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）：我们寻求开发一种新型胰岛素类似物，以提高胰岛素泵治疗的安全性和有效性，并广泛应用于人工胰腺项目（“智能泵”）。基于胰岛素分子中氯芳香族取代所赋予的有利物理化学特性，提出了一种专有方法。因此，该第 2 阶段 SBIR 应用建立在第 1 阶段计划在 4-Cl-PheB24-KP-胰岛素表征方面取得的进展的基础上。在赖脯胰岛素的这种衍生物（优泌乐的活性成分；礼来公司）中，PheB24 芳环的对位质子被更大且带负电的卤素原子取代。第一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天然生物效力相容； (ii) 导致胰岛素六聚体在体外的分解速度加快； (iii) 与猪模型正常血糖钳夹研究中胰岛素作用的药效学缩短有关； (iv) 在泵储存器中轻轻搅拌时增强胰岛素对高于室温的物理降解的抵抗力。这种独特的优势特征融合预示着在患者便利性和 CGM 耦合闭环系统中采用的控制算法性能方面的显着临床优势。因此，提出了第二阶段开发计划，以支持临床规模生产和配方优化，从而实现 I-GMP 生产（目标 1-3）和动物正式毒性/耐受性测试，以支持向 FDA 提交 IND 申请（目标 4）。这些里程碑的实现将使未来的 2B 期应用能够支持首次人体试验，预计将成为健康志愿者的 1a 期钳夹研究。因此，本申请在 1 期 SBIR 计划中生成的极具前景的体外和动物数据与关键的 IND 前里程碑之间提供了一座逻辑桥梁。