A novel highly stable pancreatic enzyme replacement therapy to improve outcomes for patients with pancreatic insufficiency.

摘要 当身体不能适当地消化或吸收大量营养素时，就会出现吸收不良综合征。 被摄取的食物。吸收不良是由于胰酶分泌受损[胰腺外分泌 功能不全(EPI)]，胃肠道转运障碍，严重的肠粘膜丧失或胃、十二指肠、肝脏的改变， 胆汁或胆汁的生理或分泌物。吸收不良综合征可导致危及生命的情况 囊性纤维化、慢性胰腺炎、胰腺癌或其他疾病。目前唯一的治疗方法是 从屠宰场加工的猪胰腺衍生的胰酶替代疗法(PERTS)。 PERT很少消除消化不良或严重的胃肠道症状，患者继续达不到目标营养 状况--尽管长期与重要的无反应者群体一起使用。PERT需要大量的 每天服用大药丸(20-40粒)，不提供液体制剂，大大限制了其疗效 婴儿、儿童或吞咽药物有困难的人。Synspira正在开发SNSP003，以提供卓越的 性能，并对需要PERT的人产生改变生活的影响。SNSP003是 三种关键酶(脂肪酶、蛋白酶和淀粉酶)有助于消化和吸收关键物质 常量营养素。SNSP003已被开发用于改善脂肪酸异常(特别是生理上的 相关的LCPUFAs)、蛋白质和碳水化合物吸收不良、临床结果、胃肠道症状和生活质量。这个 通过酶工程对SNSP003中的脂肪酶进行了改良，使其对低pH和 蛋白质降解直接转化为酶，不需要肠溶包衣。该系统的稳定性 经过改造的脂肪酶将允许它在胃和通过小肠消化脂肪，同时还允许 液体相容配方。Synspira打算创造一种快速崩解片(RDT)配方， 可作为婴儿、患有罕见疾病的儿童或成人的液体治疗选择 无法吞咽所需的大量胶囊。SNSP003每餐只需要一片药，并提供 新的RDT配方既旨在减轻治疗负担，简化治疗，提高依从性， 并为原本无法使用胰酶的患者提供了一个机会。这 RDT是新颖的，将解决一个50年来没有解决的问题，在 病人护理。在这项研究中，Synspira将重新配方现有SNSP003中的脂肪酶、蛋白酶和淀粉酶 RDT配方中使用的迷你片剂。RDT配方的有效性将使用EPI进行测试 猪模型被证明是评估大量营养素吸收的敏感工具 血浆、红细胞、组织和粪便中的脂肪酸摄取。分析测试随后将使用HIGH 通过量分析方法测量游离脂肪酸(C14-C24)、氨基酸和葡萄糖的释放。Synspira 将对SNSP003进行为期28天的毒理学研究，为临床研究提供信息并评估基础酶 (脂肪酶、蛋白酶和淀粉酶)。SNSP003将拥有确保供应和满足需求的制造能力。

ABSTRACT Malabsorption syndromes occurs when the body is not able to properly digest or absorb macronutrients from ingested food. Malabsorption results from impaired secretion of pancreatic enzymes [exocrine pancreatic insufficiency (EPI)], disturbed GI transit, critical loss of intestinal mucosa or changes in gastric, duodenal, liver, bile or gallbladder physiology or secretion. Malabsorption syndromes can be life-threatening conditions resulting from cystic fibrosis, chronic pancreatitis, pancreatic cancer, or other diseases. Currently the only treatment is pancreatic enzyme replacement therapies (PERTs) derived from pig pancreas processed in slaughterhouses. PERT rarely eliminates maldigestion or severe GI symptoms and patients continue to not meet target nutritional status in-spite of chronic use with significant groups of non-responders. PERT requires enormous volumes of large pills to be taken daily (20-40) and does not provide a liquid formulation dramatically limiting its effectiveness for infants, children or those with difficulty swallowing pills. Synspira is developing SNSP003 to provide superior performance and make a life-changing impact for the people who require PERT. SNSP003 is a mixture of the three critical enzymes (lipase, protease and amylase) necessary to aid digestion and absorption of key macronutrients. SNSP003 has been developed to improve fatty acid abnormalities (specifically physiologically relevant LCPUFAs), protein and carbohydrate malabsorption, clinical outcomes, GI symptoms and QoL. The lipase in SNSP003 has been improved through enzyme engineering to be build stability against low pH and proteolytic degradation directly into the enzyme without the need for enteric coating. The stability of the engineered lipase will allow it to digest fats in the stomach and through the small intestine while also allowing for a liquid compatible formulation. Synspira intends to create a Rapidly Disintegrating Tablet (RDT) formulation, that can be given as a liquid treatment option for infants, children suffering from rare diseases or adults who are unable to swallow the requisite large volume of capsules. SNSP003 will only require one pill per meal and provide the novel RDT formulation both aimed at reducing treatment burden, simplifying therapy, improving adherence, QoL and provide an opportunity for patients who otherwise would not be able to use pancreatic enzymes. This RDT is novel and will solve a problem that has been unmet for 50-years providing a dramatic improvement in patient care. In this study, Synspira will reformulate the lipase, protease and amylase in the existing SNSP003 mini-tablets for use in the RDT formulation. The effectiveness of the RDT formulation will be tested using an EPI porcine model demonstrated to be a sensitive tool for the evaluation of macronutrient absorption by determining fatty acid uptake in plasma, RBCs, tissues and stool. Analytical testing will then be performed using high throughput analytical methods measuring free fatty acid release (C14-C24), amino acids and glucose. Synspira will conduct a 28-day toxicology study for SNSP003 to inform clinical studies and evaluate the base enzymes (lipase, protease and amylase). SNSP003 will have manufacturing capacity to ensure supply and meet demand.