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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。胰腺执行各种正常消化、营养和新陈代谢所需的内分泌和外分泌功能。胰腺外分泌的主要功能是产生消化和吸收脂肪、蛋白质和碳水化合物所必需的酶。多种疾病过程可导致胰腺功能障碍和随后的胰腺功能不全（PI）。囊性纤维化（CF）、慢性胰腺炎、胰腺继发恶性肿瘤手术切除均与PI相关。囊性纤维化是高加索人群中最常见的缩短寿命的常染色体隐性遗传病。囊性纤维化跨膜传导调节基因（CFTR）的缺陷导致许多器官系统中组织细胞膜上的异常离子运动。这会导致身体大部分外分泌腺功能障碍。在胃肠道系统中，CF的特征是胰管阻塞，随后胰腺功能不全，导致脂肪吸收不良、脂肪漏和营养不良。CF患者胰功能不全的标准治疗是口服胰酶替代品。目前市面上有多种含有脂肪酶、淀粉酶和蛋白酶的猪制剂。他们已经证明饮食脂肪吸收量增加了85-90%。然而，现有的准备工作有一些明显的局限性。效力和药物性质在产品内部和产品之间是可变的，所有现有产品都容易随着时间的推移而失去活性。此外，现有产品对酸敏感，在胃肠道中失活，除非使用肠包衣。许多CF患者需要h2阻滞剂来提高酶替代治疗的疗效。Altus Biologics开发了一种研究性的新型胰腺酶替代产品，TheraCLEC- Total，其中含有来自细菌和真菌来源的脂肪酶，蛋白酶和淀粉酶。本产品使用高度纯化的酶交联（仅脂肪酶）和结晶，以提供增强的稳定性和酶效力，同时保持最大的溶解度。theraclecl - total在较低剂量下提供了比现有产品更好的酶活性的潜力。一种更纯净、更稳定、更有效的胰酶替代产品有可能降低与高剂量产品相关的不良反应风险，如纤维化性结肠病。Altus Biologics已经完成了健康志愿者和CF患者的早期临床试验（Altus研究TC-1A、TC-1B和TC-1C）。在这些研究中，没有严重的不良事件报告，thereclect - total在所有剂量水平下都具有良好的耐受性。CF基金会的DSMB报告说，没有安全问题会阻止theraclecl - total的二期试验。

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.