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 Once the study drug is given, it cannot be withdrawn.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.

Start Date01 Jan 2014

Sponsor / Collaborator

Tacere Therapeutics, Inc.

100 Clinical Results associated with TT-034

100 Translational Medicine associated with TT-034

100 Patents (Medical) associated with TT-034

Literatures (Medical) associated with TT-034

01 Dec 2017·Molecular therapy. Nucleic acidsQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

Author: Ed Schwalbe ; Christopher K. Kortschak ; Pantazis I. Theotokis ; Louise Usher ; 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.

01 Jan 2014·Molecular therapy. Nucleic acidsQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

Author: 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 ; Perkins, Hannah ; Sidders, Benjamin

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.

01 Apr 2011·MMWR. Morbidity and mortality weekly report

Tetanus surveillance --- United States, 2001-2008.

Article

Tetanus is a life-threatening but preventable disease caused by the toxin of Clostridium tetani, a ubiquitous, spore-forming, gram-positive bacillus found in high concentrations in soil and animal excrement. Reported tetanus cases have declined >95%, and deaths from tetanus have declined >99% in the United States since 1947, when the disease became reportable nationally. To update a previous report and to determine the populations at greatest risk for the disease, CDC analyzed cases reported to the National Notifiable Diseases Surveillance System (NNDSS) during 2001--2008. This report summarizes the results of that analysis, which found that 233 tetanus cases were reported during 2001--2008; among the 197 cases with known outcomes, the case-fatality rate was 13.2%. Average annual incidence during that period was 0.10 per 1 million population overall and 0.23 among persons aged ≥65 years. Incidence among Hispanics was nearly twice that among non-Hispanics, a difference accounted for by 16 cases among Hispanic injection drug users (IDUs). Among the 92 patients for whom tetanus toxoid-containing (TT) vaccination status was available, 37 (40.2%) had received no doses of TT vaccine. Thirty (15.4%) of 195 patients had diabetes, and 27 (15.3%) of 176 were IDUs. Of 51 patients with an acute wound and a surveillance report complete enough to evaluate tetanus prophylaxis, 49 (96.1%) had not received appropriate prophylaxis. Tetanus remains a rare but life-threatening disease in the United States. Health-care providers should ensure up-to-date TT vaccination of all their patients, especially persons aged ≥65 years, persons with diabetes, and injection drug users.

News (Medical) associated with TT-034

07 Apr 2015

·www.biospace.com

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.

Gene Therapy

100 Deals associated with TT-034

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis C, Chronic	Phase 2	US	Tacere Therapeutics, Inc.	01 Jan 2014
Pseudohyperkalemia Cardiff	Phase 2	US	Tacere Therapeutics, Inc.	01 Jan 2014
Hepatitis C	Phase 2	-	Benitec Biopharma, Inc.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Phase I/IIa Study of TT-034 (ASGCT2016)	Phase 1/2	Hepatitis C, Chronic	8	TT-034 at 4.00E10 vg/kg	lxxkjrrsrf(nopzkitthz) = No long term TT-034 shedding has been detected in the urine, stool, semen, or sputum rsymefndim (blesoxseju ) View more	Positive	01 May 2016
				TT-034 at 1.25E11 vg/kg

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