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

描述（由申请人提供）：我们寻求开发一种新型胰岛素类似物，以增强胰岛素泵治疗的安全性和有效性，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取代所赋予的有利理化性质，提出了一种专有方法。因此，该2期SBIR应用建立在1期项目在4-Cl-PheB 24-KP-胰岛素表征方面取得的进展基础上。在赖脯胰岛素的这种衍生物中（Humanoid的活性成分; Eli Lilly and Co），PheB 24芳环的帕拉质子被较大的电负性卤素原子取代。1期研究的结果证实，这种取代（i）与天然受体结合亲和力和天然生物学效力相容;（ii）导致体外胰岛素六聚体分解速率加快;（iii）与猪模型正葡萄糖钳夹研究中胰岛素作用的缩短药效学相关;和（iv）增强胰岛素在室温以上在如泵储液器中的温和搅拌下对物理降解的抵抗力。有利特征的这种独特融合预测了在患者便利性和在CGM耦合闭环系统中采用的控制算法的性能方面的显著临床优势。因此，拟定了II期开发计划，以支持临床规模生产和处方优化，从而实现I-GMP生产（目标1-3）和正式的动物毒性/耐受性试验，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期申请能够支持首次人体试验，预计将是健康志愿者的1a期钳夹研究。因此，本申请提供了如在I期SBIR计划中产生的高度有希望的体外和动物数据与关键的IND前里程碑之间的逻辑桥梁。

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.