IND Enabling Studies and Manufacturing Scale Up of Human Placental Extract to Prevent Surgical Necrotizing Enterocolitis

PROJECT SUMMARY Necrotizing Enterocolitis (NEC), an acute inflammatory necrosis of the intestinal tract, is the most commonly acquired gastrointestinal and surgical emergency for preterm, very low-birth weight infants in the neonatal intensive care unit. Despite considerable advances in neonatal care, there is no cure for NEC, and it remains a devastating disease with mortality rates ranging from 30-50%. Management is largely nonspecific and includes the administration of broad-spectrum antibiotics, initiation of bowel rest and the provision of fluid and inotropic support to maintain cardiorespiratory function. Surgical intervention is required in up to 50% of NEC cases. Studies have shown that swallowed amniotic fluid by the infant is anti-inflammatory, matures the fetal gut, and may prevent infection. However, there are no treatments that mimic amniotic fluid or its function in the fetal gut. Plakous Therapeutics has developed and patented methods to extract and preserve the cytokines and growth factors stored within the placental disc to create Human Placental Extract (HPE), an acellular preparation of full-term, post-delivery human placenta. These methods yield high concentrations of chemokines with a much lower pro-inflammatory chemokine composition compared to term amniotic fluid. The hypothesis is that oral administration of a therapeutic similar to 16-20-week amniotic fluid to the infant during the transition between birth and normal feeding volumes will bolster and sustain gut maturation while reducing the hyperinflammatory milieu that drives intestinal mucosal injury of the premature gut to prevent NEC. Preliminary data indicate that HPE can increase gut cell number and differentiation and modulate cell response to lipopolysaccharides by decreasing TNF-α secretion. In a Phase II SBIR, HPE reduced disease severity and elicited no toxicity findings in the piglet model of the disease. In this Phase IIB, Plakous Therapeutics will conduct a GLP toxicity study for inclusion in a subsequent investigational new drug (IND) filing and scale manufacturing to clinical lot size to improve efficiency and reduce variance lot-to-lot. These objectives will be accomplished through testing HPE in vivo in a FDA-reviewed toxicology model and identifying the minimum toxic dose to support an IND submission that will clear a path for clinical trials. Based on FDA feedback, a juvenile piglet model will be used to establish dosing safety for the neonatal population. Plakous must also optimize the manufacturing process to generate commercial scale lots of HPE in a more efficient and cost-effective manner. The manufacturing process of HPE will result in an acellular, lyophilized, and terminally sterilized shelf-stable powder that can be easily reconstituted for use. Once reconstituted, the solution will have growth factor concentrations similar to mid-pregnancy amniotic fluid and will have reduced variance, delivering a more consistent product. This should lead to more consistent outcomes for patients. Successful completion of this project will allow Plakous to put together an IND dossier for FDA review.