Chlorolog: Production Scaling and Testing of a Fast-Acting, Ultra-stable Insulin

Chlorolog：速效、超稳定胰岛素的生产规模和测试

• 批准号: 8458109
• 负责人: Bruce Hill Frank
• 金额: $ 147.44万
• 依托单位: THERMALIN DIABETES, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-25 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458109
• 关键词: Achievement; Adopted; Affinity; Agitation; Algorithms; Amino Acids; Animals; Artificial Pancreas; Biological; Biotechnology; Buffers; Canis familiaris; Chemicals; Clinical; Clinical Trials; Coupled; Cyclic GMP; Deltastab; Development; Development Plans; Devices; Diabetes Mellitus; Diabetic Angiopathies; Dose; Drug Formulations; Drug Kinetics; Electrostatics; Engineering; Equipment; Euglycemic Clamping; Excipients; Family suidae; Future; Generations; Genetic; Glucose Clamp; Grant; Halogens; Health Care Costs; Human; In Vitro; Infusion procedures; Insulin; Insulin Infusion Systems; Insulin Resistance; Insulin, Lispro, Human; Insulin-Dependent Diabetes Mellitus; Life; Mediating; Modeling; NovoLog; Oryctolagus cuniculus; Outcome; Patient Care; Patients; Performance; Pharmaceutical Chemistry; Pharmacodynamics; Phase; Phase I Clinical Trials; Physiological; Prevalence; Procedures; Process; Production; Protein Engineering; Proteins; Protons; Pump; Rattus; Relative (related person); Replacement Therapy; Risk; Safety; Salts; Seminal; Small Business Innovation Research Grant; Structure; System; Temperature; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Trypsin; Universities; Validation; Zinc; absorption; analog; animal data; base; blood glucose regulation; chemical property; design; dipole moment; experience; frontier; glucose monitor; glycemic control; healthy volunteer; hemodynamics; improved; innovation; novel; phase 1 study; physical property; pre-clinical; programs; receptor binding; research clinical testing; satisfaction; subcutaneous

DESCRIPTION (provided by applicant): We seek to develop a novel insulin analog to enhance the safety and efficacy of insulin pump therapy with broad application to the Artificial Pancreas Project ("smart pumps"). A proprietary approach is proposed based on the favorable physico-chemical properties conferred by chloro-aromatic substitutions in the insulin molecule. This Phase 2 SBIR application thus builds on progress obtain in the Phase 1 program in the characterization of 4-Cl-PheB24-KP-insulin. In this derivative of insulin lispro (the active component of Humalog; Eli Lilly and Co) the para proton of the aromatic ring of PheB24 is substituted by a larger and electronegative halogen atom. Results of Phase 1 studies established that this substitution (i) is compatible with native receptor-binding affinity and natie biological potency; (ii) leads to an accelerated rate of disassembly of the insulin hexamer in vitro; (iii) is associated with foreshortened pharmacodynamics of insulin action in euglycemic clamp studies in a pig model; and (iv) augments the resistance of insulin to physical degradation above room temperature on gentle agitation as in a pump reservoir. This unique confluence of advantageous features predicts significant clinical advantages both with respect to patient convenience and with respect to the performance of control algorithms employed in CGM-coupled closed-loop systems. Accordingly, a Phase 2 development plan is proposed in support of clinical-scale manufacture and optimization of formulation leading to I-GMP production (Aims 1-3) and formal toxicity/tolerance testing in animals in support of an IND application to the FDA (Aim 4). Achievement of these milestones will enable a future Phase 2B application in support of first-in-human trials, anticipated to be a phase 1a clamp study of healthy volunteers. The present application thus provides a logical bridge between highly promising in vitro and animal data, as generated in the Phase 1 SBIR program, and key pre-IND milestones.

描述（由申请人提供）：我们试图开发一种新型的胰岛素类似物，以增强胰岛素泵疗法的安全性和功效，并在人工胰腺项目中广泛应用（“智能泵”）。提出了一种专有方法，该方法是基于胰岛素分子中氯芳族取代赋予的有利的物理化学特性。因此，该阶段2 SBIR应用是基于在4-CL-PHEB24-KP-胰岛素的表征中在第1阶段程序中获得的进度。在这种胰岛素lispro（Humalog的活性成分； Eli Lilly and Co）中，Pheb24芳香环的Para质子被较大和电负性的卤素原子取代。第1阶段研究的结果表明，这种替代（i）与天然受体结合亲和力和Natie生物学效力兼容。 （ii）在体外导致胰岛素己酯的拆卸速率加速； （iii）与猪模型中的葡萄糖夹具研究中的胰岛素作用的预先进行的药效学有关； （iv）像在泵储层中一样，在轻度搅拌时增强胰岛素对物理降解的耐药性。这种有利特征的独特汇合度预测了患者便利性以及CGM耦合闭环系统中使用的控制算法的性能。因此，提出了第2阶段的开发计划，以支持临床规模的制造和优化导致I-GMP产生的配方（AIMS 1-3）和动物中的正式毒性/耐受性测试，以支持对FDA的IND应用（AIM 4）。这些里程碑的实现将实现未来的2B阶段应用，以支持首次人类试验，预计将是对健康志愿者的1A期夹具研究。因此，本应用程序在第1阶段SBIR计划中产生的高度有希望的体外和动物数据与关键的预印度里程碑之间提供了逻辑桥。