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.

摘要 吸收不良综合征发生时，身体不能正确消化或吸收宏量营养素， 摄入的食物胰腺酶分泌受损导致吸收不良[胰腺外分泌 功能不全（EPI）]，GI转运障碍，肠粘膜严重损失或胃、十二指肠、肝脏的变化， 胆汁或胆囊生理或分泌。吸收不良综合征可能是危及生命的疾病， 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 胰酶替代疗法（PERT）来源于屠宰场加工的猪胰腺。 PERT很少消除消化不良或严重的GI症状，患者仍然不能满足目标营养 尽管长期使用，但无应答者的显著群体的状态。PERT需要大量的 每天服用大药丸（20-40粒），并且不提供显著限制其有效性的液体制剂 适用于婴儿、儿童或吞咽药片有困难的人。Synspira正在开发SNSP 003，以提供上级 绩效，并为需要PERT的人带来改变生活的影响。SNSP 003是以下物质的混合物： 三种关键酶（脂肪酶，蛋白酶和淀粉酶），帮助消化和吸收的关键 大量营养素SNSP 003已被开发用于改善脂肪酸异常（特别是生理上的 相关LCPUFA）、蛋白质和碳水化合物吸收不良、临床结局、GI症状和QoL。的 SNSP 003中的脂肪酶已经通过酶工程进行了改进，以建立对低pH的稳定性， 蛋白水解降解直接进入酶中，而不需要肠溶包衣。的稳定性 工程脂肪酶将允许它消化脂肪在胃和通过小肠，同时也允许 液体相容性制剂。Synspira打算开发一种快速崩解片（RDT）配方， 可作为婴儿、患有罕见疾病的儿童或患有 无法吞下所需的大量胶囊。SNSP 003每餐只需要一粒药丸， 新的RDT制剂既旨在减少治疗负担，简化治疗，提高依从性， QoL，并为无法使用胰酶的患者提供机会。这 RDT是新颖的，它将解决一个50年来一直没有解决的问题， 病人护理在本研究中，Synspira将重新配制现有SNSP 003中的脂肪酶、蛋白酶和淀粉酶 用于RDT制剂的迷你片剂。将使用EPI测试RDT制剂的有效性 猪模型被证明是一个敏感的工具，通过测定大量营养素吸收的评价 血浆、RBC、组织和粪便中的脂肪酸摄取。然后将使用高浓度的 测量游离脂肪酸释放（C14-C24）、氨基酸和葡萄糖的通量分析方法。合成螺属 将对SNSP 003进行为期28天的毒理学研究，以告知临床研究并评估基础酶 （脂肪酶、蛋白酶和淀粉酶）。SNSP 003将具有确保供应和满足需求的制造能力。