IND, FIH study and 3-month tox for PTI-125, a novel therapeutic for Alzheimer's disease
PTI-125(一种阿尔茨海默病的新型疗法)的 IND、FIH 研究和 3 个月毒性
基本信息
- 批准号:9337906
- 负责人:
- 金额:$ 22.5万
- 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:2017-06-01 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdverse eventAffinityAgeAlzheimer&aposs DiseaseAmyloidAutopsyBindingBiodistributionBiological AvailabilityBloodBlood PressureBrainBrain DiseasesCanis familiarisChemistryChronicClinicalClinical ResearchClinical TrialsCognitionComplexDataDiseaseDocumentationDoseDouble-Blind MethodDrug or chemical Tissue DistributionElectrocardiogramEmployeeEnrollmentFemaleFrequenciesFunctional disorderGoalsHeart RateHematologyHepatocyteHumanHuman ResourcesImpairmentInflammationInflammatoryInfusion proceduresInsulin ReceptorMemoryMetabolismMusN-Methyl-D-Aspartate ReceptorsNerve DegenerationNeurofibrillary TanglesNicotinic ReceptorsOralPathologicPatientsPharmaceutical PreparationsPharmacology StudyPhasePhase I Clinical TrialsPhenotypePlacebosRattusReceptor SignalingRecoveryRecruitment ActivityReportingSafetyScaffolding ProteinSignal TransductionSiteSmall Business Innovation Research GrantSynaptic plasticityTLR4 geneTestingTherapeuticTimeToxic effectToxicologyUrinalysisUrineWorkabeta toxicityagedalpha-bungarotoxin receptorbasebrain tissueclinical developmentclinical lotcytokinedesignefficacy studyexposed human populationfilaminhealthy volunteerhyperphosphorylated taumalemetabolic profilemouse modelneuroinflammationneuronal survivalnovelnovel strategiesnovel therapeuticspreclinical efficacypreclinical studypreventreceptorrespiratorysafety studysmall moleculetau Proteinsvolunteer
项目摘要
7. Project Summary/Abstract
PTI-125 is a novel compound with a novel target, designed to treat and slow the progression of
Alzheimer's disease (AD). PTI-125 binds with femtomolar affinity to a particular site on filamin A
(FLNA), a scaffolding protein we recently demonstrated is critical to beta amyloid's toxicity. Beta
amyloid1-42 (Aβ42) exerts its toxic effects by hijacking the α7-nicotinic acetylcholine receptor
(α7nAChR) and signaling via this receptor to hyperphosphorylate tau. In addition to disrupting
normal function of α7nAChR and tau, this toxic signaling leads to the signature tangles and
plaques found in brains of AD patients. We have shown that this toxic signaling of Aβ42 requires
FLNA recruitment to α7nAChR. The recruited FLNA stabilizes Aβ42-α7nAChR complexes
(promoting a femtomolar interaction) to enable further Aβ42 piling and the toxic signaling that leads
to eventual neurodegeneration. PTI-125 binding to FLNA prevents or reverses the FLNA –
α7nAChR association and Aβ42's tight binding and subsequent toxic effects. Aβ42 also impairs the
function of two other receptors that are pivotal to neuronal survival, cognition and memory, the
NMDA receptor and the insulin receptor. By binding to FLNA, PTI-125 restores normal function
of all three receptors. PTI-125 also disrupts a similar association of FLNA with toll-like receptor-4
(TLR-4), a receptor responsible for releasing inflammatory cytokines. Hence, PTI-125 has a
second function of blocking the inflammation noted in AD brain. Preclinical efficacy was
demonstrated in an acute ICV Aβ42 infusion mouse model, in normal aged mice, and most
importantly, in human postmortem AD brain tissue. The effective concentration in postmortem
human brain is as low as 1 pM. PTI-125 has completed and cleared all IND-enabling studies, and
the GMP manufacture and Phase I clinical drug supply is underway. The 28-day toxicity studies
demonstrated a 50-fold safety margin between the NOAEL (no observable adverse event level)
in rat and a 15-fold safety margin in dog compared to the efficacious doses in both mouse efficacy
studies. PTI-125 is rapidly absorbed and eliminated with nearly 100% oral bioavailability, dose
proportional PK and no accumulation. Metabolic profiling showed minimal metabolism across
species. In Phase I of this Fast-track proposal, we will file an IND. With a successful IND
submission, we will initiate Phase II: a single ascending dose (SAD) study in healthy volunteers,
followed by 3-month toxicity studies in two species. Further work outside this proposal included a
SAD clinical study in AD patients, which will determine the dosing frequency for a multi-dose PK
and safety study in AD patients. The 3-month toxicity studies will support clinical trials of 3-month
duration but are also needed to determine doses for the chronic toxicity studies needed to support
clinical trials of any duration as well as an NDA.
7.项目摘要/摘要
PTI-125是一种具有新靶点的新型化合物,旨在治疗和减缓癌症的进展。
阿尔茨海默病(AD)。PTI-125与细丝蛋白A上的特定位点结合
我们最近证明了一种支架蛋白(FLNA),它对β淀粉样蛋白的毒性至关重要。测试版
淀粉样蛋白1-42(Aβ42)通过劫持α7-烟碱型乙酰胆碱受体发挥毒性作用
(α7nAChR),并通过该受体发出信号过度磷酸化tau。除了扰乱
α7nAChR和tau的正常功能,这种有毒的信号导致签名缠结和
阿尔茨海默病患者大脑中发现的斑块。我们已经证明,Aβ42的这种有毒信号需要
α7nAChR.募集的Flna稳定Aβ42-α7nAChR复合体
(促进毫微子分子相互作用),以实现进一步的Aβ42堆积和导致
最终导致神经退化。PTI-125与Fla结合可阻止或逆转Flna-
α7nAChR结合和Aβ42‘S紧密结合及随后的毒性效应。β42还会损害
对神经元存活、认知和记忆至关重要的另外两个受体的功能,
NMDA受体和胰岛素受体。通过与FLNA结合,PTI-125恢复正常功能
所有三种受体的。PTI-125也破坏了FLNA与Toll样受体-4的类似联系
(TLR-4),一种负责释放炎症细胞因子的受体。因此,PTI-125具有
阻断阿尔茨海默病脑内炎症的第二功能。临床前疗效是
在急性ICV Aβ42输注小鼠模型中显示,在正常老年小鼠和大多数
重要的是,在人类死后阿尔茨海默病的脑组织中。尸检中的有效浓度
人脑低至下午1点PTI-125已完成并通过了所有支持IND的研究,以及
GMP的生产和一期临床药物供应正在进行中。28天的毒性研究
NOAEL之间的安全裕度为50倍(没有可观察到的不良事件水平)
在大鼠身上和狗身上的安全边际是有效剂量的15倍
学习。PTI-125被迅速吸收和消除,几乎100%的口服生物利用度,剂量
成比例的PK和无积累。新陈代谢图谱显示
物种。在此快速通道提案的第一阶段,我们将提交IND。拥有成功的IND
提交,我们将启动第二阶段:健康志愿者的单次递增剂量(SAD)研究,
随后对两个物种进行了为期3个月的毒性研究。这项提案之外的进一步工作包括
AD患者的SAD临床研究,将确定多剂量PK的剂量频率
以及AD患者的安全性研究。为期3个月的毒性研究将支持为期3个月的临床试验。
持续时间,但也需要确定慢性毒性研究所需的剂量
任何持续时间的临床试验以及保密协议。
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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Lindsay H Burns其他文献
Lindsay H Burns的其他文献
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{{ truncateString('Lindsay H Burns', 18)}}的其他基金
Food Effect study and drug supply scale-up for PTI-125
PTI-125 的食物效应研究和药物供应规模扩大
- 批准号:
10216906 - 财政年份:2021
- 资助金额:
$ 22.5万 - 项目类别:
Increasing size of Phase 2b clinical trial to 60 patients
2b 期临床试验规模扩大至 60 名患者
- 批准号:
10018305 - 财政年份:2018
- 资助金额:
$ 22.5万 - 项目类别:
Development of PTI-125-DX, a blood-based diagnostic for Alzheimer's disease
开发阿尔茨海默病的血液诊断剂 PTI-125-DX
- 批准号:
9758123 - 财政年份:2018
- 资助金额:
$ 22.5万 - 项目类别:
Solid oral dosage form and chronic tox for PTI-125
PTI-125的固体口服剂型和慢性毒性
- 批准号:
9624887 - 财政年份:2017
- 资助金额:
$ 22.5万 - 项目类别:
Additional bioanalytical, dose analysis and DSMB costs for PTI-125 development
PTI-125 开发的额外生物分析、剂量分析和 DSMB 成本
- 批准号:
9524402 - 财政年份:2017
- 资助金额:
$ 22.5万 - 项目类别:
IND, FIH study and 3-month tox for PTI-125, a novel therapeutic for Alzheimer's disease
PTI-125(一种阿尔茨海默病的新型疗法)的 IND、FIH 研究和 3 个月毒性
- 批准号:
9541054 - 财政年份:2017
- 资助金额:
$ 22.5万 - 项目类别:
IND- and NDA-enabling toxicology studies for PTI-125, a novel small molecule for Alzheimer's disease
PTI-125(一种治疗阿尔茨海默病的新型小分子)的 IND 和 NDA 毒理学研究
- 批准号:
9186714 - 财政年份:2015
- 资助金额:
$ 22.5万 - 项目类别:
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