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

Chlorolog：速效、超稳定胰岛素类似物的生产和测试

• 批准号: 8315271
• 负责人: Bruce Hill Frank
• 金额: $ 133.98万
• 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/8315271
• 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. PUBLIC HEALTH RELEVANCE: Diabetes is increasing in prevalence; continuous subcutaneous insulin infusion (CSII; pump therapy) can enhance glycemic control and mitigate risk of microvascular complications, thereby improving outcomes and quality and quantity of life and, at the same time, lowering health-care costs. To improve the pharmacokinetics of pump therapy and the efficacy of closed-loop systems, this project will complete pre-clinical development of Chlorolog (a 4-Cl-PheB24 derivative of insulin lispro, the active ingredient of Humalog(R)). The chloro-substitution was designed to accelerate hexamer disassembly at neutral pH (relative to Humalog) and has been demonstrated in a Phase I SBIR program to have ultra-rapid pharmacodynamics.

描述(申请人提供)：我们寻求开发一种新的胰岛素类似物，以提高胰岛素泵疗法的安全性和有效性，并广泛应用于人工胰腺项目(“智能泵”)。基于胰岛素分子中氯代芳香族取代所赋予的良好的物理化学性质，提出了一种专利方法。因此，这一第二阶段SBIR应用建立在第一阶段计划在4-氯-PheB24-KP-胰岛素表征方面取得的进展的基础上。在胰岛素Lispro(Humalog的活性成分；礼来公司和Co)的这个衍生物中，PheB24的芳环上的对质子被一个更大的电负性卤素原子取代。第一阶段研究的结果证实，这种替代(I)与天然受体结合亲和力和天然生物效力相兼容；(Ii)导致胰岛素六聚体在体外的分解速度加快；(Iii)在猪模型的正常血糖钳研究中与胰岛素作用的药效学缩短有关；以及(Iv)增强胰岛素对室温以上温和搅拌的物理降解的抵抗力，如在泵储存器中。这种独特的优势特征的融合预示着显著的临床优势，无论是在患者便利性方面，还是在CGM耦合闭环系统中所采用的控制算法的性能方面。因此，提出了第二阶段开发计划，以支持临床规模的生产和导致I-GMP生产的配方优化(目标1-3)和动物正式毒性/耐受性测试，以支持向FDA申请IND(目标4)。这些里程碑的实现将使未来的2B阶段应用能够支持第一次人体试验，预计将是健康志愿者的1a阶段钳制研究。因此，本申请在第一阶段SBIR计划中产生的非常有希望的体外和动物数据与关键的Pre-IND里程碑之间提供了一座逻辑桥梁。 与公共卫生相关：糖尿病的患病率正在上升；持续皮下胰岛素输注(CSII；泵疗法)可以加强血糖控制，降低微血管并发症的风险，从而改善预后，提高生活质量和数量，同时降低医疗成本。为了提高泵疗法的药代动力学和闭环系统的疗效，这个项目将完成Chlorolog(一种4-氯-PheB24胰岛素的衍生物，Humalog(R)的活性成分)的临床前开发。氯代取代的目的是在中性pH(相对于Humalog)下加速六聚体的分解，并已在第一阶段SBIR计划中证明具有超快的药效学。