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的胰岛素类似物，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性质，提出了一种专有方法。因此，这项2期SBIR申请是建立在4- cl - pheb24 - kp -胰岛素的1期研究进展的基础上的。在胰岛素lispro （Humalog的活性成分；Eli Lilly and Co）的衍生物中，PheB24芳香环的对质子被一个更大的电负性卤素原子取代。1期研究结果证实，这种替代(i)与天然受体结合亲和力和天然生物效力相容；（ii）导致体外胰岛素六聚体的分解速度加快；（iii）与猪模型中血糖钳夹研究中胰岛素作用的缩短药效学有关；（iv）增强胰岛素在室温以上，如在泵储存器中温和搅拌时对物理降解的抵抗力。这种独特的优势特征的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的性能方面具有显著的临床优势。因此，提出了2期开发计划，以支持临床规模生产和配方优化，从而生产I-GMP（目标1-3），并在动物中进行正式的毒性/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期应用支持首次人体试验，预计将是健康志愿者的1a期夹钳研究。因此，目前的应用程序在高度有希望的体外和动物数据之间提供了逻辑桥梁，如在1期SBIR项目中产生的数据，以及ind前的关键里程碑。

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.