Fluorolog: A Rapid-Acting Ultra-Concentrated Insulin Formulation

描述（由申请人提供）：在这个2期SBIR申请中，我们寻求一种新型基于卤素蛋白设计的速效超浓缩单体胰岛素类似物的人体临床试验。指定的Fluorolog，这种类似物在I期研究中发现，无论蛋白质浓度在0.6 - 3.0 mM范围内，即从U-100到U-500强度，都表现出速效PK/PD特性。我们预计，U-500配方的Fluorolog将特别有利于治疗2型糖尿病（T2DM）在设置显著胰岛素抵抗。这些患者不成比例地来自贫困的少数群体，包括非洲裔美国人、西班牙裔美国人和土著美国人。2型糖尿病是美国社会医疗保健差距的一个主要组成部分。我们的一期研究验证了Fluorolog设计的一个关键假设：在胰岛素的受体结合表面（para-F-PheB24）引入单个氟原子可以同时(i)保护胰岛素单体免受降解，（ii）调节有丝分裂性，从而减轻AspB10对培养细胞增殖和与IGF受体交叉结合的不利影响。在第二阶段，我们寻求扩展这些研究，以获得IND申请所需的数据。为此，试点稳定性数据将扩大，以包括化学和物理降解的各个方面的正式测试（如二硫裂解、共价聚合物形成和纤颤），按照程序和在IND应用中通常提供的条件。同样，试点细胞培养数据将扩展到裸鼠肿瘤异种移植物生长速率的分析和Sprague-Dawley大鼠的正式毒性研究。因此，该2期申请的总体目标是提交一份适当且有充分文件证明的IND申请。

DESCRIPTION (provided by applicant): In this Phase 2 SBIR application we seek to advance toward human clinical trials a rapid-acting and ultra- concentrated monomeric insulin analog of novel halogen-based protein design. Designated Fluorolog, this analog was found in Phase I studies to exhibit rapid-acting PK/PD properties irrespective of protein concentration in the range 0.6 - 3.0 mM, i.e., from U-100 to U-500 strengths. We anticipate that a U-500 formulation of Fluorolog will be of particular benefit to the treatment of Type 2 diabetes mellitus (T2DM) in the setting of marked insulin resistance. Such patients are disproportionately members of underprivileged minority communities, including African-Americans, Hispanic Americans, and Indigenous Americans. T2DM represents a major component of health-care disparities in American society. Our Phase 1 studies validated a key hypothesis underlying design of Fluorolog: that introduction of a single fluorine atom at the receptor-binding surface of insulin (para-F-PheB24) can at the same time (i) protect the insulin monomer from degradation and (ii) modulate mitogenicity such that untoward effects of AspB10 on cellular proliferation in culture and on cross-binding to the IGF receptor are each mitigated. In Phase 2 we seek to extend these studies to obtain data required in an IND application. To this end, pilot stability data willbe enlarged to include formal testing of the individual aspects of chemical and physical degradation (such as disulfide cleavage, covalent polymer formation, and fibrillation) by procedures and under conditions customarily provided in an IND application. Similarly, pilot cell-culture data wil be extended to analysis of tumor xenograft growth rates in nude mice and by formal toxicity studies in Sprague-Dawley rats. The overarching goal of this Phase 2 application is thus the submission of an appropriate and well-documented IND application.