Development of a Potent Engineered Microbial Lipase for the Treatment of Exocrine Pancreatic Insufficiency

Exocrine pancreatic insufficiency (EPI) is a chronic condition associated with inadequate digestive enzyme secretion from the pancreas, causing impaired digestion, malabsorption, and malnutrition. EPI affects 10%-20% of the general population, and the standard of care includes pancreatic enzyme replacement therapy (PERT) that is exclusively derived from porcine pancreatic extracts. However, PERT is associated with several limitations, including suboptimal efficacy, which results in increased pill burden and high treatment costs. This work aimed to identify and engineer a potent microbial lipase that can function in the gastrointestinal tract without needing enteric coating and capable of hydrolyzing a wide range of dietary fats for the development of an alternative PERT.

State-of-the-art protein engineering and biochemical characterization techniques were applied to optimize and characterize a therapeutically relevant lipase. The lipase was evaluated in a pancreatic duct ligation minipig model, as well as in a clinical trial involving healthy subjects and EPI patients.

The engineered lipase exhibited very high stability under simulated gastric and intestinal conditions while it can hydrolyze a wide range of dietary fats. Coefficient of fat absorption analysis demonstrated that the enzyme enabled pancreatic duct ligation minipigs to digest fat at levels comparable to porcine-derived PERT while using 10-fold lower dosing by mass of non-enteric-coated recombinant protein vs porcine PERT. Clinically, patients with EPI receiving orally administered lipase demonstrated a favorable safety profile and improvement of fat absorption as assessed by a ¹³CO₂-mixed triglyceride breath test in a proof-of-concept, integrated phase 1a-1b clinical trial.

These results provide a foundation for the clinical development of a novel engineered recombinant lipase for treating EPI and warrant further evaluation in clinical trials.