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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。胰腺执行适当消化、营养和代谢所需的各种内分泌和外分泌功能。胰腺的主要外分泌功能是产生脂肪、蛋白质和碳水化合物的消化和吸收所需的酶。各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）、慢性胰腺炎和继发于恶性肿瘤的胰腺手术切除均与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因子（CFTR）基因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、脂肪过多和营养不良。CF患者胰腺功能不全的标准治疗是口服胰酶替代品。目前可获得含有脂肪酶、淀粉酶和蛋白酶的多种猪制剂。他们已经证明，膳食脂肪吸收增加85- 90%。然而，现有的制剂有一些重大的局限性。产品内部和产品之间的效力和药物特性是可变的，所有现有产品都容易随着时间的推移而丧失活性。此外，现有产品对酸敏感，除非使用肠溶包衣，否则在胃肠道中会失活。许多CF患者需要H2受体阻滞剂来增强酶替代疗法的疗效。Altus Biologics开发了一种研究性新型胰酶替代产品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（脂肪酶）和结晶，以提供增强的稳定性和酶的效力在小肠，同时保持最大的溶解度。TheraCLEC-Total在较低剂量下提供了比目前可用产品更好的酶活性的潜力。一种更纯、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，如纤维化结肠病。Altus Biologics已在健康志愿者和CF患者中完成了早期临床试验（Altus研究TC-1A、TC-1B和TC-1C）。在这些研究中，没有报告严重不良事件，并且ThereCLEC-Total在所有剂量水平下均耐受良好。CF基金会的DSMB报告称，没有任何安全性问题会阻止TheraCLEC-Total的2期测试。

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.