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

一种新型高度稳定的胰酶替代疗法，可改善胰腺功能不全患者的预后。

• 批准号: 10543210
• 负责人: Shenda Baker
• 金额: $ 179.66万
• 依托单位: SYNSPIRA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543210
• 关键词: Abattoirs; Adherence; Adult; Affect; Affective; Amino Acids; Amylases; Bile fluid; Biological Markers; Blood; Carbohydrates; Child; Childhood; Chronic; Climacteric; Clinical; Clinical Research; Cystic Fibrosis; Deglutition; Development; Digestion; Disease; Dosage Forms; Duodenum; Effectiveness; Engineering; Ensure; Enteral; Enzymes; Evaluation; Exocrine pancreatic insufficiency; Family suidae; Fatty Acids; Fatty acid glycerol esters; Feces; Food; Formulation; Future; Gallbladder; Glucose; Goals; Growth; Human; Hydrolysis; Impairment; Infant; Ingestion; Intestinal Mucosa; Investigational New Drug Application; Life; Life Expectancy; Ligation; Lipase; Liquid substance; Liver; Macronutrients Nutrition; Malabsorption Syndromes; Malignant Neoplasms; Malignant neoplasm of pancreas; Malnutrition; Measures; Methods; Modeling; Monitor; Nonesterified Fatty Acids; Nutrient; Nutritional status; Oncology; Oral; Oral Administration; Oral Ingestion; Outcome; Pancreas; Pancreatic duct; Pancreatic enzyme; Pancreatitis; Pancrelipase; Patient Care; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Performance; Persons; Pharmaceutical Preparations; Physiological; Physiology; Plasma; Process; Proteins; Proteolysis; Rare Diseases; Research; Safety; Small Intestines; Solid; Steatorrhea; Stomach; Symptoms; Tablets; Testing; Tissues; Toxicology; Work; absorption; analytical method; base; capsule; chronic pancreatitis; cystic fibrosis patients; design; effectiveness evaluation; enzyme replacement therapy; improved; improved outcome; in vitro testing; liquid formulation; microbial; novel; novel therapeutics; nutrition; pancreatic juice; pill; porcine model; programs; prototype; response; tablet formulation; tool; uptake

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.

抽象的 当身体无法正确消化或吸收大量营养素时，就会发生吸收不良综合症 摄入的食物。吸收不良是由于胰酶[外分泌胰酶]分泌受损所致 机能不全（EPI）]、胃肠道运输紊乱、肠粘膜严重丧失或胃、十二指肠、肝脏的变化， 胆汁或胆囊的生理或分泌。吸收不良综合症可能会危及生命 来自囊性纤维化、慢性胰腺炎、胰腺癌或其他疾病。目前唯一的治疗方法是 来自屠宰场加工的猪胰腺的胰酶替代疗法（PERT）。 PERT 很少能消除消化不良或严重胃肠道症状，并且患者仍然无法达到目标营养 尽管长期使用，仍有大量无反应者。 PERT 需要大量 每天服用大药片（20-40 颗），并且不提供液体配方，极大地限制了其有效性 适用于婴儿、儿童或吞咽药片有困难的人。 Synspira 正在开发 SNSP003，以提供卓越的 绩效并为需要 PERT 的人们带来改变生活的影响。 SNSP003 是以下物质的混合物 帮助消化和吸收关键物质所必需的三种关键酶（脂肪酶、蛋白酶和淀粉酶） 宏量营养素。 SNSP003 的开发是为了改善脂肪酸异常（特别是生理上的异常） 相关的 LCPUFA）、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 SNSP003 中的脂肪酶通过酶工程进行了改进，可针对低 pH 值和 蛋白水解直接降解为酶，无需肠溶衣。的稳定性 工程脂肪酶将使其能够消化胃中和小肠中的脂肪，同时还可以 液体相容制剂。 Synspira 打算创建一种快速崩解片（RDT）配方， 可以作为婴儿、患有罕见疾病的儿童或患有罕见疾病的成人的液体治疗选择 无法吞咽所需的大量胶囊。 SNSP003 每餐仅需服用一粒药片，并提供 新型 RDT 配方旨在减轻治疗负担、简化治疗、提高依从性、 生活质量，并为否则无法使用胰酶的患者提供机会。这 RDT 很新颖，将解决 50 年来一直未解决的问题，并在以下方面提供显着改进： 病人护理。在这项研究中，Synspira 将重新配制现有 SNSP003 中的脂肪酶、蛋白酶和淀粉酶 用于 RDT 配方的迷你片剂。 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，通过确定 血浆、红细胞、组织和粪便中的脂肪酸摄取。然后将使用高通量进行分析测试 测量游离脂肪酸（C14-C24）、氨基酸和葡萄糖释放的通量分析方法。辛螺属 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将具备制造能力，以确保供应并满足需求。