Safety, Tolerability, and Pharmacokinetics of ARC-520 Injection, an RNA Interference-Based Therapeutic for the Treatment of Chronic Hepatitis B Virus Infection, in Healthy Volunteers

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Efficacy and cost-effectiveness of an outcall program to reduce carer burden and depression among carers of cancer patients (PROTECT) : rationale and design of a randomized controlled trial

Published: 6 January 2014BACKGROUND: Carers provide extended and often unrecognized support to people with cancer. The aim of this study is to test the hypothesis that excessive carer burden is modifiable through a telephone outcall intervention that includes supportive care, information and referral to appropriate psycho-social services. Secondary aims include estimation of changes in psychological health and quality of life. The study will determine whether the intervention reduces unmet needs among patient dyads. A formal economic program will also be conducted. METHODS/DESIGN: This study is a single-blind, multi-centre, randomized controlled trial to determine the efficacy and cost-efficacy of a telephone outcall program among carers of newly diagnosed cancer patients. A total of 230 carer/patient dyads will be recruited into the study; following written consent, carers will be randomly allocated to either the outcall intervention program (n = 115) or to a minimal outcall / attention control service (n = 115). Carer assessments will occur at baseline, at one and six months post-intervention. The primary outcome is change in carer burden; the secondary outcomes are change in carer depression, quality of life, health literacy and unmet needs. The trial patients will be assessed at baseline and one month post-intervention to determine depression levels and unmet needs. The economic analysis will include perspectives of both the health care sector and broader society and comprise a cost-consequences analysis where all outcomes will be compared to costs. DISCUSSION: This study will contribute to our understanding on the potential impact of a telephone outcall program on carer burden and provide new evidence on an approach for improving the wellbeing of carers.Patricia M Livingston, Richard H Osborne, Mari Botti, Cathy Mihalopoulos, Sean McGuigan, Leila Heckel, Kate Gunn, Jacquie Chirgwin, David M Ashley and Melinda William

Losartan Decreases p42/44 MAPK Signaling and Preserves LZ+ MYPT1 Expression

Heart failure is associated with impairment in nitric oxide (NO) mediated vasodilatation, which has been demonstrated to result from a reduction in the relative expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase. Further, captopril preserves normal LZ+ MYPT1 expression, the sensitivity to cGMP-mediated vasodilatation and modulates the expression of genes in the p42/44 MAPK and p38 MAPK signaling cascades. This study tests whether angiotensin receptor blockade (ARB) with losartan decreases p42/44 MAPK or p38 MAPK signaling and preserves LZ+ MYPT1 expression in a rat infarct model of heart failure. In aortic smooth muscle, p42/44 MAPK activation increases and LZ+ MYPT1 expression falls after LAD ligation. Losartan treatment decreases the activation of p42/44 MAPK to the uninfarcted control level and preserves normal LZ+ MYPT1 expression. The expression and activation of p38 MAPK, however, is low and does not change following LAD ligation or with losartan therapy. These data suggest that either reducing or blocking the effects of circulating angiotensin II, both decreases the activation of the p42/44 MAPK signaling cascade and preserves LZ+ MYPT1 expression. Thus, the ability of ACE-inhibitors and ARBs to modulate the vascular phenotype, to preserve normal flow mediated vasodilatation may explain the beneficial effects of these drugs compared to other forms of afterload reduction in the treatment of heart failure

A Wide Extent of Inter-Strain Diversity in Virulent and Vaccine Strains of Alphaherpesviruses

Alphaherpesviruses are widespread in the human population, and include herpes simplex virus 1 (HSV-1) and 2, and varicella zoster virus (VZV). These viral pathogens cause epithelial lesions, and then infect the nervous system to cause lifelong latency, reactivation, and spread. A related veterinary herpesvirus, pseudorabies (PRV), causes similar disease in livestock that result in significant economic losses. Vaccines developed for VZV and PRV serve as useful models for the development of an HSV-1 vaccine. We present full genome sequence comparisons of the PRV vaccine strain Bartha, and two virulent PRV isolates, Kaplan and Becker. These genome sequences were determined by high-throughput sequencing and assembly, and present new insights into the attenuation of a mammalian alphaherpesvirus vaccine strain. We find many previously unknown coding differences between PRV Bartha and the virulent strains, including changes to the fusion proteins gH and gB, and over forty other viral proteins. Inter-strain variation in PRV protein sequences is much closer to levels previously observed for HSV-1 than for the highly stable VZV proteome. Almost 20% of the PRV genome contains tandem short sequence repeats (SSRs), a class of nucleic acids motifs whose length-variation has been associated with changes in DNA binding site efficiency, transcriptional regulation, and protein interactions. We find SSRs throughout the herpesvirus family, and provide the first global characterization of SSRs in viruses, both within and between strains. We find SSR length variation between different isolates of PRV and HSV-1, which may provide a new mechanism for phenotypic variation between strains. Finally, we detected a small number of polymorphic bases within each plaque-purified PRV strain, and we characterize the effect of passage and plaque-purification on these polymorphisms. These data add to growing evidence that even plaque-purified stocks of stable DNA viruses exhibit limited sequence heterogeneity, which likely seeds future strain evolution

Chronic hepatitis B: Virology, natural history, current management and a glimpse at future opportunities

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Effective inhibition of cccDNA derived mRNA/viral antigens and tolerability with ARC-520

This journal suppl. entitled: Conference Abstracts: 25th Annual Conference of APASL, February 20–24, 2016, Tokyo, JapanOral Presentation: O-103BACKGROUND: ARC-520, an RNA interference drug, targets ccc-DNA-derived mRNA in chronic hepatitis B patients (CHB); herein we report tolerability/activity in normal healthy volunteers (NHV) and CHB. METHODS: 54 NHV (36 ARC-520, 18 placebo) and 58 CHB (48 ARC-520, 10 placebo) were included. At entry, 32 of 38 HBeAg-neg and 14 of 20 HBeAg-pos CHB had taken entecavir for mean 5 years (range 2–8) and continued throughout the study. NHV and CHB received 0.01 to 4 mg/kg IV ARC-520 or placebo; CHB had viral parameters measured. RESULTS: ARC-520 therapy was well tolerated—67 % NHV (placebo or ARC-520) and 23 % CHB reported a mild or moderate adverse event (AE) with no AE rated serious, severe, or causing withdrawal. A modest occurrence of abnormal laboratory tests was observed. Two NHV showed moderate hypersensitivity reactions (urticarial rash, flushing) during infusion. After addition of pretreatment oral antihistamine, no hypersensitivity reactions were seen. ARC-520 reduced viral antigens with qHBeAg best reduction of 1.7 log (mean max 1.2 log) following a single 4 mg/kg dose. In treatment-naïve CHB, best qHBsAg reductions of 1.9 log (mean max 1.3 log) in HBeAg-pos and 0.8 log (mean max 0.3 log) in HBeAg-neg were observed. Similar reductions in HB core related antigen were observed where measurable. CONCLUSIONS: (1) ARC-520 effectively inhibited cccDNA-derived mRNA with protein reductions up to 1.9 logs (99 %) (2) ARC-520 was well tolerated and hypersensitivity symptoms were controlled by antihistamine pretreatment. (3) This is the first time direct antiviral effects on HBeAg and HBsAg have been demonstrated

Differential reductions in viral antigens expressed from cccDNAVS integrated DNA in treatment naïve HBeAg positive and negative patients with chronic HBV after RNA interference therapy with ARC-520

Poster Presentations: Viral hepatitis: Hepatitis B & D – experimental: no. THU-193BACKGROUND AND AIMS: ARC-520 (ARC), a RNA interference drug, targets cccDNA-derived mRNA in chronic hepatitis B patients (CHB); we previously reported safety and activity of ARC in entecavir (ETV) experienced CHB and preliminary results in treatment-naïve CHB enrolled in a single dose phase 2a study; herein we report full safety and activity against multiple viral antigens and DNA in naïve CHB