TT-034(TT-034) - 药物靶点：RNA_专利_临床

概要

基本信息

药物类型

腺相关病毒基因治疗

别名

TT 034

靶点

RNA

作用方式

抑制剂

作用机制

RNA抑制剂、丙型肝炎病毒复制抑制剂、RNA干扰

治疗领域

感染消化系统疾病内分泌与代谢疾病

在研适应症-

非在研适应症

慢性丙型肝炎假性高钾血症Cardiff型

原研机构

Benitec Biopharma, Inc.

在研机构-

非在研机构

Tacere Therapeutics, Inc.

最高研发阶段无进展临床1/2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

2

项与 TT-034 相关的临床试验

NCT02315638

/ TerminatedN/A

Follow-up to Study Protocol B2801001, A Phase I/II, Open-Label Dose Escalation Study to Evaluate the Safety and Efficacy of Single Doses of TT-034 in Patients With Chronic Hepatitis C [CHC] Infection

This is a long-term safety follow-up protocol for subjects who received TT-034 under the B2801001 protocol and consists of monitoring for at least 4.5 years.

开始日期2014-11-01

申办/合作机构

Tacere Therapeutics, Inc.

NCT01899092

/ Completed临床1/2期

A Phase I,II Open-Label Dose Escalation Study to Evaluate the Safety and Efficacy of Single Doses of TT-034 for Subjects With Chronic Hepatitis C (CHC) Infection

The study is a first in man, dose escalation study that will measure the safety and efficacy of TT-034 in the treatment of patients with chronic hepatitis C. The study is divided into 5 dose levels. Subjects will be given a single dose delivered by IV infusion. The subjects will be monitored and the data analyzed. After a set time, between 6 and 10 weeks depending on the dose level, the next set of subjects will be dosed. The study drug is a gene therapy treatment that produces molecules that destroy the Hepatitis C virus (HCV) in infected cells. Once the study drug is given, it cannot be withdrawn. Additionally, once an individual receives a dose, he or she will not be able to receive a second dose, but will remain eligible to receive most other HCV treatments.

开始日期2014-01-01

申办/合作机构

Tacere Therapeutics, Inc.

100 项与 TT-034 相关的临床结果

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100 项与 TT-034 相关的转化医学

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100 项与 TT-034 相关的专利（医药）

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2

项与 TT-034 相关的文献（医药）

2017-12-01·Molecular therapy. Nucleic acids2区 · 医学

Profiling the Mismatch Tolerance of Argonaute 2 through Deep Sequencing of Sliced Polymorphic Viral RNAs

2区 · 医学

ArticleOA

作者: Ed Schwalbe ; Christopher K. Kortschak ; Louise Usher ; Pantazis I. Theotokis ; Sterghios A. Moschos

Low allelic and clonal variability among endogenous RNAi targets has focused mismatch tolerance studies to RNAi-active guide strands. However, the inherent genomic instability of RNA viruses such as hepatitis C virus (HCV) gives rise to quasi-species mutants within discrete clones: this facilitates mismatch tolerance studies from a target perspective. We recently quantified the slicing imprecision of Argonaute 2 using small interfering RNA (siRNA) analogs of the DNA-directed RNAi drug TT-034 and next-generation sequencing of 5' RNA ligase-mediated rapid amplification of cDNA ends (RACE-SEQ). Here, we present an open-source, customizable, and computationally light RACE-SEQ bioinformatic pipeline, describing adaptations that semiquantitatively report the impact of RNAi hybridization site mismatches from the target perspective. The analysis shows that Argonaute 2 has a substitution-specific, 3- to 5-log activity window between fully complementary targets and targets with mismatches across positions 10-11. It further focuses the endonucleotic Slicer imprecision around positions 13-17, demonstrating its dependence on guide strand central region complementarity, and potentiation by even a single mismatch. We further propose pharmacogenomics value in testing endogenous targets using recombinant replicon systems and RACE-SEQ to report the pharmacodynamics of sequence-specific oligonucleotide therapeutics against all possible polymorphisms in a population, in a minimally biased, patient-free manner.

2014-01-01·Molecular therapy. Nucleic acids2区 · 医学

Deep Sequencing Insights in Therapeutic shRNA Processing and siRNA Target Cleavage Precision

2区 · 医学

ArticleOA

作者: Kennedy, Michael ; Lavender, Helen ; Carter, Nikki ; Burden, Frances ; Denise, Hubert ; Stroud, Tim ; Fancy, Sally-Ann ; Lapthorn, Cris ; Corbau, Romu ; Kinloch, Ross ; Moschos, Sterghios A ; Suhy, David ; Sidders, Benjamin ; Perkins, Hannah

TT-034 (PF-05095808) is a recombinant adeno-associated virus serotype 8 (AAV8) agent expressing three short hairpin RNA (shRNA) pro-drugs that target the hepatitis C virus (HCV) RNA genome. The cytosolic enzyme Dicer cleaves each shRNA into multiple, potentially active small interfering RNA (siRNA) drugs. Using next-generation sequencing (NGS) to identify and characterize active shRNAs maturation products, we observed that each TT-034-encoded shRNA could be processed into as many as 95 separate siRNA strands. Few of these appeared active as determined by Sanger 5' RNA Ligase-Mediated Rapid Amplification of cDNA Ends (5-RACE) and through synthetic shRNA and siRNA analogue studies. Moreover, NGS scrutiny applied on 5-RACE products (RACE-seq) suggested that synthetic siRNAs could direct cleavage in not one, but up to five separate positions on targeted RNA, in a sequence-dependent manner. These data support an on-target mechanism of action for TT-034 without cytotoxicity and question the accepted precision of substrate processing by the key RNA interference (RNAi) enzymes Dicer and siRNA-induced silencing complex (siRISC).Molecular Therapy-Nucleic Acids (2014) 3, e145; doi:10.1038/mtna.2013.73; published online 4 February 2014.

1

项与 TT-034 相关的新闻（医药）

2015-04-07

·BioSpace

Benitec, Inc. Provides Update On TT-034 Trial

SYDNEY, April 7, 2015 /PRNewswire/ -- Benitec Biopharma (ASX:BLT; OTCPK:BTEBY), a biopharmaceutical company focused on providing potentially curative therapies with its proprietary gene-silencing technology called ddRNAi or "expressed RNAi," is pleased to advise that laboratory results from liver biopsies in the company's 'first in man', Phase I/IIa clinical trial of TT-034 for hepatitis C confirmed that the trial is proceeding according to expectations. TT-034 works by producing (in the liver) three silencing short hairpin RNAs (shRNAs), each responsible for targeting a different part of the hepatitis C virus' genome. The expression of the three shRNAs in patients' liver cells is thus an essential requirement for TT-034 to exert a clinical reduction of hepatitis C viral load. The most recent assay of the biopsies confirmed this expression occurred in all three patients dosed to date. These results were obtained from the biopsies of the first two patients in cohort 1 and the first patient in cohort 2. The second patient in cohort 2 has not yet been biopsied, and the third patient in cohort 2 is yet to be dosed due to a personal issue. In cohorts 1 and 2, the dose of TT-034 is sub-therapeutic and, therefore, the amount of shRNA produced will not result in reduction of hepatitis C viral load. Furthermore, to date there have been no treatment-related serious adverse effects (SAEs) in any of the four patients dosed. More detail on the TT-034 trial TT-034 is a ddRNAi-based therapeutic, designed to treat and potentially cure hepatitis C (HCV) with a single administration. TT-034 targets the hepatitis C viral RNA at three separate, highly conserved sites. As such it acts as a "triple therapy" even though it is a monotherapy, and minimises the ability of the virus to mutate and escape the therapy. Once it reaches the liver cells it enters the nucleus and produces three separate short hairpin RNAs continuously for the life time of the cell. Thus it has the potential to not only treat the existing HCV infection but to guard against reinfection for months to years without the need to re-treat. It has been extensively tested in pre-clinical in vivo studies and no adverse effects were seen at any therapeutic dose. However, as it is regulated as a gene therapy, the trial design is to primarily ensure that treatment with TT-034 is safe, hence the gradual dose escalation. About Benitec Biopharma Limited Benitec Biopharma Limited is an ASX-listed biotechnology company (ASX:BLT; OTC:BTEBY) which has developed a patented gene-silencing technology called ddRNAi or 'expressed RNAi'. Based in Sydney, Australia with labs in Hayward CA (USA) and collaborators and licensees around the world, the company is developing ddRNAi-based therapeutics for chronic and life-threatening human conditions including Hepatitis C and B, drug resistant lung cancer and wet age-related macular degeneration. Benitec has also licensed ddRNAi to other biopharmaceutical companies for applications including HIV/AIDS, Huntington's disease, chronic neuropathic pain and retinitis pigmentosa. For further information regarding Benitec and its activities, please contact the persons below, or visit the Benitec website at . CompanyInvestor relations (Australia)United StatesCarl Stubbings Chief Business Officer Tel: +61 (2) 9555 6986 Email: cstubbings@benitec.comKyahn Williamson Buchan Consulting Tel: 61 3 8866 1200 Email: kwilliamson@buchanwe.com.auTiberend Strategic Advisors, Inc. Joshua Drumm (Investors)Tel: +1 212-375-2664 Email: jdrumm@tiberend.com Andrew Mielach (Media)Tel: +1 212-375-2694 Email: amielach@tiberend.com To view the original version on PR Newswire, visit: SOURCE Benitec Biopharma Limited Help employers find you! Check out all the jobs and post your resume.

基因疗法

100 项与 TT-034 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
慢性丙型肝炎	临床2期	美国	Tacere Therapeutics, Inc.	2014-01-01
假性高钾血症Cardiff型	临床2期	美国	Tacere Therapeutics, Inc.	2014-01-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01899092 (ASGCT2016)	临床1/2期	慢性丙型肝炎	8	TT-034 at 4.00E10 vg/kg	廠網遞廠淵淵繭鏇願鹹(獵蓋鏇糧膚鹽構餘構鬱) = No long term TT-034 shedding has been detected in the urine, stool, semen, or sputum 繭顧遞衊醖壓獵鹽餘築 (鑰獵艱鑰襯淵窪鏇壓網 ) 更多	积极	2016-05-01
NCT01899092 (ASGCT2016)	临床1/2期	慢性丙型肝炎	8	TT-034 at 1.25E11 vg/kg		积极	2016-05-01
ASGCT2016	临床1/2期	-	-	TT-034	憲鬱繭窪膚構蓋襯構簾(齋衊顧簾鑰醖鏇淵獵鹽) = 糧醖觸選積鹹蓋憲襯餘艱衊醖醖顧餘構構構繭 (鏇網膚夢餘觸糧壓蓋鏇 ) 更多	积极	2016-05-01