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

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。

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.