manuscript in the Journal of Inherited Metabolic Disease indicates increased survival in patients treated with fosdenopterin Solana Beach, CA – April 2, 2025 – Sentynl Therapeutics, Inc. (“Sentynl”), a U.S.-based biopharmaceutical company wholly-owned by Zydus Lifesciences, Ltd. (“Zydus Group”), is pleased to announce the publication of NULIBRY’s three clinical studies comparing the treatment effect of NULIBRY versus a natural history study in the Journal of Inherited Metabolic Disease. Fosdenopterin gained its approval by the United States Food and Drug Administration (FDA) in February 2021, the Israeli Ministry of Health (MoH) in July 2022, the European Medicines Agency (EMA) in September 2022, and the Medicines and Healthcare products Regulatory Agency (MHRA) in April 2024 for the treatment of MoCD Type A. These data represent the first comprehensive body of clinical research in the only approved treatment for MoCD Type A patients, as well as the most abundant findings on the natural progression of the disease. The results showed statistically significant prolonged survival in treated versus untreated patients, as well as genotype-match controls with the risk of death at 5.1 times higher in the untreated patients (Cox proportional hazards 5.1; 95% CI 1.32-19.36; p=0.01). Additionally, significant improvements were seen in cognitive and motor functioning in the treated versus the untreated patients. Fosdenopterin-treated patients experienced mild to moderate treatment emergent adverse events with the most common adverse events being catheter-related complications and infections. There were no discontinuations or dose modifications due to adverse events. MoCD Type A is an ultra-rare, autosomal recessive disease caused by variants in the MOCS1 gene. It typically presents at birth or shortly thereafter and if left untreated causes rapid, irreversible neurogeneration due to a build up of toxic sulfite levels in the brain, and ultimately a premature death. Fosdenopterin, a synthetic form of cPMP, restores normal sulfite levels thereby reducing the toxic sulfite concentration. “This publication marks the end of a truly collaborative and enthusiastic path from basic research to the bedside that started 21 years ago, when we reported the successful treatment of a mouse model of MoCD type A with cPMP (cyclic pyranopterin monophosphate, fodenopterin),” said Guenter Schwarz, Professor, Institute of Biochemistry, Department of Chemistry and Biochemistry & Center for Molecular Medicine, Cologne University, Germany. “Increased awareness and expeditious testing upon suspicion of MoCD are critical to improve neurological outcomes and overall survival in patients with MoCD Type A who can be treated early with fosdenopterin.” “It is important that clinicians consider the diagnosis of MoCD type A in neonates with intractable seizures, encephalopathy, feeding difficulties or increased startle response as earlier treatment appeared to improve achievement of developmental milestones,” said Liza Squires, MD, Sentynl Medical Consultant. Sentynl Therapeutics is committed to treating rare genetic diseases, which often present in infancy and early childhood. “The publication of these data in JIMD is a huge milestone for MoCD Type A patients, caregivers, and the medical community,” said Matt Heck, CEO, Sentynl. “It is the culmination of four companies’ commitment in NULIBRY’s clinical development program spanning over two decades.” About Molybdenum Cofactor Deficiency (MoCD) Type A MoCD Type A is an autosomal recessive, inborn error of metabolism caused by mutations in the molybdenum cofactor synthesis 1 gene and characterized by a deficiency in molybdenum cofactor production, leading to a lack of molybdenum-dependent enzyme activity.1,2 The lack of activity leads to decreased sulfite oxidase activity with buildup of sulfite and secondary metabolites (such as S-sulfocysteine) in the brain, which causes irreversible neurological damage.2 MoCD Type A is an ultra-rare disease. The incidence and prevalence of MoCD Type A in the United States are not known, but the estimated incidence is 1 per 342,000 to 411,000 live births (0.24 and 0.29 per 100,000).3 Based on these estimates, MoCD Type A is likely to be underdiagnosed. The most common presenting symptoms of MoCD Type A are seizures, feeding difficulties and encephalopathy. Patients with MoCD Type A who survive beyond infancy typically suffer from progressive brain damage, which presents in characteristic patterns on magnetic resonance imaging (MRI). This damage leads to severe psychomotor impairment and an inability to make coordinated movements or communicate with their environment. Mechler K et al. Genet Med. 2015;17(12):965-970. Veldman A et al. Pediatrics. 2010;125(5):e1249-e1254 Mayr SJ, et al. Forecasting the incidence of rare diseases: an iterative computational and biochemical approach in molybdenum cofactor deficiency type A. Presented at the 2019 SSIEM meeting; September 3-6, 2019; Rotterdam, The Netherlands. About NULIBRY® (fosdenopterin) for Injection NULIBRY (fosdenopterin) for Injection is a substrate replacement therapy that provides a synthetic source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulfite oxidase, an enzyme that reduces levels of neurotoxic sulfites. NULIBRY was approved by the U.S. FDA in February 2021, and by the Israel Ministry of Health in July 2022 and is indicated to reduce the risk of mortality in patients with MoCD Type A. NULIBRY was also approved by the EMA in September 2022, with an indication for treatment of patients with MoCD Type A. Important Safety Information Warnings and Precautions Potential for Photosensitivity NULIBRY can make the patient oversensitive to sunlight. NULIBRY-treated patients or their caregivers are advised to avoid or minimize patient exposure to sunlight and artificial UV light and adopt precautionary measures when exposed to the sun, including wearing protective clothing and sunglasses, and use broad-spectrum sunscreen with high SPF in patients 6 months of age and older. If photosensitivity occurs, caregivers/patients are advised to seek medical attention immediately and consider a dermatological evaluation. Adverse Reactions The most common adverse reactions in NULIBRY-treated patients were infusion catheter–related complications (89%), pyrexia (fever) (78%), viral infection (56%), pneumonia (44%), otitis media (ear infection) (44%), vomiting (44%), cough/sneezing (44%), viral upper respiratory infection (33%), gastroenteritis (33%), diarrhea (33%) , and bacteremia (33%). Adverse reactions for rcPMP-treated patients were similar to the NULIBRY-treated patients. Patient Counseling Information Please read the FDA-approved NULIBRY Prescribing Information and Instructions for Use and follow the instructions on how to prepare and administer NULIBRY. NULIBRY has a potential for photosensitivity; see Warnings and Precautions. Seek medical attention immediately if the patient develops a rash or if they notice symptoms of photosensitivity reactions (redness, burning sensation of the skin, blisters). You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. About Sentynl Therapeutics Sentynl Therapeutics, Inc. (“Sentynl”) is a U.S.-based biopharmaceutical company focused on bringing innovative therapies to patients living with rare diseases. The company was acquired by the Zydus Group in 2017. Sentynl’s experienced management team has previously built multiple successful pharmaceutical companies. With a focus on commercialization, Sentynl looks to source effective and well-differentiated products across a broad spectrum of therapeutic areas to address unmet needs. Sentynl is dedicated to ensuring no patient is overlooked, and is committed to the highest ethical standards and compliance with all applicable laws, regulations and industry guidelines. For more information, visit https://sentynl.com. About Zydus Group Zydus Lifesciences Ltd. with an overarching purpose of empowering people with freedom to live healthier and more fulfilled lives, is an innovative, global life sciences company that discovers, develops, manufactures, and markets a broad range of healthcare therapies. The group employs over 27,000 people worldwide, including 1,400 scientists engaged in R & D, and is driven by its mission to unlock new possibilities in life sciences through quality healthcare solutions that impact lives. The group aspires to transform lives through path-breaking discoveries. For more information, visit https://www.zyduslife.com/zyduslife. Contacts: Media: Maureen Roberts, maureen.roberts@fleishman.com Sentynl: Michael Hercz, ir@sentynl.com For U.S. Audiences Only < Back This website uses cookies for data analytics. This website may also use cookies to enhance your experience with the website. We do not use cookies to sell or share your personal information. By selecting “Accept all,” you agree to our use of cookies. By selecting “Reject all,” you agree to a single strictly necessary cookie to prevent the use of data analytics cookies. For more information, please read our privacy statement.

本期导读 在生物制品生产过程中，有可能受到内源性或外源性病毒的污染，从而危及患者的安全。病毒清除验证研究旨在评估生物制品下游纯化工艺在灭活和去除潜在病毒污染物方面的效果，以确保产品的安全性。 药明生物安全性检测团队深耕病毒清除验证领域逾十年，积累了1200多个新药临床试验申请（IND）以及150多个生物制品许可申请（BLA）病毒清除验证研究项目经验。承接上篇《科学制定生物制品病毒清除验证研究策略》，本文将进一步介绍如何高效地执行生物制品病毒清除验证研究。 为了避免将病毒引入GMP厂房，生物制品的病毒清除验证研究通常在第三方实验室进行。一个周密的研究计划对于确保病毒清除验证研究高效和顺利地开展至关重要。 那么，在病毒清除验证研究执行过程中有哪些要点需要关注？哪些工艺步骤具备稳定的病毒清除效果？ 药明生物安全性检测团队分享了他们的洞见。 高品质模型病毒是病毒清除验证研究 成功开展的基础 病毒清除验证研究通常包括预实验和正式加标实验两个阶段。预实验的目的是排除供试品对病毒检测系统的潜在影响和干扰。在加标实验中，模型病毒会添加至工艺中间品中，以评价某一下游工艺步骤的病毒清除效果。 高品质的模型病毒是成功进行病毒清除验证研究的基础。使用高纯度高滴度模型病毒可最大限度降低加标百分比，使缩小模型更能代表实际生产工艺。根据相关法规要求（EMA/CPMP/BWP/268/95），“病毒加标体积应小于10%”。同时，在制备高滴度模型病毒过程中需要避免发生病毒聚集，因为聚集的病毒更容易被过滤等物理方式去除，从而高估实际的病毒清除效果。 药明生物安全性检测团队通过特殊工艺制备的高纯度高滴度模型病毒，被用于除病毒过滤步骤和精纯层析步骤的病毒清除验证研究。研究中的加标百分比通常小于1%，可以显著减少过滤器堵塞、通量衰减等异常现象，从而保证相关研究的顺利进行。 同时，高纯度高滴度的模型病毒有助于稳健的下游工艺步骤获得更高的对数降低值（LRV）。因为对于给定的工艺步骤，LRV是通过工艺处理前后样品间的病毒量差值计算获得的。 病毒清除工艺步骤的选择 在病毒清除验证研究中，不需要对下游工艺中的所有步骤进行评价。如果通过有限的工艺步骤就能获得足够的总体LRV并满足安全性要求，就可以减少其它步骤的验证，从而帮助生产商节约成本和资源。 在生物制品下游纯化工艺中常用的病毒灭活和去除方法包括：低pH孵育、有机溶剂/去污剂处理、层析、除病毒过滤等。 低pH孵育 在抗体类产品下游工艺中，低pH孵育步骤通常衔接在Protein A亲和层析步骤之后，因为Protein A亲和层析大多使用低pH缓冲液进行洗脱。低pH条件会引起病毒表面电荷和蛋白空间结构的不可逆变化，从而使其失去感染性。 低pH孵育是一种有效的包膜病毒灭活步骤。药明生物安全性检测团队完成的超过2100个X-MuLV（异嗜性鼠白血病病毒）灭活实验结果显示，该步骤的平均LRV可达到6.2 log10。当孵育的pH值低于3.6时，所有实验的LRV均大于4 log10。 然而，低pH孵育不适用于大多数细胞和基因疗法（CGT）产品，因为存在损伤细胞或治疗载体的风险。但腺相关病毒（Adeno-associated virus, AAV）载体是一个例外。 有机溶剂/去污剂(S/D)处理 S/D可以破坏病毒包膜的脂质结构，使其丧失感染性。S/D处理是一种重要的包膜病毒灭活方法，尤其适用于不能耐受低pH条件处理的生物制品。 需要注意的是S/D组分对指示细胞有一定的毒性，因此在病毒检测过程中需要进行稀释处理，从而影响最终的LRV。在药明生物执行的近500个S/D灭活实验中，X-MuLV和PrV（伪狂犬病病毒）的平均LRV分别达到5.8 log10和5.9 log10。 在AAV载体下游工艺的前端，通常会使用去污剂（如吐温80）裂解细胞并释放AAV载体。该步骤也可用于包膜病毒的灭活。 除病毒过滤 除病毒过滤是基于体积排阻原理的专用病毒清除步骤。在抗体下游纯化工艺中，通常使用孔径为20nm的除病毒滤器。在药明生物安全性检测团队进行的2600多个MVM（鼠细小病毒）过滤实验中，平均LRV达到6.1 log10，仅有不到1.5%的实验对MVM的截留效果小于4 log10。 对于CGT产品，20nm孔径的滤器并不适用。根据CGT产品的具体特性，可以考虑采用35nm或50nm孔径的除病毒滤器截留大粒径病毒（如：杆状病毒、疱疹病毒、逆转录病毒等）。 层析 层析步骤（包括亲和层析、离子交换层析和混合模式层析等）原本用于纯化目标产品和去除宿主细胞蛋白（host cell proteins, HCPs）等杂质。但层析步骤同时具备一定的病毒去除效果，因此也被用于病毒清除验证研究。在抗体类产品病毒清除验证研究中，亲和层析和阴离子交换（Anion exchange, AEX）层析步骤的应用较为广泛。 在部分病毒载体产品（如AAV载体）的下游工艺中，也包括亲和层析和精纯层析等步骤。可考虑采用这些步骤去除潜在的病毒污染物。 选择经验丰富的第三方病毒清除实验室 病毒清除验证研究的执行涉及生产商、供应商以及第三方实验室，三者间的良好沟通与协作是病毒清除验证研究成功的关键。 经验丰富的第三方实验室掌握病毒学和下游工艺领域的专业知识，熟悉最新的病毒清除技术、病毒检测方法以及全球监管要求。并且能够根据产品及其工艺特点，充分评估相关风险并定制科学的研究方案，确保研究结果得到监管机构的认可。经验丰富的第三方实验室还能提供病毒清除工艺优化、病毒清除数据挖掘等全方位服务，帮助生产商管控和降低产品开发过程中的风险。 关于药明生物安全性检测中心 病毒清除验证研究服务 药明生物安全性检测中心，依托苏州和上海两地的BSL-2实验室，为全球客户提供符合法规要求的研发类（R&D）、新药临床试验申请（IND）和生物制品许可申请（BLA）等不同阶段的病毒清除验证研究服务，服务能力覆盖抗体、融合蛋白、ADC、重组亚单位疫苗、病毒载体、酶以及动物提取物等。 经验丰富的专业团队：120位科研人员，15位专题负责人，累计完成1400+病毒清除验证研究项目； 高标准质量体系：拥有完善的GLP/GMP质量体系，顺利通过全球监管机构和客户的300多次审计（包括30多次EU QP审计）； 高品质模型病毒：拥有12种模型病毒，可满足不同类型产品的病毒清除验证研究需求；制备的高纯度高滴度模型病毒可最大程度的降低对产品和下游工艺的潜在影响，确保病毒清除结果的准确性； 符合国际标准的病毒检测方法：建立了包括噬斑法，TCID50法和qPCR法在内的病毒定量检测方法，所有方法均严格按照ICH Q2的要求完成方法验证。经过验证的大体积样品检测可以显著提高稳健工艺步骤的病毒清除结果（LRV）； 完善的设施设备：拥有30多台AKTA Avant/Pure蛋白纯化系统以及12套客户实验室，随时响应客户需求。相关实验设备严格按照法规要求进行验证和校准，保证实验数据的可靠性。为到访客户提供专属的客户休息室，严格保护客户IP； 快速交付：病毒清除验证研究IND项目最短2个月交付，BLA项目最短3个月交付； 数据挖掘服务：独有的病毒清除验证研究数据库，海量数据助力客户提前预测相关步骤的病毒清除效果； Remote病毒清除支持服务：无需客户亲临现场，由训练有素的下游工艺服务团队根据技术转移方案，执行包括层析装柱、柱效测定、层析/过滤操作、缓冲液配制等各项工作； 客户无忧VIP服务：每个病毒清除验证研究项目均配备有专属项目经理（PM）和专题负责人(SD)，及时更新项目进展，快速响应客户需求。 如需了解更多生物药安全性检测服务 欢迎扫描下方二维码填写 我们的工作人员会尽快联系您 关于药明生物 药明生物（股票代码：2269.HK）是一家全球领先的合同研究、开发和生产（CRDMO）公司。公司通过开放式、一体化生物制药能力和技术赋能平台，提供全方位的端到端服务，帮助合作伙伴发现、开发及生产生物药，实现从概念到商业化生产的全过程，加速全球生物药研发进程，降低研发成本，造福病患。 药明生物在中国、美国、爱尔兰、德国和新加坡拥有超过12000名员工。通过药明生物的专业服务团队，以及先进技术和精深洞见，公司为客户提供高效经济的生物药解决方案。截至2024年6月底，药明生物帮助客户研发和生产的综合项目高达742个，其中包括16个商业化生产项目（不包括新冠项目和非活跃项目）。 药明生物将环境、社会和治理（ESG）视为业务发展和企业精神的重要组成部分，并致力于成为全球生物药CRDMO领域的ESG领导者，例如应用更绿色环保的新一代生物制药技术和能源等引领行业发展。公司成立了由首席执行官领导的ESG委员会，全面落实ESG战略并践行可持续性发展承诺。更多信息，请访问：www.wuxibiologics.com。