A novel highly stable pancreatic enzyme replacement therapy to improve outcomes for patients with pancreatic insufficiency.

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ABSTRACT Malabsorption syndromes occurs when the body is not able to properly digest or absorb macronutrients from ingested food. Malabsorption results from impaired secretion of pancreatic enzymes [exocrine pancreatic insufficiency (EPI)], disturbed GI transit, critical loss of intestinal mucosa or changes in gastric, duodenal, liver, bile or gallbladder physiology or secretion. Malabsorption syndromes can be life-threatening conditions resulting from cystic fibrosis, chronic pancreatitis, pancreatic cancer, or other diseases. Currently the only treatment is pancreatic enzyme replacement therapies (PERTs) derived from pig pancreas processed in slaughterhouses. PERT rarely eliminates maldigestion or severe GI symptoms and patients continue to not meet target nutritional status in-spite of chronic use with significant groups of non-responders. PERT requires enormous volumes of large pills to be taken daily (20-40) and does not provide a liquid formulation dramatically limiting its effectiveness for infants, children or those with difficulty swallowing pills. Synspira is developing SNSP003 to provide superior performance and make a life-changing impact for the people who require PERT. SNSP003 is a mixture of the three critical enzymes (lipase, protease and amylase) necessary to aid digestion and absorption of key macronutrients. SNSP003 has been developed to improve fatty acid abnormalities (specifically physiologically relevant LCPUFAs), protein and carbohydrate malabsorption, clinical outcomes, GI symptoms and QoL. The lipase in SNSP003 has been improved through enzyme engineering to be build stability against low pH and proteolytic degradation directly into the enzyme without the need for enteric coating. The stability of the engineered lipase will allow it to digest fats in the stomach and through the small intestine while also allowing for a liquid compatible formulation. Synspira intends to create a Rapidly Disintegrating Tablet (RDT) formulation, that can be given as a liquid treatment option for infants, children suffering from rare diseases or adults who are unable to swallow the requisite large volume of capsules. SNSP003 will only require one pill per meal and provide the novel RDT formulation both aimed at reducing treatment burden, simplifying therapy, improving adherence, QoL and provide an opportunity for patients who otherwise would not be able to use pancreatic enzymes. This RDT is novel and will solve a problem that has been unmet for 50-years providing a dramatic improvement in patient care. In this study, Synspira will reformulate the lipase, protease and amylase in the existing SNSP003 mini-tablets for use in the RDT formulation. The effectiveness of the RDT formulation will be tested using an EPI porcine model demonstrated to be a sensitive tool for the evaluation of macronutrient absorption by determining fatty acid uptake in plasma, RBCs, tissues and stool. Analytical testing will then be performed using high throughput analytical methods measuring free fatty acid release (C14-C24), amino acids and glucose. Synspira will conduct a 28-day toxicology study for SNSP003 to inform clinical studies and evaluate the base enzymes (lipase, protease and amylase). SNSP003 will have manufacturing capacity to ensure supply and meet demand.