SBIR-STTR Award

This application is a Phase I SBIR grant application. One of the major causes of morbidity and mortality of low birth weight neonates relates to injury, inflammation, perforation and obstruction of the lower GI tract, which can be manifest in the related diseases Necrotizing Enterocolitis (NEC) and Spontaneous Intestinal Perforation (SIP). These digestive diseases, which affect 2-5% of preterm babies, frequently require major surgery and are associated with a mortality rate of 20-50%, and have replaced respiratory distress syndrome as the major complication that afflicts these high-risk neonatal patients. The etiology of both NEC and SIP have yet to be elucidated, and risk factors that have been identified, in addition to a weight of < 1.5 kg, include formula feeding and the use of indomethacin, the standard of care to treat and/or prevent the development of Patent Ductus Arteriosus (PDA). PDA is a condition which results in the circulation short circuiting the pulmonary vasculature, leading to inadequate oxygenation, increasing the risk of intraventricular hemorrhage, bronchopulmonary dysplasia, and death. In this Phase I application we will further develop and evaluate a novel indomethacin parenteral, in which the NSAID is associated with phosphatidylcholine (PC), utilizing the proprietary formulation method developed by PLx Pharma Inc; this composition non-covalently associates indomethacin with PC, which appears to reduce the GI injury caused by indomethacin alone. In the initial experiments we will validate our preliminary observations that indicate that intravenously (i.v.) administered Indomethacin-PC has a greatly reduced GI toxicity than indomethacin alone utilizing adult rodent models of NSAID-induced GI bleeding. These studies will then be followed by a series of pilot studies performed on neonatal rat pups using established rodent models of NEC and PDA closure to evaluate the GI safety and efficacy of our drug formulation. Also in Phase I, we propose to optimize the laboratory formulation of Indomethacin-PC so that it can be sterile filtered and packaged to assure a sufficiently long shelf-life for it to be used parenterally as a "hospital care" product. These studies will be continued and expanded, during Phase II in a more involved, piglet model of NEC which may more closely simulate the clinical condition, and carry out further formulation development in partnership with a commercial manufacturer. The results of these experiments will allow selection of a single, validated lead Indomethacin-PC formulation. The activities encompassed in this grant proposal will significantly advance the Indomethacin-PC development toward commercialization and are explicitly designed to serve as the basis for a Phase II SBIR grant proposal. If the Indomethacin-PC formulation is shown in subsequent development efforts to possess an improved GI safety profile, together with equivalent efficacy compared with indomethacin, it will represent an important improvement in the standard of care for the treatment of low birth weight neonates with potential or confirmed PDA, with reduced risk of developing NEC and SIP, devastating diseases of the GI tract.

Public Health Relevance:
Nearly all currently available non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin, naproxen, ibuprofen, and aspirin, cause significant GI damage. Intravenously administered indomethacin is the standard of care for the treatment of a serious cardiac defect that is common in low- and very-low birth weight infants, called patent ductus arteriosus. However, IV indomethacin frequently causes or contributes to serious GI damage that can be lethal to these infants. This grant proposal will partially fund the development of a new molecular complex of indomethacin and phosphatidylcholine, a new formulation of indomethacin that significantly reduces GI injury.

Public Health Relevance Statement:


Project narrative:
Nearly all currently available non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin, naproxen, ibuprofen, and aspirin, cause significant GI damage. Intravenously administered indomethacin is the standard of care for the treatment of a serious cardiac defect that is common in low- and very-low birth weight infants, called patent ductus arteriosus. However, IV indomethacin frequently causes or contributes to serious GI damage that can be lethal to these infants. This grant will partially fund the development of a new molecular complex of indomethacin and phosphatidylcholine, a new formulation of indomethacin that significantly reduces GI injury.

Project Terms:
1-(4-chlorobenzoyl)-5-methoxy- 2-methyl-1-H-indole-3-acetic acid; 1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-; 2-(Acetyloxy)benzoic Acid; 2-Naphthaleneacetic acid, 6-methoxy-alpha-methyl-, (S)-; 2-Propanone; 21+ years old; Accounting; Acetone; Acetylsalicylic Acid; Adult; Advanced Development; Affect; Alimentary Canal; Animal Model; Animal Models and Related Studies; Animal Testing; Anti Inflammatory Analgesics; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; Antiinflammatory Agents, Non Steroidal; Antiinflammatory Agents, Nonsteroidal; Applications Grants; Aspergum; Aspirin; Attenuated; BPD; Bile; Bile Juice; Bile fluid; Biological Models; Biology; Bleeding; Blood Circulation; Bloodstream; Body Tissues; Bovine Species; Bronchopulmonary Dysplasia; Caliber; Cardiac Abnormalities; Cardiac Defects, Congenital; Cardiac Malformation; Cardiac defect; Caring; Cattle; Causality; Cells; Cessation of life; Childhood; Choline Glycerophospholipids; Choline Phosphoglycerides; Chronic; Circulation; Clinical; Clinical Trials; Clinical Trials, Unspecified; Common Rat Strains; Complex; Complication; Computer Systems Development; Congenital Heart Defects; Consumption; Data; Death; Development; Development and Research; Development, Computer Systems; Diameter; Digestive Diseases; Digestive System Diseases; Digestive System Disorders; Digestive Tract; Dimethyl formaldehyde; Dinoprostone; Disease; Disorder; Dose; Drug Formulations; Drugs; Ecotrin; Emergencies; Emergency Situation; Empirin; Ensure; Entericin; Epithelium; Etiology; Evaluation; Extren; FDA; Family; Food and Drug Administration; Food and Drug Administration (U.S.); Formulation; Formulations, Drug; Frequencies (time pattern); Frequency; Funding; GI Tract; Gastrointestinal Diseases; Gastrointestinal Diseases and Manifestations; Gastrointestinal Injury; Gastrointestinal Tract; Gastrointestinal tract structure; Gestation; Glucocorticoids; Goals; Grant; Grant Proposals; Grants, Applications; HOSP; Health Sciences; Heart Abnormalities; Heart Defects, Congenital; Heart Malformation; Hemorrhage; Hospitals; Human, Adult; INFLM; IV drip; Ibuprofen; Incidence; Indocin; Indometacin; Indomethacin; Infant; Infant, Premature; Infant, Very Low Birth Weight; Inflammation; Injury; Intensive Care Units, Neonatal; Intestinal; Intestinal Perforation; Intestines; Intravenous; Intravenous Drip; Intravenous Infusion; Investigational New Drug Application; Investigators; Laboratories; Lead; Lecithin; Legal patent; Life; Low Birth Weight Infant; Lower GI Tract; Lower Gastrointestinal Tract; Lung; MNPA; Mammals, Rats; Mammals, Rodents; Manufacturer; Manufacturer Name; Measurin; Medication; Methods; Methoxypropiocin; Model System; Modeling; Models, Biologic; Modification; Molecular; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Motrin; Mucosa; Mucosal Tissue; Mucous Membrane; Mucous body substance; Mucus; NSAIDs; Naprosin; Naprosyn; Naproxen; Necrotizing Enterocolitis; Neonatal; Neonatal Intensive Care Units; Newborn Intensive Care Units; Non-Rodent Model; Non-Steroidal Anti-Inflammatory Agents; Nonsteroidal Anti-Inflammatory Agents; Nonsteroidal Antiinflammatory Drug; Obstruction; Operation; Operative Procedures; Operative Surgical Procedures; PGE2; PGE2 alpha; PGE2alpha; Particle Size; Patent Ductus Arteriosus; Patents; Pathway interactions; Patients; Pb element; Perforation; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacology; Phase; Phosphatides; Phosphatidylcholines; Phospholipids; Pilot Projects; Play; Pre-Clinical Model; Preclinical Models; Pregnancy; Premature Infant; Preparation; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Prosta-5,13-dien-1-oic acid, 11,15-dihydroxy-9-oxo-, (5Z,11alpha,13E,15S)-; Prostaglandin E2; Prostaglandin E2 alpha; Prostaglandin E2alpha; R & D; R&D; Rat; Rattus; Regimen; Replacement Therapy; Reporting; Research Personnel; Researchers; Residual; Residual state; Respiratory System, Lung; Risk; Risk Factors; Rodent; Rodent Model; Rodentia; Rodentias; Role; SBIR; SBIRS (R43/44); Safety; Series; Severities; Simulate; Small Business Innovation Research; Small Business Innovation Research Grant; Solvents; Source; Sterility; Surface; Surgical; Surgical Interventions; Surgical Procedure; Systems Development; Technology; Testing; Texas; Therapeutic Glucocorticoid; Tissues; Toxic effect; Toxicities; Toxicology; Toxin; Treatment Efficacy; USFDA; United States Food and Drug Administration; Universities; VLBW (human); Very Low Birth Weight Infant; Weight; Work; adult human (21+); alimentary tract; alpha-Methyl-4-(2-methylpropyl)benzeneacetic Acid; base; blood loss; bovid; bovine; bowel; chronic lung disease in infants; chronic lung disease in neonatal infants; chronic lung disease in neonates; chronic lung disease in newborns; chronic lung disease in prematurity; clinical investigation; commensal bacteria; commensal microbes; commercialization; comparative; comparative efficacy; cow; design; designing; digestive canal; digestive disorder; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; drip infusion; drug/agent; effective therapy; experiment; experimental research; experimental study; feeding; gastrointestinal; gastrointestinal disorder; heart defect; heavy metal Pb; heavy metal lead; high risk; human disease; improved; infant chronic lung disease; intravenous administration; intraventricular hemorrhage; low birth weight infant human; low birthweight; medical schools; model organism; mucous; neonatal chronic lung disease; neonate; newborn chronic lung disease; non-drug; nonsteroidal anti-inflammatory drugs; novel; p-Isobutylhydratropic Acid; pathway; pediatric; pilot study; pre-clinical; preclinical; premature; premature baby; premature infant human; preterm baby; preterm infant; preterm infant human; preterm neonate; prevent; preventing; programs; prototype; public health relevance; pulmonary; pup; research and development; research study; respiratory distress syndrome; scale up; social role; soy; stability testing; standard of care; sterile; success; surfactant; surgery; therapeutic efficacy; therapeutically effective; trend; vein infusion; very low birth weight infant human

This application is for a SBIR Phase II grant. One of the major causes of morbidity and mortality of low birth weight neonates relates to injury, inflammation, perforation and obstruction of the lower GI tract, which can be manifest in the related diseases Necrotizing Enterocolitis (NEC) and Spontaneous Intestinal Perforation (SIP). These digestive diseases, which affect 2-5% of preterm babies, frequently require major surgery and are associated with a mortality rate of 20-50%. The etiology of both NEC and SIP have yet to be fully elucidated, and risk factors that have been identified, in addition to a birth weight o <1.5 kg, include formula feeding and the use of indomethacin, the standard of care to treat and/or prevent the development of Patent Ductus Arteriosus (PDA), a condition which results in the circulation short-circuiting the pulmonary vasculature, leading to inadequate oxygenation, increasing the risk of intraventricular hemorrhage, bronchopulmonary dysplasia, and death. In this Phase II application we will further develop and evaluate a novel proprietary parenteral formulation of indomethacin, in which the NSAID is non-covalently associated with phosphatidylcholine (PC) to make it safer for the GI tract. This composition of Indomethacin-PC (PL4500) appears to reduce the GI injury caused by indomethacin alone in adult animals. In the prior Phase I experiments, we found that there was an apparent resistance to GI toxicity of indomethacin in rat neonates before weaning if the animals were breast- fed, but not if they were formula-fed. Also, during weaning there were developmentally increasing levels of both intestinal bile acid and ileal bile acid uptake transporter (apical sodium-dependent bile acid transporter, ASBT) which may be associated with indomethacin GI toxicity. It is important for later FDA filings to understand the possible mechanism of GI injury by indomethacin and how indomethacin-PC may offer protection. Thus, the first aim is to evaluate the GI toxicity of indomethacin-PC versus unmodified indomethacin in neonatal mice by comparing toxicity in breast-fed and formula-fed mice at different postnatal ages;comparing toxicity in a model of NEC;and comparing toxicity in wildtype and ASBT knockout mice and in mice induced to express ASBT early. The second aim is to determine the efficacy of indomethacin-PC versus indomethacin in a model of PDA. The third aim is to carry out technology transfer to a contract commercial manufacturer and initiate scale- up of Indomethacin-PC production, with the goal of yielding a prototype parenteral formulation that is suitable for stability, dispersibility, and subsequent safety evaluation in Phase I clinical trials. The development activities encompassed in this grant proposal will significantly advance PL4500 toward commercialization. If the Indomethacin-PC formulation continues to possess an improved GI safety profile, together with equivalent efficacy compared with indomethacin, it will represent an important improvement in the standard of care for the treatment of low birth weight neonates with potential or confirmed PDA, by reducing risk of developing NEC and SIP, devastating diseases of the GI tract.

Public Health Relevance:
Low birth weight infants, that are born prematurely, are highly susceptible to a number of potentially life- threatening conditions including Patent Ductus Arteriosus (PDA) and Necrotizing Enterocolitis (NEC). PDA is a congenital disease of the heart commonly found in premature infants that can lead to inadequate oxygenation and death. The standard treatment for PDA is intravenous indomethacin (Indocin(R)) which is known to be associated with gastrointestinal (GI) tract side effects including: intestinal bleeding, perforatios and sepsis in mature animals and humans. NEC is the most common surgical emergency that affects premature infants in the neonatal intensive care unit causing perforations, excessive GI bleeding, and an invasion of pathogenic and commensal bacteria. It is our hypothesis that the use of Indocin(R) in low birth weight infants to treat PDA may be an important etiological factor in NEC. The product under development in this proposal, designated PL4500, is a formulation of indomethacin that is associated with phosphatidylcholine to make it safer for the GI tract, and help protect low birth weight babies from developing NEC-like disease.