Nonclinical development of Nervelight, an intra-operative peripheral nerve imaging agent
术中周围神经显像剂 Nervelight 的非临床开发
基本信息
- 批准号:9345832
- 负责人:
- 金额:$ 122.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-25 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAmyotrophic Lateral SclerosisAnimalsAwardAxillary Lymph Node DissectionBenignBilateralCanis familiarisChemicalsChemistryClinicalCyclic GMPDataDevelopmentDiabetic NeuropathiesDiagnosticDistalDoseDyesEffectivenessEventExcisionFluorescenceFundingGoalsGrantHandHistopathologyHumanImageImageryImpotenceIncontinenceInjectableInjection of therapeutic agentIntramuscularIntravenousInvestigational DrugsInvestigational New Drug ApplicationLeftLesionLinkLymph Node DissectionsMalignant - descriptorMalignant NeoplasmsMediatingMedical ImagingMethodsModelingNerveNerve Growth FactorsNervous System TraumaNeuronsNeurotrophic Tyrosine Kinase Receptor Type 1Nuclear AntigensOperative Surgical ProceduresPaintPeripheralPeripheral NervesPhasePilot ProjectsProteinsProtocols documentationRadical ProstatectomyRattusRecombinantsRiskRoboticsRouteSafetySideSiteSlideSmall Business Innovation Research GrantStaining methodStainsSurgeonSurgical incisionsSurgical marginsSyringesTestingTimeTissue SampleTissuesToxic effectTranslatingUrologistVial deviceVisualWorkacute toxicityafferent nerveaxonopathycGMP productioncancer recurrencecancer riskcancer surgerycohortcommercializationdermatomefunctional outcomesimage guidedimaging agentimprovedin vivoinnovationliquid formulationmalemalignant breast neoplasmmanmeetingsmenneurovascularnovelphase 1 studyphase 3 studypre-clinicalretrograde transportsafety studyspared nervesubcutaneoustooluptake
项目摘要
In 2015, about 130,000 men elected to undergo radical prostatectomies (RPs). Even with nerve-sparing,
incontinence and/or impotence can occur in up to 75% of cases. In our SBIR Phase I grant, we showed in vivo
Proof-of-Concept of “Nervelight,” a peripheral nerve imaging agent comprised of a Near InfraRed (NIR) dye,
Dyomics 800, attached to recombinant human Nerve Growth Factor. Nervelight may spare nerves at risk in
other cancer surgeries, i.e. lymph node dissection for breast cancer, or oncological parotidectomies.
Hypothesis. Our scientific hypothesis is that a single dose of peripherally administered Nervelight will localize
bilaterally to cavernous nerves at risk in RPs. Our commercial hypothesis is that we can translate this data into
a commercial medical imaging agent to aid nerve-sparing by showing that a single dose of Nervelight: (1) can
be visually detected in target nerves; (2) is safe in a GLP single dose acute toxicity study; and (3) can be
produced to cGMP supporting an Investigational New Drug (IND). We will test these hypotheses in these Aims:
Aim 1.1. We will confirm effectiveness by showing bilateral localization in cavernous nerves in adult,
male naïve rats after a single central injection in three pilot studies (n=90) to identify preferred injection site,
route of administration (sub-cutaneous or intra-muscular), and dose. Immediately after euthanization, using the
Fluobeam, we will collect a single image of neurovascular bundle from inside the incision. Using the approach
established in our SBIR Phase I, we will dissect left side target nerves to assess duration of effect in large
tissue samples. From right side target nerves we will confirm visual observations from Fluobeam that
Nervelight has localized to target nerves by comparing two sets of contiguous sections, one set stained with
nerve markers (neuronal nuclear antigen, NeuN; PGP 9.5), and the other set cryo-preserved for NIR imaging.
Aim 1.2. Using best site, route and dose from Aim 1.1, we will determine dose in naïve male adult rats
(n=240) at two dose cohorts, low from Aim 1.1 and high (10X low) over eight timepoints (n=6 per timepoint
group, both dose cohorts). We will analyze within- and between-group variances to statistical significance by
quantifying pixels in target nerves, and will assess fluorescence in a whole body distribution study.
Aim 2. We will assess safety per Guidance, with best route from Aim 1.1 and intravenous (IV) route, in
a GLP study of acute, single dose toxicity to statistical significance in rat (n=240) and dog (n=50).
Aim 3. We will complete a Chemistry, Manufacturing and Controls (CMC) Plan by developing protocols,
and bioanalytics for liquid formulation GMP product into hand-filled vials for use in commercial syringes.
Project Milestone. Upon funding, we will request a pre-IND meeting to review our nonclinical plan. Our Project
Milestone is to complete all nonclinical work to support and open an IND for a pivotal Phase 1 safety study
(n=20). We have the regulatory, clinical, and scientific team to conduct Phase III studies for commercialization.
2015年,约有13万名男性选择接受根治性前列腺切除术(RP)。即使是神经保护,
失禁和/或阳痿可发生在高达75%的病例中。在我们的SBIR第一阶段研究中,
“Nervelight”概念验证,一种由近红外(NIR)染料组成的外周神经成像剂,
Dyomics 800,附着于重组人神经生长因子。Nervelight可能会使处于危险中的神经免受伤害,
其他癌症手术,即乳腺癌淋巴结清扫术或肿瘤腮腺切除术。
假说.我们的科学假设是单剂量的神经之光
在RP中,双侧海绵体神经处于危险之中。我们的商业假设是,我们可以将这些数据转化为
一种商业医学成像剂,通过显示单剂量的Nervelight:(1)可以
在靶神经中目视检测到;(2)在GLP单次给药急性毒性研究中安全;(3)可以
按照cGMP生产,以支持研究性新药(IND)。我们将在这些目标中检验这些假设:
目标1.1。我们将通过显示成人海绵体神经的双侧定位来证实有效性,
在三项初步研究(n=90)中单次中枢注射后的雄性未处理大鼠,以确定首选注射部位,
给药途径(皮下或肌内)和剂量。安乐死后,立即使用
荧光束,我们将从切口内收集神经血管束的单一图像。使用该方法
在我们的SBIR第一阶段建立,我们将解剖左侧靶神经,以评估大范围的影响持续时间。
组织样本从右侧靶神经,我们将确认Fluobeam的目视观察结果,
Nervelight通过比较两组连续切片定位到目标神经,一组用
神经标记物(神经元核抗原,NeuN; PGP 9.5),另一组冷冻保存用于NIR成像。
目标1.2。使用目标1.1中的最佳部位、途径和剂量,我们将确定未处理雄性成年大鼠的剂量
(n=240)在两个剂量队列中,低于目标1.1和高于目标1.1(10倍低),超过8个时间点(每个时间点n=6
组,两个剂量队列)。我们将分析组内和组间方差的统计学显著性,
量化目标神经中的像素,并将在全身分布研究中评估荧光。
目标2.我们将根据指南评估安全性,目标1.1中的最佳途径和静脉(IV)途径,
大鼠(n=240)和犬(n=50)中急性、单次给药毒性的GLP研究,具有统计学显著性。
目标3.我们将通过制定方案来完成化学、生产和控制(CMC)计划,
和生物分析,用于将液体制剂GMP产品装入手动灌装的小瓶中,用于商业注射器。
项目里程碑。一旦获得资助,我们将要求召开IND前会议,以审查我们的非临床计划。我们的项目
里程碑是完成所有非临床工作,以支持和开放关键I期安全性研究的IND
(n=20)。我们拥有监管、临床和科学团队,可进行III期商业化研究。
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(0)
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{{ truncateString('STEPHEN B KAHL', 18)}}的其他基金
In vivo feasibility of a peripheral nerve imaging agent
周围神经成像剂的体内可行性
- 批准号:
8590174 - 财政年份:2013
- 资助金额:
$ 122.02万 - 项目类别:
BORONATED TUMOR SEEKING PORPHYRINS SYNTHESIS & TESTING
硼化肿瘤寻找卟啉的合成
- 批准号:
8363726 - 财政年份:2011
- 资助金额:
$ 122.02万 - 项目类别:
BORONATED TUMOR SEEKING PORPHYRINS SYNTHESIS & TESTING
硼化肿瘤寻找卟啉的合成
- 批准号:
8169720 - 财政年份:2010
- 资助金额:
$ 122.02万 - 项目类别:
BORONATED TUMOR SEEKING PORPHYRINS SYNTHESIS & TESTING
硼化肿瘤寻找卟啉的合成
- 批准号:
7957357 - 财政年份:2009
- 资助金额:
$ 122.02万 - 项目类别:
BORONATED TUMOR SEEKING PORPHYRINS SYNTHESIS & TESTING
硼化肿瘤寻找卟啉的合成
- 批准号:
7724150 - 财政年份:2008
- 资助金额:
$ 122.02万 - 项目类别:
BORONATED TUMOR SEEKING PORPHYRINS SYNTHESIS & TESTING
硼化肿瘤寻找卟啉的合成
- 批准号:
7601800 - 财政年份:2007
- 资助金额:
$ 122.02万 - 项目类别:
BORONATED TUMOR SEEKING PORPHYRINS SYNTHESIS & TESTING
硼化肿瘤寻找卟啉的合成
- 批准号:
7369019 - 财政年份:2006
- 资助金额:
$ 122.02万 - 项目类别:
BORONATED TUMOR SEEKING PORPHYRINS SYNTHESIS & TESTING
硼化肿瘤寻找卟啉的合成
- 批准号:
7180901 - 财政年份:2005
- 资助金额:
$ 122.02万 - 项目类别:
BORONATED TUMOR SEEKING PORPHYRINS SYNTHESIS & TESTING
硼化肿瘤寻找卟啉的合成
- 批准号:
6976588 - 财政年份:2004
- 资助金额:
$ 122.02万 - 项目类别:
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