Results of a clinical trial of ANG003, a non-porcine pancreatic enzyme replacement therapy, in people with cystic fibrosis

Background Pancreatic enzyme replacement therapy (PERT) prevents malnutrition in people with exocrine pancreatic insufficiency, including those with cystic fibrosis (CF). We developed a lipase that is stable against proteolysis and at the pH of the fed stomach, so it can be taken during a meal to promote mixing of enzyme and substrate. We designed a dose-ranging study of ANG003, a microbial PERT combining this lipase with low pH-stable protease and amylase, also of microbial origin. Methods This was a multicenter, randomized evaluation of ANG003 in subjects with CF, studied once without PERT and again after randomization to a single dose level of four possible combinations of lipase, protease, and amylase. We developed blood-based substrate absorption challenge tests employing DHA+EPA, whey and potato starch to determine dose-response to each of these enzymes, respectively. Results ANG003 improved DHA+EPA absorption with a statistically significant increase with 80 mg and 120 mg lipase doses compared to 20 mg (p = 0.03; p = 0.004). The absorption of total fats followed a similar pattern to DHA+EPA. There was a significant increase in absorbed amino acid equivalents, reflecting proteolysis, over no PERT in the highest (75 mg) dose of protease (p = 0.03). In subjects without diabetes, glucose was slightly lower while c-peptide levels remained unchanged with all amylase doses. Adverse events were mild and transient. No serious adverse events occurred. Conclusions ANG003 lipase significantly improves DHA+EPA and total fat absorption in a dose dependent manner. Results for ANG003 protease and amylase activity suggest that doses lower than those in current porcine-derived PERTs may be efficacious.