Novel IL-23 inhibitor for the treatment of alcohol associated liver disease
用于治疗酒精相关性肝病的新型 IL-23 抑制剂
基本信息
- 批准号:10266186
- 负责人:
- 金额:$ 78.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-20 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAdverse effectsAffectAlcoholic HepatitisAlcoholic steatohepatitisAlcoholsAnti-Inflammatory AgentsAntibodiesAntibody TherapyAutoimmuneBiologicalBiological MarkersBlocking AntibodiesCause of DeathCellsCirrhosisClinicClinicalClinical ResearchClinical TrialsCollagen Type IDoseDrug KineticsEnrollmentFDA approvedFamilyFatty LiverFatty acid glycerol estersFibrosisFunctional disorderFundingFutureHepaticHepatocyteHumanInflammationInflammatoryInterleukin-1Interleukin-17Interleukin-6InterleukinsLiverLiver FailureLiver FibrosisLiver diseasesMagnetic Resonance ElastographyMagnetic Resonance ImagingMaintenanceMalignant NeoplasmsMediatingMediator of activation proteinMeta-AnalysisMonoclonal AntibodiesMusMyelogenousMyeloid CellsMyofibroblastOrganParticipantPatient RecruitmentsPatientsPharmaceutical PreparationsPharmacodynamicsPharmacologyPhasePhase I Clinical TrialsPopulationPrimary carcinoma of the liver cellsPrincipal InvestigatorProductionProtonsPsoriasisPublishingRecording of previous eventsRegimenResearch InfrastructureRoleSafetySamplingScheduleSerumSerum MarkersSeverity of illnessSignal TransductionSteatohepatitisTNF geneTestingTherapeuticTranslatingUnited StatesWorkalcohol abuse therapyalcohol use disorderbasechronic liver diseaseclinical developmentclinical trial analysiscommercializationcomplement C3 precursorcytokinedensityearly detection biomarkersfirst-in-humanimprovedinhibitor/antagonistinterleukin-23lipid biosynthesisliver inflammationliver injurymRNA Expressionmedication safetymembernovelpharmacokinetics and pharmacodynamicsphase I trialphase II trialphase III trialpre-clinicalpreclinical studypreventreceptorresponsesafety testingsuccesstreatment responsetrial design
项目摘要
PROJECT SUMMARY
Alcohol-associated liver disease (ALD) is a major cause of cirrhosis and liver failure, and the 12th leading cause
of death in adult patients in the United States. ALD progresses from fatty liver, to alcoholic steatohepatitis,
fibrosis/cirrhosis and hepatocellular carcinoma (HCC). Pharmacological therapies for ALD are urgently needed
as FDA-approved medications are currently available. In published work, we have demonstrated that the
proinflammatory cytokine interleukin-17A (IL-17A) is a critical mediator of alcohol-related liver damage in both
humans and mice. IL-17A is mainly produced by CD4+ Th17 cells. IL-17A production is regulated by IL-23, a
cytokine that promotes the maintenance, survival, and proliferation of Th17 cells. Our preclinical studies clearly
demonstrate that blocking IL-17 signaling with an anti-IL-23 antibody-based treatment significantly improves
alcohol-related liver fibrosis, cirrhosis, and cancer. Here, we evaluate whether the IL-23 blocking antibody
guselkumab effectively reduces serum levels of IL-23 and IL-17A as well as the number of circulating Th17
cells48,49 in samples from treated patients from our Phase I clinical trial. This Phase 1 trial will enroll adult
participants who have a history of moderate to severe alcohol use disorder (AUD) along with documented clinical
evidence of chronic liver disease due to alcohol but no evidence of cirrhosis or severe hepatic dysfunction or
alcoholic hepatitis. It will follow a standard 3+3 Phase I dose escalation trial design with a maximum of 24
subjects. We will assess the drug’s safety, pharmacokinetics, and pharmacodynamics in a population that meets
criteria for AUD and early signs of end-organ-damage to the liver, as made evident and quantified by advanced
non-invasive MRI based biomarkers of liver fat and fibrosis. We will assess biomarkers for both guselkumab
target engagement as well as biomarkers for early treatment response (ALT, ELF, Pro-C3).
Aim 1: Assess safety and tolerability of guselkumab (anti-IL-23 monoclonal antibody) in a Phase 1 dose
escalation study in patients with alcohol use disorder and alcohol-associated liver disease.
Aim 2: Assess the pharmacokinetics of guselkumab in patients with alcohol-associated liver disease.
Aim 3: Assess pharmacodynamics of guselkumab target engagement and biomarkers of early treatment
response.
项目总结
酒精相关性肝病(ALD)是导致肝硬变和肝功能衰竭的主要原因,也是第12位主要原因
美国成年患者的死亡人数。ALD从脂肪肝发展到酒精性脂肪性肝炎,
肝纤维化/肝硬变和肝细胞癌。ALD的药物治疗亟待解决
因为FDA批准的药物目前是可用的。在已发表的作品中,我们已经证明了
促炎细胞因子白介素17A(IL-17A)是酒精性肝损伤的关键介质
人类和老鼠。IL-17A主要由CD4+Th17细胞产生。IL-17A的产生受IL-23,一种
促进Th17细胞维持、存活和增殖的细胞因子。我们的临床前研究很清楚
证明用基于IL-23抗体的抗IL-17治疗阻断IL-17信号显著改善
与酒精有关的肝纤维化、肝硬变和癌症。在这里,我们评估IL-23封闭抗体是否
Guselkumab有效降低血清IL-23、IL-17A水平及循环Th17
在我们I期临床试验的治疗患者的样本中有48,49个细胞。这一阶段的试验将招收成人
有中到重度酒精使用障碍(AUD)病史并有记录的临床记录的参与者
有因酒精引起的慢性肝病的证据,但没有证据表明有肝硬变或严重肝功能障碍或
酒精性肝炎。它将遵循标准的3+3 I期剂量递增试验设计,最多24
研究对象。我们将在符合以下条件的人群中评估该药物的安全性、药代动力学和药效学
AUD的标准和肝脏终末器官损害的早期迹象,由Advanced
基于非侵入性磁共振成像的肝脏脂肪和纤维化生物标志物。我们将评估Guselkumab的生物标记物
靶参与以及早期治疗反应的生物标志物(ALT、ELF、Pro-C3)。
目的1:评价Guselkumab(抗IL-23单抗)第1期剂量的安全性和耐受性
酒精使用障碍和酒精相关性肝病患者的升级研究。
目的2:评价古赛库单抗在酒精性肝病患者体内的药代动力学。
目的3:评估Guselkumab的药效学和早期治疗的生物标志物
回应。
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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Tatiana Kisseleva其他文献
Tatiana Kisseleva的其他文献
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{{ truncateString('Tatiana Kisseleva', 18)}}的其他基金
The role of IL-17 signaling in alcohol-induced HCC
IL-17 信号在酒精诱导的 HCC 中的作用
- 批准号:
10463697 - 财政年份:2021
- 资助金额:
$ 78.14万 - 项目类别:
The role of IL-17 signaling in alcohol-induced HCC
IL-17 信号在酒精诱导的 HCC 中的作用
- 批准号:
10299157 - 财政年份:2021
- 资助金额:
$ 78.14万 - 项目类别:
Novel IL-23 inhibitor for the treatment of alcohol associated liver disease
用于治疗酒精相关性肝病的新型 IL-23 抑制剂
- 批准号:
10482350 - 财政年份:2020
- 资助金额:
$ 78.14万 - 项目类别:
The Role of Portal Fibroblasts in Cholestatic Liver Fibrosis
门静脉成纤维细胞在胆汁淤积性肝纤维化中的作用
- 批准号:
10441586 - 财政年份:2014
- 资助金额:
$ 78.14万 - 项目类别:
Inactivation of Hepatic Stellate Cells During Reversal of Liver Fibrosis
肝纤维化逆转过程中肝星状细胞失活
- 批准号:
8694267 - 财政年份:2014
- 资助金额:
$ 78.14万 - 项目类别:
The Role of Portal Fibroblasts in Cholestatic Liver Fibrosis
门静脉成纤维细胞在胆汁淤积性肝纤维化中的作用
- 批准号:
10312314 - 财政年份:2014
- 资助金额:
$ 78.14万 - 项目类别:
Epigenetics of human Hepatic Stellate Cells (HSCs) in NASH
NASH 中人肝星状细胞 (HSC) 的表观遗传学
- 批准号:
10367096 - 财政年份:2014
- 资助金额:
$ 78.14万 - 项目类别:
Inactivation of Hepatic Stellate Cells During Reversal of Liver Fibrosis
肝纤维化逆转过程中肝星状细胞失活
- 批准号:
9271180 - 财政年份:2014
- 资助金额:
$ 78.14万 - 项目类别:
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