SBIR-STTR Award

Preeclampsia (PE) is a pregnancy-induced hypertensive disorder without an effective treatment. The goal of this project is to produce a novel biologic for treatment of 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 onset of hypertension and proteinuria 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 manage symptoms but do not target the underlying causes of the disease. One potential cause of PE is hypothesized to be 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 PlGF1 protein (rhPlGF1) as a parenteral 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 therapeutic for PE to improve health outcomes by reducing maternal symptoms and extending fetal gestation toward 36 weeks. For Phase I, we hypothesize the recombinant protein will bind sFlt1 from PE patients and show efficacy in a rat PE model. In phase II, Aggamin will initiate manufacturing and a safety/toxicology study. 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 severe 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 for 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 severe early-onset PE cases in the US is estimated at $0.5-1.5 billion.

Public Health Relevance Statement:


Public Health Relevance:
PUBLIC HEALTH RELEVANCE Preeclampsia is a serious disorder of pregnancy associated with high maternal and fetal morbidity and mortality. Currently, there is no therapy to treat preeclampsia except for premature delivery, which poses a significant risk to the fetus. The proposed work is to develop a novel drug therapy to restore the angiogenic balance that is disrupted in preeclampsia. This therapy is expected to reverse maternal symptoms and prolong pregnancy toward 36 weeks of gestation, thus enabling safe and full term delivery.

Project Terms:
Address; Affect; Angiogenesis Inhibitors; Angiogenic Factor; Animal Model; Animals; Anticonvulsants; Antihypertensive Agents; Binding (Molecular Function); Biological; Biotechnology; Blood Pressure; Caring; Cell Line; Cerebral hemisphere hemorrhage; Cessation of life; Child; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; commercial application; commercialization; cost; Development; Diabetes Mellitus; Diagnostic tests; Disease; Drug Targeting; early onset; Eclampsia; Edema; effective therapy; Enzyme-Linked Immunosorbent Assay; Enzymes; Equilibrium; fetal; Fetus; Gestational Age; Goals; Health; Healthcare Systems; Hemolysis; Human; Hypertension; Hyperuricemia; improved; Incidence; infant death; Intervention; Intravenous infusion procedures; Kidney; Lead; Life; Ligands; Liver; Magnesium Sulfate; manufacturing scale-up; Marketing; Maternal Age; Measures; Modeling; Morbidity - disease rate; Mortality Vital Statistics; Mothers; Multiple Birth Offspring; Neonatal; Neonatal Intensive Care; Newborn Infant; novel; Obesity; Organ failure; Outcome; Patients; Perfusion; PGF gene; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Placenta; Plasma; Platelet Count measurement; Pre-Eclampsia; Pregnancy; pregnancy disorder; Pregnancy Rate; Pregnant Women; Premature Birth; pressure; Price; Prolonged Pregnancy; Proteins; Proteinuria; public health relevance; Rattus; Recombinant Proteins; Recombinants; Renal function; Risk; Risk Factors; Role; Safety; safety study; Sampling; Seizures; Severity of illness; Small Business Innovation Research Grant; Staging; Symptoms; Syndrome; Therapeutic; therapy development; Toxicology; Woman; Work

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.

Public Health Relevance Statement:
Preeclampsia is a serious disorder of pregnancy associated with high maternal and fetal morbidity and mortality. Currently, there is no therapy to treat preeclampsia except for premature delivery, which poses a significant risk to the fetus. The proposed work is to develop a novel drug therapy to restore the angiogenic balance that is disrupted in preeclampsia, reverse maternal symptoms, and prolong pregnancy toward 36 weeks of gestation, thus enabling safe and full term delivery.

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