A PHASE 2, RANDOMIZED, DOUBLE BLIND, PARALLEL DOSE RANGING STUDY OF ORAL THER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The pancreas performs a variety of endocrine and exocrine functions required for proper digestion, nutrition, and metabolism. A primary pancreatic exocrine function is the production of enzymes necessary for the digestion and absorption of fat, protein, and carbohydrate. A variety of disease processes can lead to dysfunction of the pancreas and subsequent pancreatic insufficiency (PI). Cystic fibrosis (CF), chronic pancreatitis, and surgical resection of the pancreas secondary to malignancy are all associated with PI. Cystic fibrosis is the most common life-shortening autosomal recessive disease encountered in the Caucasian population. Defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene lead to abnormal ion movement across the cell membranes of tissues in many organ systems. This leads to dysfunction of most of the body's exocrine glands. In the gastrointestinal system, CF is characterized by obstruction of the pancreatic ducts with subsequent pancreatic insufficiency which leads to fat malabsorption, steatorrhea, and malnutrition. The standard therapy for pancreatic insufficiency among CF patients is oral administration of pancreatic enzyme replacements. A variety of porcine preparations containing lipase, amylase, and protease are currently available. They have demonstrated an increase in dietary fat absorption of 85-90%. However, the existing preparations have a number of significant limitations. Potency and pharmaceutical properties are variable within and between products and all existing products are susceptible to loss of activity over time. Additionally, existing products are sensitive to acid and are inactivated in the GI tract unless enteric coatings are used. Many CF patients require H2-blockers to enhance the efficacy of enzyme replacement therapy. Altus Biologics has developed an investigational new type of pancreatic enzyme replacement product, TheraCLEC- Total, which contains lipase, protease, and amylase derived from bacterial and fungal sources. This product uses highly purified enzymes cross linked (lipase only) and crystallized to provide enhanced stability and enzyme potency in the small bowel while maintaining maximum solubility. TheraCLEC-Total offers the potential of better enzyme activity at lower dosages than currently available products. A purer, more stable, and more potent pancreatic enzyme replacement product has the potential to reduce the risks of adverse effects, such as fibrosing colonopathy, associated with higher dose products. Altus Biologics has completed early phase clinical trials in healthy volunteers and CF patients (Altus studies TC-1A, TC-1B, and TC-1C). In these studies, no serious adverse events were reported and ThereCLEC-Total was well tolerated at all dose levels. The CF Foundation's DSMB reported no safety concerns that would prevent Phase 2 testing of TheraCLEC-Total.