Fluorolog: A Rapid-Acting Ultra-Concentrated Insulin Formulation

Fluorolog：一种速效超浓缩胰岛素制剂

• 批准号: 8645450
• 负责人: Bruce Hill Frank
• 金额: $ 127.53万
• 依托单位: THERMALIN DIABETES, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645450
• 关键词: Adolescent; Adopted; Advanced Development; African American; Age of Onset; American; Apoptosis; Attention; Binding; Biological; Biotechnology; Breast Cancer Cell; Budgets; Buffers; Canis familiaris; Cell Culture Techniques; Cell Proliferation; Chemicals; Clinical; Clinical Research; Clinical Trials; Communities; Conscious; Cyclic GMP; Data; Diabetes Mellitus; Disadvantaged; Disulfides; Dose; Drug Formulations; Drug Kinetics; Electrostatics; Endocrine; Engineering; Epidemiology; Equipment; Euglycemic Clamping; Excipients; Exhibits; Failure; Family suidae; Female; Fluorine; Foundations; Future; Genetic; Glucose Clamp; Glycosylated hemoglobin A; Goals; Grant; Growth; Halogens; Health; Health system; Healthcare; Hispanic Americans; Human; Indiana; Indigenous; Individual; Insulin; Insulin Resistance; Insulin, Lispro, Human; Insulin-Like Growth Factor Receptor; MCF7 cell; Mediating; Medical; Minority; Modification; Mutagenesis; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nude Mice; Obesity; Oral; Oryctolagus cuniculus; Patients; Phase; Phase I Clinical Trials; Polymers; Population; Prevalence; Printing; Procedures; Production; Proliferation Marker; Property; Protein Engineering; Proteins; Publications; Rattus; Resources; Risk; Safety; Salts; Site; Small Business Innovation Research Grant; Societies; Solutions; Sprague-Dawley Rats; Streptozocin; Structure; Surface; System; Testing; Therapeutic; Time; Toxic effect; Trypsin; Universities; Xenograft procedure; Zinc; absorption; analog; base; cancer risk; design; feeding; frontier; glycemic control; hemodynamics; improved; innovation; insulin tolerance; meetings; member; monomer; novel; patient population; phase 1 study; preclinical study; programs; receptor binding; trend; tumor growth; tumor progression; tumor xenograft; ward

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.

描述（由申请人提供）：在此 2 期 SBIR 申请中，我们寻求推进人体临床试验，一种基于卤素的新型蛋白质设计的速效、超浓缩单体胰岛素类似物。该类似物被命名为 Fluorolog，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），都表现出快速起效的 PK/PD 特性。我们预计 Fluorolog 的 U-500 制剂对于治疗存在明显胰岛素抵抗的 2 型糖尿病 (T2DM) 特别有益。此类患者不成比例地属于贫困少数群体，包括非裔美国人、西班牙裔美国人和土著美国人。 T2DM 是美国社会医疗保健不平等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) 保护胰岛素单体免于降解，(ii) 调节有丝分裂性，从而使 AspB10 对培养物中的细胞增殖和与 IGF 受体的交叉结合产生不良影响 均得到缓解。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，中试稳定性数据将扩大到包括通过 IND 申请中通常提供的程序和条件对化学和物理降解的各个方面（例如二硫键裂解、共价聚合物形成和原纤化）进行正式测试。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率分析以及 Sprague-Dawley 大鼠的正式毒性研究。因此，第二阶段申请的总体目标是提交适当且记录齐全的 IND 申请。