Liprotamase, a Non-porcine Enzyme Therapy, Restores Growth, and Normalizes Lipid Absorption in Pigs with Exocrine Pancreatic Insufficiency (EPI)

Abstract

Purpose: Liprotamase is a biotechnology-derived, non-porcine product that contains 3 highly purified and stable enzymes: crystalline cross-linked lipase, crystalline protease, amorphous amylase. The particular enzymes selected for inclusion in liprotamase were based on their stability in the pH of the GI tract without enteric coating and their broad substrate specificity without the need for co-factors. Because of this purity and stability, we are able to administer liprotamase utilizing a novel rapid disintegrating formulation (LipRDT) that is easily suspended in liquid. The LipRDT was tested in a surgical model of exocrine pancreatic insufficiency, young EPI pigs that have total lack of pancreatic enzymes, resulting in poor nutrient absorption and arrested growth. Efficacy of LipRDT was measured by changes in fat digestion (%CFA) and fat and protein absorption (TG, NEFA and growth). Methods: A cross over randomized dose study was used to test two daily doses of liprotamase, high (HRDT) and low (LRDT), or placebo in 8 EPI pigs fed a high fat diet (HFD, ˜80g fat). Study included 1 control and 2 treatment periods with a washout in between, each 1 week. During the fifth week all pigs were placed on LRDT. As a comparator, 6 healthy pigs, same age and breed, were maintained on the HFD. Fat absorption was assessed by postprandial changes in TG and NEFA in blood samples collected before the morning meal and then in 1h intervals on last day of the control and treatment weeks. Results: One week of treatment enhanced fat and protein digestion and reversed impairment of growth with body mass increase of 6% and 8% on HRDT and LRDT. Treatment CFA was 84% and 79% with HRDT and LRDT respectively, from a basal value of 24%, vs. 92% in healthy pigs. LRDT efficacy was confirmed during extension week when CFA was 79%. Enhanced fat absorption with both tested doses was associated with normalization of blood TG and NEFA levels. Calculated AUC values for TG were the same as in healthy pigs: 4.1±1.9 and 4.5±1.6 for each RDT dose, vs. 4.1±0.7 in healthy. Similarly NEFA AUCs were 1.61±0.4 and 1.6±0.6 for each vs. 1.4±0.1 in healthy animals. Conclusion: Both tested doses of LipRDT improved digestion of fat and protein. As an important measure of nutrient absorption, LipRDT normalized postprandial TG and NEFA serum levels, and facilitated significant growth in EPI pigs. Postprandial TG and NEFA, as a measure of efficacy, are a viable endpoint to the difficult CFA that should be explored in human trials. Thus, our study demonstrates successful in vivo activity of a liquid suspension of a pancreatic enzyme replacement therapy designed for the treatment of EPI in infants, children, and patients with a G-tube. Disclosure: Dr Grujic employee of Alnara Pharmaceuticals; Dr Pierzynowski-Consultant. This research was supported by an industry grant from Alnara Pharmaceuticals.