Clinical Testing of an Insulin Analog

胰岛素类似物的临床测试

基本信息

  • 批准号:
    7613905
  • 负责人:
  • 金额:
    $ 25.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-30 至 2011-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The central goal of insulin replacement therapy in the treatment of Type 1 diabetes mellitus (T1DM) is tight control of blood glucose concentration. This Phase I STTR application, submitted by Thermalin Diabetes, Inc., in conjunction with Case Western Reserve University, seeks support for the pre-clinical testing and commercial development of an ultra-stable and ultra-fast-acting insulin analog for use in insulin pumps. The novel physico- chemical features of this insulin analog (designated Thermalin) promise to make feasible the long-term use of implantable intraperitoneal insulin pumps. This technology promises to enhance the safety and efficacy of insulin replacement therapy. Clinical trials have established the potential of implantable insulin pumps in the treatment of diabetes mellitus, but such pumps are presently regarded experimental by the FDA. A major problem is posed by the limited stability of present insulin formulations as stored for 1-3 months within the pump reservoir at 37oC within the peritoneal cavity. Such instability causes aberrant protein aggregation, which frequently impairs insulin delivery due to partial or complete obstruction of the pump. This problem is more severe with use of rapid- acting insulin analogs (HumalogTM (Lilly) and NovalogTM (Novo-Nordisk)), whose favorable pharmacokinetic properties otherwise offer significant advantages for use in external insulin pumps. Thermalin is a monomeric single-chain insulin analog refractory to aggregation and degradation in vitro for > 6 months on agitation at 37oC. Whereas its thermodynamic stability is markedly higher than wild-type human insulin or insulin analogs currently approved for human use, the receptor-binding affinity of Thermalin and its biological activity in diabetic rat model of Type I diabetes mellitus are essentially identical to that of wild-type human insulin. No adverse increase in cross-binding to the IGF receptor or aberrant mitogenicity in cell culture is observed. These preliminary results strongly suggest that Thermalin will prove to be a "perfect pump insulin" for an implantable system, combining rapid pharmacokinetics with long-term stability at high protein concentration as stored in a pump reservoir with gentle agitation at 37oC. Design of Thermalin was based on general principles of biophysical chemistry together with analysis of the structure of insulin and its pathways of non-native aggregation and chemical degradation. Support is requested for the GLP manufacture of Thermalin in quantities (10 grams) sufficient (a) to permit rigorous testing of its chemical and physical stability and (b) to enable in vivo assessment of its potency, pharmacokinetics, and pharmacodynamics in pigs, a standard model for studies of insulin analogs. PUBLIC HEALTH RELEVANCE: We propose to develop an ultra-stable and ultra-fast-acting insulin analog for use in implantable insulin pumps. With this technology, patients with Type I diabetes mellitus may need only 3 or 4 injections per year (to refill the pump reservoir) rather than 3 or 4 injections per day. Whereas existing insulin formulations tend to degrade at body temperature over a period of weeks, often obstructing the pump, our product (designated "Thermalin") is stable for more than 6 months and is predicted to have both optimal durability and optimal rapid action for long-term implantable pump therapy.
描述(申请人提供):胰岛素替代疗法治疗1型糖尿病(T1 DM)的中心目标是严格控制血糖浓度。这项由Thermarin糖尿病公司与凯斯西部储备大学联合提交的第一阶段STTR申请旨在为胰岛素泵中使用的超稳定、超快速作用的胰岛素类似物的临床前测试和商业开发提供支持。这种胰岛素类似物(命名为Thermarin)的新的物理化学特征有望使植入式腹膜内胰岛素泵的长期使用成为可能。这项技术有望提高胰岛素替代疗法的安全性和有效性。临床试验已经确定了植入式胰岛素泵治疗糖尿病的潜力,但目前FDA认为这种泵是实验性的。一个主要的问题是,目前的胰岛素制剂在37℃的腹膜腔内的泵储存库中储存1-3个月,稳定性有限。这种不稳定性会导致蛋白质的异常聚集,由于泵的部分或完全阻塞,这经常会损害胰岛素的输送。在使用快速作用的胰岛素类似物(HumalogTM(礼来公司)和NovalogTM(诺和诺德))时,这个问题更加严重,它们良好的药代动力学特性在其他方面为外部胰岛素泵的使用提供了显著的优势。Thermarin是一种单体单链胰岛素类似物,在37℃下搅拌6个月,在体外不易聚集和降解。虽然其热力学稳定性明显高于目前批准用于人类使用的野生型人胰岛素或胰岛素类似物,但其受体结合亲和力及其在糖尿病大鼠I型糖尿病模型中的生物活性与野生型人胰岛素基本相同。在细胞培养中,没有观察到与IGF受体交叉结合的不利增加或异常的有丝分裂。这些初步结果有力地表明,Thermarin将被证明是植入式系统的“完美胰岛素泵”,它结合了快速的药代动力学和在高蛋白浓度下的长期稳定性,储存在37 oC的泵容器中。Thermarin的设计基于生物物理化学的一般原理,并分析了胰岛素的结构及其非天然聚集和化学降解的途径。要求支持GLP生产足够数量(10克)的Thermarin(A)以允许对其化学和物理稳定性进行严格测试,以及(B)能够在猪体内评估其效力、药代动力学和药效学,这是研究胰岛素类似物的标准模型。公共卫生相关性:我们建议开发一种用于植入式胰岛素泵的超稳定和超快速起作用的胰岛素类似物。有了这项技术,I型糖尿病患者每年可能只需要注射3到4次(来补充泵的储液罐),而不是每天注射3到4次。现有的胰岛素制剂在体温下往往会在几周内降解,往往会堵塞泵,而我们的产品(指定为“Thermarin”)可以稳定6个月以上,预计对于长期植入式泵疗法来说,具有最佳的耐用性和最佳的快速作用。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(2)

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MICHAEL Aaron WEISS其他文献

MICHAEL Aaron WEISS的其他文献

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{{ truncateString('MICHAEL Aaron WEISS', 18)}}的其他基金

Biochemical Studies of a Transcription Factor
转录因子的生化研究
  • 批准号:
    8004618
  • 财政年份:
    2010
  • 资助金额:
    $ 25.5万
  • 项目类别:
How Insulin Binds to the Insulin Receptor
胰岛素如何与胰岛素受体结合
  • 批准号:
    8003136
  • 财政年份:
    2010
  • 资助金额:
    $ 25.5万
  • 项目类别:
Design of an Implantable Pump Insulin
植入式胰岛素泵的设计
  • 批准号:
    8003137
  • 财政年份:
    2010
  • 资助金额:
    $ 25.5万
  • 项目类别:
Design of an Implantable Pump Insulin
植入式胰岛素泵的设计
  • 批准号:
    7795721
  • 财政年份:
    2008
  • 资助金额:
    $ 25.5万
  • 项目类别:
Biochemical Studies of a Transcription Factor
转录因子的生化研究
  • 批准号:
    7665133
  • 财政年份:
    2008
  • 资助金额:
    $ 25.5万
  • 项目类别:
Design of an Implantable Pump Insulin
植入式胰岛素泵的设计
  • 批准号:
    7600456
  • 财政年份:
    2008
  • 资助金额:
    $ 25.5万
  • 项目类别:
Biochemical Studies of a Transcription Factor
转录因子的生化研究
  • 批准号:
    7522890
  • 财政年份:
    2008
  • 资助金额:
    $ 25.5万
  • 项目类别:
Biochemical Studies of a Transcription Factor
转录因子的生化研究
  • 批准号:
    7901159
  • 财政年份:
    2008
  • 资助金额:
    $ 25.5万
  • 项目类别:
Biochemical Studies of a Transcription Factor
转录因子的生化研究
  • 批准号:
    8118570
  • 财政年份:
    2008
  • 资助金额:
    $ 25.5万
  • 项目类别:
Design of an Implantable Pump Insulin
植入式胰岛素泵的设计
  • 批准号:
    8055273
  • 财政年份:
    2008
  • 资助金额:
    $ 25.5万
  • 项目类别:

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