Development of a Novel Biologic to Treat Preeclampsia

开发治疗先兆子痫的新型生物制剂

基本信息

批准号：
9347522
负责人：
ADELENE TAN
金额：
$ 84.99万
依托单位：
AGGAMIN PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-25 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9347522
关键词：
Affect Angiogenesis Inhibitors Angiogenic Factor Animal Model Anticonvulsants Antihypertensive Agents Binding Binding Proteins Biological Factors Biological Response Modifier Therapy Biotechnology Blood Pressure Cerebral hemisphere hemorrhage Cessation of life Clinical Clinical Research Clinical Trials Cyclic GMP Development Diabetes Mellitus Disease Dose Eclampsia Edema Endotoxins Enzyme-Linked Immunosorbent Assay Enzymes Equilibrium Etiology Fetus Goals Growth Factor Health Healthcare Systems Hemolysis Human Hypertension Hyperuricemia In Vitro Incidence Infant Intervention Investigational New Drug Application Japan Kidney Lead Letters Life Ligands Liver Macaca Magnesium Sulfate Maternal Age Medical Modeling Morbidity - disease rate Mothers Multiple Birth Offspring Neonatal Intensive Care Neonatal Intensive Care Units Newborn Infant Obesity Organ failure Outcome Patients Perfusion Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase Placenta Placental Growth Factor Platelet Count measurement Pre-Eclampsia Pregnancy Pregnancy Rate Pregnant Women Premature Birth Price Production Proteins Proteinuria Rattus Recombinants Renal function Replacement Therapy Risk Risk Factors Role Safety Seizures Serum Severity of illness Small Business Innovation Research Grant Symptoms Syndrome Therapeutic Therapeutic Agents Third Pregnancy Trimester Time Toxic effect Toxicology Vascular Diseases Woman Work blood pressure reduction clinical development commercial application commercialization cost effective therapy enzyme replacement therapy fetal high risk improved in vivo meetings mortality neonatal outcome neonate nonhuman primate novel novel therapeutics pregnancy disorder pregnant pressure prevent safety study standard of care symptom management

项目摘要

Preeclampsia (PE) is a pregnancy-induced hypertensive disorder without an effective treatment. The goal of this project is to produce a safe and effective biologic for treatment of very preterm PE. PE is the leading cause of pregnancy-related morbidity and mortality in the US, affecting over 200,000 pregnant women and newborns annually, at a significant cost to the healthcare system and lifelong consequences. PE is characterized by the new onset of hypertension and can lead to more serious complications, such as seizure (eclampsia) and HELLP syndrome associated with systemic organ failure and death. Current interventions to treat PE include magnesium sulfate as an anticonvulsant and antihypertensive drugs, which may manage symptoms but do not target the underlying causes of the disease. One potential cause of PE is an imbalance of angiogenic factors, specifically antiangiogenic sFlt1 and proangiogenic PlGF. Higher sFlt1:PlGF ratios correlate with increased severity of disease and poor clinical outcome. The product of this SBIR will be recombinant human PlGF protein (rhPlGF) as a replacement therapy to treat very preterm PE and prolong pregnancy without adverse maternal or fetal effects. The long term goal is to develop and commercialize a safe therapeutic for very preterm PE to improve health outcomes by reducing maternal symptoms and extending fetal gestation toward >34 weeks. For SBIR Phase I, we successfully 1) expressed and purified rhPlGF then demonstrated that rhPlGF can bind endogenous free sFlt1 in PE serum in vitro, and 2) showed efficacy in the RUPP rat model of PE in vivo, as rhPlGF restored circulating free sFlt1, blood pressure and renal function towards normal pregnant levels. For SBIR Phase II, we will 1) demonstrate that rhPlGF can be safely administered in third trimester pregnant non-human primates without toxicity, and 2) complete a cGMP manufacturing campaign for use in a Phase I clinical study. After the SBIR Phase II, Aggamin has plans for a clinical trial partnership and commercialization with an established pharmaceutical company. PE affects 3-8% of all pregnancies and disease incidence is rising as risk factors such as obesity, diabetes, women’s age at pregnancy, and rate of multiple births increase. The market for Aggamin’s treatment for preterm PE cases, evident before 34 weeks, is estimated at up to 60,000 patients worldwide, and could later increase to include PE cases where symptoms appear after 34 weeks. Reimbursement rates will be justified by reducing or eliminating neonatal ICU costs and improving health outcomes for the newborn and mother. The total market for Aggamin’s therapeutic product to treat very preterm PE cases in the US is estimated at $0.5-1.5 billion. The rhPlGF replacement therapy will be a first-in-class treatment for PE, and if proven safe and effective, its medical and commercial value will be substantial.

先兆子痫（PE）是一种妊娠引起的高血压疾病，目前尚无有效的治疗方法，该项目的目标是生产一种安全有效的生物制剂来治疗早产儿先兆子痫，这是妊娠相关发病率和死亡率的主要原因。在美国，PE 每年影响超过 200,000 名孕妇和新生儿，给医疗保健系统造成巨大损失，并造成终生后果，其特点是新发高血压，并可能导致更严重的并发症，例如癫痫（子痫）。目前治疗肺栓塞的干预措施包括使用硫酸镁作为抗惊厥药和抗高血压药物，这些药物可以控制症状，但不能针对疾病的根本原因。血管生成因子，特别是抗血管生成 sFlt1 和促血管生成 PlGF 较高的 sFlt1:PlGF 比率与疾病严重程度增加和不良临床结果相关。重组人 PlGF 蛋白 (rhPlGF) 作为替代疗法，用于治疗极早产儿 PE 并延长妊娠，且不会对母体或胎儿产生不良影响。长期目标是开发一种安全的治疗极早产儿 PE 的方法并将其商业化，通过减少母体症状来改善健康结果。对于 SBIR I 期，我们成功地 1) 表达并纯化了 rhPlGF，然后证明 rhPlGF 可以在体外结合 PE 血清中的内源性游离 sFlt1，并且将胎儿妊娠期延长至 >34 周。 2) 在 RUPP 大鼠体内 PE 模型中显示出功效，因为 rhPlGF 将循环游离 sFlt1、血压和肾功能恢复到正常妊娠水平对于 SBIR II 期，我们将 1) 证明 rhPlGF 可以在妊娠晚期安全施用。怀孕的非人类灵长类动物无毒性，2) 完成用于 I 期临床研究的 cGMP 生产活动，在 SBIR II 期之后，Aggamin 计划与美国建立临床试验合作伙伴关系并进行商业化。 PE 影响 3-8% 的妊娠，并且随着肥胖、糖尿病、女性怀孕年龄和多胎出生率等危险因素的增加，阿加明治疗早产儿 PE 病例的市场不断增加。估计全球有多达 60,000 名患者在 34 周前出现明显症状，以后可能会增加，包括 34 周后出现症状的 PE 病例，通过降低或降低报销率来证明其合理性。消除新生儿 ICU 费用并改善新生儿和母亲的健康结果在美国，用于治疗极早产儿 PE 病例的 Aggamin 治疗产品的总市场估计为 0.5-15 亿美元，rhPlGF 替代疗法将是一流的。治疗PE，如果被证明安全有效，其医疗和商业价值将是巨大的。