Second-generation direct-acting-antiviral hepatitis C virus treatment: Efficacy, safety, and predictors of SVR12

World J Gastroenterol. Sep 21, 2016; 22(35): 8050-8059
Published online Sep 21, 2016. doi: 10.3748/WJG.v22.i35.8050

Second-generation direct-acting-antiviral hepatitis C virus treatment: Efficacy, safety, and predictors of SVR12

Christoph R Werner, Julia M Schwarz, Daniel P Egetemeyr, Robert Beck, Nisar P Malek, Ulrich M Lauer, Christoph P Berg

Abstract
AIM
To gather data on the antiviral efficacy and safety of second generation direct acting antiviral (DAA) treatment with respect to sustained virological response (SVR) 12 wk after conclusion of treatment, and to determine predictors of SVR12 in this setting.

METHODS
Two hundred and sixty patients treated with SOF combination partners PR (n = 51), R (n = 10), SMV (n = 30), DCV (n = 81), LDV (n = 73), or 3D (n = 15). 144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were post-liver transplantation patients. 194/260 had HCV GT1, 44/260 HCV GT3.

RESULTS
Two hundred and forty/256 (93.7%) patients achieved SVR12 (mITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/nL, 88% post-liver transplantation, 95% for GT1a, 93% for GT1b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10 (P < 0.0001), liver cirrhosis (P = 0.005) at baseline. In Interferon-free treatment GT3 had significantly lower SVR rates than GT1 (P = 0.016). Side effects were mild.

CONCLUSION
Excellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into “real-world”. Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/nL and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.

Key Words: Sofosbuvir, Simeprevir, Ledipasvir, Hepatitis C, Liver transplant, Sustained virological response, Liver cirrhosis, Side effects, Resistance, Daclatasvir

Core tip: From 2014 on the second wave of direct acting antiviral agents was available for treatment of chronic hepatitis C infection. Due to the more heterogeneous character of patients in the “real world”, the therapeutic performance of these new drugs outside randomized clinical trials is of interest. Therefore, in this monocentric retrospective cohort study, we analyzed the efficacy, safety, and predictors of sustained virological response 12 for treatment with combinations of second generation direct acting antivirals in a “real-world” setting.

DISCUSSION ONLY

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This “real-world” monocentric retrospective cohort study analyzing safety, efficacy, and predictors of SVR12 of second generation DAA treatment shows impressive overall SVR rates (93.7%).

Due to the relatively small number of patients and the retrospective character of this study a comparison between subgroups according to DAA combination partners is only of limited significance.

Furthermore, due to the lesser tolerability and presumed lower activity of SOF/PR in patients with advanced liver disease, this treatment a priori was reserved in our hands to patients showing up with a well-compensated liver function only.

The results in our heterogeneous cohort, containing meaningful fractions of hard-to-treat patients (liver cirrhosis, portal hypertension, post-liver transplantation) are similar to SVR rates of so far published study trials: our cohort of PR or R co-treated patients achieved a SVR rate of 93%, while in the NEUTRINO trial the cohort treated with SOF/PR achieved a SVR rate in previously untreated patients of 90%[19], and the VA-real world cohort achieved SVR12 in 66.8%-79%[20].

In other “real-world” analyses with SMV ± R as combination partners of SOF, SVR rates of 74.1%-84.2% were achieved[20-22]. In the OPTIMIST study, a phase III trial, a SVR12 rate of 97% in non-cirrhotic patients[23], while in the OPTIMIST-2 study treating cirrhotic patients with SOF, SMV ± R, SVR 12 in 83% of patients was achieved[24]. However, in our cohort, with more than half of patients being patients with liver cirrhosis, we achieved a SVR rate of 93% with this combination of drugs.

For patients with SOF, DCV ± R as combination partners, SVR rates of 86%-93% have been reported[25]. In our cohort, we were in line with those results and could achieve a SVR rate of 92%, including two patients with recurrent cholestatic Hepatitis C post-liver transplantation, one of those being a non-responder to a prior Telaprevir triple therapy being undertaken post-liver transplantation, and both decompensated at the beginning of treatment.

In previously treated and untreated patients with HCV, a combination of LDV ± R, and SOF led to SVR rates of 94%-99%[26-28], which is in line with results of our cohort, in which we could register a SVR12 rate of 94%, while in another real-world analysis, SVR rates of 91.3%-92% were achieved[29].

For our small group of 3D regimen-receiving patients, we could achieve SVR in 100%, while in the Phase III trials SVR rates of 91.8%-99.5% were observed[30,31].

Thus, altogether, favorable SVR rates achieved in the randomized controlled clinical trials could be translated into the “real-world”, and importantly, in our cohort; even extra hard-to-treat groups of patients exhibited favorable treatment outcomes (SVR12 post-liver transplantation: 88%, SVR12 in cirrhotic patients with platelets < 100/nL: 82%), which exceed results with former treatment options by far[15,32].

Nevertheless, patients with liver cirrhosis show significantly lower response rates (87% with liver cirrhosis, 97% without; P = 0.005), and especially those with advanced portal hypertension (platelets < 100/nL), or high MELD score (≥ 10) show significantly lower SVR12 rates than patients without (P < 0.0001, uni- and multivariate analysis). These findings were also observed in other real world studies with low platelets, low albumin and liver cirrhosis as negative predictors of SVR in larger cohorts[21,33,34]. Thus, this subgroup of patients still resembles a group of patients in the “catch 22”-situation of being in the greatest need of treatment while showing the lowest response rates. Moreover, the whole drug class of HCV protease inhibitors (represented by SMV, and Paritaprevir/r) is not recommendeded for those patients (CTP B “plus”) due to hepatotoxicity. Therefore, new strategies are needed to tackle this problem, e.g., by implementation of screening programs to identify patients infected with HCV at an early stage of their liver disease, and more importantly by development of more potent agents in the near future. However, 4 patients were lost in our cohort. Even if not associated with anti-HCV medication, this emphasizes, that treatment of patients with advanced liver disease should remain in the hands of experienced tertiary centers even in times of “easy” treatment with second generation DAA.

In our cohort, results of early viral kinetics had no impact on prediction of SVR12, thus costly “in-between” measurements of HCV viral load possibly are expendable.

Previous treatment with PR may not play a role any more in treatment decisions, as in our cohort previous treatment was not identified as a negative predictor of SVR, as it was in the HCV-TARGET cohort[21].

Most probably due to the favorable tolerability and low-toxicity profile of second generation DAA, and the omission of pegylated Interferon, now also senior patients benefit from SOF-based DAA treatment on the same scale as younger patients do[21].

Another subgroup of patients in need of further research efforts seems to be the one with GT3: Even though we could achieve a favorable overall SVR rate of 90%, at least in IFN-free treatment regimens, the SVR rates in a “per-protocol” analysis are significantly lower in GT3 patients than in GT1 (80% in GT3, 98% in GT1, respectively, P = 0.016; univariate analysis), again with a special negative focus on patients with GT3 and concomitant advanced liver disease. Moreover, means are limited with respect to treatment of GT3 due to the insufficient antiviral activity of protease- and NS5A-inhibitors (except DCV) in this GT. However, new pangenotypic NS5A inhibitors like Velpatasvir or upcoming new pangenotypic protease inhibitors hopefully close that gap in the near future.

However, since DAA treatment forms RAVs in the viriom of patients, pretreatment with DAA of any generation has to be considered more and more in future treatment attempts after any prior exposure to DAA. All patients in our cohort, who suffered from virological relapse showed RAVs at time-point of relapse. Especially NS5A-RAVs are frequent due to the low resistance barrier of NS5A-inhibitors, as exemplified also in our “real-word” cohort. Since NS5A-RAVs lead to just minimal impairment of viral “fitness”, unfortunately they are detectable for a long time in exposed patients[35]. While for some RAVs (like NS5A L31M, Y93H) clear associations between existence of RAV and virological failure exist, for others (like NS5A A30S) this association is not well established[35].

This may lead to confusion in case of a future re-treatment, if minor RAVs have been detected, and even more in case of a baseline test in treatment naïve patients. However, as the population of patients with relapse after DAA treatment grows, the need for controlled trials with new DAA-combinations (e.g., pangenotypic protease inhibitor) for those patients to address this problem is obvious. Therefore, after virological relapse we recommend resistance testing for individualized adjustment of future DAA therapies.

In our retrospective analysis excellent SVR12 rates of second generation DAA could be translated from the large study trials into “real-world” scenarios. Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/nL, or MELD ≥ 10, and patients with GT3 are at relatively higher risk to suffer from virological failure and development of resistance associated variants after exposure to DAA. To overcome this unsolved problem, further research efforts are needed.

COMMENTS

Background

From 2014 on, successively the second wave of direct acting antiviral agents (Sofosbuvir, Daclatasvir, Simeprevir, Ledipasvir, Dasabuvir, Ombitasvir, Paritaprevir/r) was available for treatment of chronic hepatitis C infection. In randomized clinical trials, superb rates of sustained virological response (SVR) 12 could be achieved.

Research frontiers

Due to the more heterogeneous character of patients in the “real world”, the therapeutic performance of these new drugs outside randomized clinical trials is of interest. Therefore, in this monocentric retrospective cohort study, we analyzed the efficacy, safety, and predictors of SVR 12 for treatment with combinations of second generation direct acting antivirals in a “real-world” setting.

Innovations and breakthroughs

In this retrospective study, similar SVR rates could be achieved compared to randomized clinical trials. However, certain subgroups of patients have significantly lower viral response rates: Significant negative predictors of SVR12 were a platelet count < 100/nL, a MELD score ≥ 10 (both P < 0.0001), liver cirrhosis at baseline (P = 0.005). Moreover, in Interferon-free treatment patients with HCV genotype 3 had significantly lower SVR rates than patients with HCV genotype 1 (P = 0.016). In the future, these subgroups of patients should be more in the focus of research efforts to overcome lower rates of SVR.

Applications

Current retrospective analysis shows that excellent SVR12 rates and the favorable side-effect profile of direct acting antiviral-combination therapy can be well translated into “real-world”.

Peer-review

Good level-study to be ameliorated in the presentation of characteristics of cirrhotic patients that are an important part of the studied population.

Abstract

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Best of viral hepatitis at ILC2016

Published on Apr 22, 2016
Video Link

In this video, Pr. Jean-Michel Pawlotsky and Pr. Thomas Berg review and discuss the “Best of viral hepatitis at ILC2016”. An extensive summary of the latest advances in the fields of hepatitis B and hepatitis C is covered

For webcasts, posters and slides from the ILC2016 see LiverTree http://livertree.easl.eu/

Successes and Challenges on the Road to Cure Hepatitis C

Successes and Challenges on the Road to Cure Hepatitis C

Stacy M. Horner , Susanna Naggie PLOS 
 Published: June 18, 2015
DOI: 10.1371/journal.ppat.1004854

Citation: Horner SM, Naggie S (2015) Successes and Challenges on the Road to Cure Hepatitis C. PLoS Pathog 11(6): e1004854. doi:10.1371/journal.ppat.1004854

Editor: Richard C. Condit, University of Florida, UNITED STATES

Published: June 18, 2015

Copyright: © 2015 Horner, Naggie. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Funding: SN is supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health under grant 1K23AI096913. SMH is supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health under grant K22AI100935, as well as the Duke University Center for AIDS Research (CFAR), an NIH funded program (5P30 A1064518), and a Whitehead Scholar Award. The funders had no role in the preparation of this manuscript and the views expressed here do not necessarily reflect those of the funders.

Competing interests: I have read the journal's policy and have the following conflicts: SN has served as a scientific advisor to Gilead, AbbVie, Janssen, Bristol Meyers Squibb, Merck, and Boehringer Ingelheim. SN's institution has received research funds on her behalf from Gilead, AbbVie, Bristol Meyers Squibb, and Janssen. This does not alter our adherence to all PLOS policies on sharing data and materials.

Introduction

Hepatitis C virus (HCV) represents a significant health burden worldwide, with an estimated 185 million people chronically infected [1]. A leading cause of liver transplantation, HCV infection can result in severe liver disease including cirrhosis and hepatocellular carcinoma [2]. Cure of HCV infection results in substantial decreases in such liver-related morbidity and mortality [3]. Prior therapies for HCV offered only 40% cure for the most difficult-to-treat genotype-1 infection, required 48 weeks of therapy with an injectable interferon, and included significant adverse events [4]. The past year has seen the approval of five interferon-free direct-acting antiviral (DAA) regimens for HCV, including combinations of DAAs and fixed-dose combination pills (Tables 1 and 2) [5–13]. Sustained virologic response (SVR), the virologic surrogate for clinical cure, has improved to >90% for most populations across all HCV genotypes (Table 2). While the successes attributable to DAA combination therapies will be many, there also remain challenges and much for us to learn as we embark on this journey to eradicate HCV. Here, we will discuss several of the greatest successes and future challenges in HCV therapeutics today.

Click Table To Enlarge

Table 1. All-oral direct acting antiviral regimens available for clinical use.
doi:10.1371/journal.ppat.1004854.t001

Click Table To Enlarge

Table 2. Sustained virologic response for all-oral direct acting antiviral regimens.

doi:10.1371/journal.ppat.1004854.t002

Potent DAA Combinations Are Closing the Gap for Unique Patient Populations

Although all patients with HCV infection will benefit from the availability of oral DAA combination therapies, several unique patient populations have seen dramatic improvements in SVR, revealing the great clinical impact of these therapies. Specifically, patients with HIV/HCV dual infection, patients with compensated and decompensated cirrhosis, and patients who have had liver transplantation for HCV-associated liver disease are exhibiting fantastic (87%–98%) SVR rates with oral DAA combination therapy [14–16]. These patients, who have a greater risk of progression of liver disease, hepatocellular carcinoma, and death, previously had low response rates or even absolute contraindications to treatments with interferon [17–18].

The potential impact of HCV eradication for these highest-risk populations could be enormous, including decreases in hepatocellular carcinoma and liver transplantation, as well as prolonged survival for those already living with liver grafts. And yet, we do not know for sure how this story ends. While the liver has the ability to repair injured tissue [19] and there is evidence to suggest that fibrosis induced by chronic HCV infection is reversible [3], is there a point of no return? Previously, patients with HCV-associated decompensated liver disease (ascites, hepatic encephalopathy, and variceal bleeding) had only one choice for survival: organ transplantation. Is viral eradication enough to change their fate? The largest study to date in patients with decompensated cirrhosis reported SVR of nearly 90% with a DAA combination regimen [15]. Importantly, the study also reported on improvement in serum markers of synthetic liver function for a majority (>50%) of patients at post-treatment week 4. Whether these improvements translate to improved clinical outcomes over time remains to be seen, but there is reason for optimism.

HCV Genotype Diversity Has Complicated the Search for a Pangenotypic Regimen

HCV is a positive-stranded RNA virus. Its 9.6-kb genome is translated into a polyprotein that is processed into structural and nonstructural (NS; including NS3, NS4A, NS4B, NS5A, and NS5B) proteins (Fig 1) [20]. The NS proteins are the targets for the current approved DAA, including NS3–4A protease inhibitors (PI), NS5A inhibitors, and NS5B nucleot(s)ide (NA) and non-nucleoside (NNA) analogues (Table 3). A major challenge to the design and implementation of DAA for HCV is the incredible genetic diversity of HCV. HCV contains six major genotypes, as defined by phylogenetic and sequence analysis of the viral genome. These genotypes vary by 30%–35% at the nucleotide level and contain nearly 70 subtypes [20]. Clinically, this genetic diversity has translated into different regimens based on genotype and even subtype (1a versus 1b).

Click On Figure To Enlarge

Fig 1. The HCV proteins.

The HCV polyprotein is processed into the structural and nonstructural proteins of the virus, as shown here. The NS3–4A, NS5A, and NS5B proteins, all targets of newly developed direct-acting antivirals for HCV, are highlighted in red and their major functions described.

doi:10.1371/journal.ppat.1004854.g001

Click Table To Enlarge

Table 3. Properties of HCV direct-acting antivirals.

doi:10.1371/journal.ppat.1004854.t003

The ideal HCV DAA regimen would have pangenotype efficacy. However, because of the viral genetic diversity and mechanisms of action of the DAAs, this has been difficult to achieve. Of the five interferon-free DAA regimens available in either the United States or Europe, only two have been approved as pangenotypic regimens. The regimen of sofosbuvir, a first-in-class NA, and ribavirin was approved for genotypes 1–4 and has in vivo evidence to support efficacy in genotypes 5 and 6 [13]. While this regimen remains the standard of care for genotypes 2 and 3, its efficacy was suboptimal in the most common HCV genotype in the US, genotype 1. Daclatasvir, a pangenotypic NS5A inhibitor, when combined with sofosbuvir, provides the most potent pangenotypic activity to date and was approved in Europe for genotypes 1–4. Daclatasvir has good activity against genotype 3 and maintains activity against genotype 2 polymorphisms [7]. Unfortunately, the recently reported efficacy of 12 weeks of this regimen in genotype 3 cirrhotic patients was quite poor [8]. Other DAA regimens either lack pangenotypic coverage or have pangenotypic activity but lack clinical data in all genotypes. Ledipasvir, an NS5A inhibitor approved in combination with sofosbuvir, loses activity for a majority of genotype 2 infections because of a common NS5A polymorphism and has suboptimal in vitro activity versus genotype 3 [10]. Simeprevir, a first-generation PI approved in combination with sofosbuvir, has limited activity versus genotype 3 and has not been studied in humans for genotypes 2, 5, or 6, although it has in vitro activity [21]. The most recently approved regimen, which combines three DAAs (all with low barrier to resistance): a pangenotypic NS5A inhibitor, ombitasvir, used with a first-generation PI (paritaprevir) and an NNA (dasabuvir), is limited by the narrow genotype 1 activity of the NNA [11].

This fragmentation of treatment by genotype complicates the clinical approach to care and limits the feasibility of HCV treatment in the resource-limited setting, where genotyping and access to multiple regimens is not feasible. Moving forward, investigational second-generation PIs with broad genotypic coverage (such as MK-5172), highly potent pangenotypic NS5A inhibitors (including GS-5816), and triple DAA combinations with NA backbones are expected to help us achieve more potent pangenotypic coverage, including better options to treat genotype 3.

The Clinical Role of Resistance-Associated Variants (RAVs) Is Becoming More Clear

Viral sequences with preexisting polymorphisms can present a therapeutic challenge. The best clinical example is the preexisting NS3 Q80K polymorphism, found in 5%–48% of those with genotype 1a. This polymorphism confers resistance to simeprevir and limits its efficacy (SVR 58% versus 84%; in combination with pegylated interferon and ribavirin), thereby necessitating pretreatment polymorphism testing [12]. Combining simeprevir with the potent DAA sofosbuvir appears to overcome this limitation only in patients without cirrhosis [22,23]. Nucleotide analogues including sofosbuvir have exceptional genetic barriers to resistance. The signature RAV with sofosbuvir is the S282T mutation, which was not detected in any patient at baseline or time of virologic failure in the sofosbuvir phase 3 program [24]. Other treatment-emergent variants (TEVs) have been reported in the phase 3 program, including the L159F and V321A mutations. The change in sofosbuvir EC50 for these TEVs does not appear to be clinically significant, and retreatment of subjects with these TEVs with sofosbuvir-containing regimens did not support a role for them in treatment failure. Baseline NS5A polymorphisms that confer resistance are significantly more common and will likely be more problematic in the setting of retreatment. In a pooled resistance analysis of the ledipasvir/sofosbuvir phase 3 programs, while only 16% of patients had NS5A RAVs at baseline, significantly more patients (43%) suffering virologic failure harbored these RAVs at baseline [25]. There are now several patient subgroups in which baseline NS5A RAVs may lower SVR, including genotype 3 patients with cirrhosis treated with daclatasvir and sofosbuvir and treatment-experienced patients receiving ledipasvir and sofosbuvir [25,26]. While baseline polymorphism testing is not recommended at this time because of the overall high SVR (>90%), it may become more relevant in the setting of retreatment. The first retreatment study of prior NS5A failures confirmed that evidence of NS5A RAVs at time of retreatment confers greater risk of relapse [27].

The ability of HCV to develop de novo resistance to antiviral drugs is quite high. HCV replicates as a quasispecies; therefore, RAVs can preexist within the viral population at baseline and emerge as the dominant species during treatment. The high mutability of HCV has to do with the high error-prone nature of the HCV RNA-dependent RNA polymerase and large viral populations [28]. In fact, it has been predicted that in a single day, HCV can generate genomes with all possible single and double nucleotide changes, and as long as these genomes maintain fitness, they could confer antiviral resistance [28]. This same model predicted that combination DAA regimens would require a genetic barrier of four or more resistance mutations to achieve clinical efficacy.

Each class of DAAs can select for RAVs; however, the genetic barriers and fitness of these RAVs varies. NAs inherently have high barriers to resistance, because they directly target the conserved polymerase active site and resistant variants have low fitness [28]. On the other hand, NS5A inhibitors, PIs, and NNAs all have low barriers to resistance, with single amino acid substitutions conferring high-level resistance. In the minority of patients who suffer virologic failure during DAA combination therapy, dual and triple RAVs are being reported [10–13].

What happens to RAVs after the cessation of treatment? This depends on the fitness of those variants. For first-generation PIs, a recent report of long-term follow-up of patients treated with boceprevir (first-generation NS3–NS4A PI) found that after 3 years, 27% of patients still had RAVs and that the median time for all RAVs to become undetectable was 1.11 years [29]. This carries important clinical implications for retreatment decisions in a patient with RAVs. For example, NS5A RAVs exhibit more replicative fitness and can persist for >96 weeks [30]. Early retreatment studies suggest this will impact success of retreatment and thus significantly limit options for patients with NS5A RAVs for the foreseeable future [27].

Even with Highly Effective DAA Combination Therapies, Some Historic Baseline Predictors of SVR Remain

One of the greatest surprises thus far in the new era of treating HCV is that some of the same factors that predicted response to interferon therapies still play a role in DAA response rates. Although SVR rates are high across all subgroups, recent pooled multivariable analyses of phase 3 trials provide some granularity on treatment response. While these predictors may vary across regimens, higher rates of relapse are being reported in patients based on genotype subtype, presence of cirrhosis (in particular those with prior treatment failure), IL28B TT genotype, sex, race, and higher baseline HCV RNA [31,32]. Based on the presence or absence of these predictors, some patients may achieve SVR with 8 weeks of therapy, while others require 24 weeks. Moving forward, these “difficult-to-treat” populations should be targeted for innovative approaches to therapy so that no patient is left without a chance of cure.

Our Greatest Challenge Just Might Be of Our Own Making

Direct-acting antivirals for HCV are likely to be heralded as one of medicine’s greatest advancements. The possibility of eradicating HCV from the globe seems within arm’s reach. With SVR pushing 100% for many HCV-infected populations and ongoing studies pushing the limits of treatment to just 6 weeks with triple DAA combinations, there is much reason for hope. Yet, the unfortunate reality is that because of the high cost of these medications, many patients will be denied coverage and the opportunity for cure. Many payers are only providing coverage to those patients with the highest stages of fibrosis. Is there another precedent in medicine in which we don’t treat a curable transmissible disease? The recent exclusivity agreements between Express Scripts and AbbVie and CVS/Caremark and Gilead mark a new era in the battle against HCV, although in this case we seem to be battling against ourselves. We should carefully consider the consequences of pricing and such relationships, as much of this has overshadowed the bright light of medical innovation—what a shame.

Source - http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004854

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HCV NEWS TONIGHT - Patient Friendly Video

Good day folks, this learning activity is one of my favorites, I hope you enjoy this witty, informative presentation.

HCV NEWS TONIGHT 

Last month Chronic Liver Disease Foundation (CLDF) launched a new extremely clever HCV TV video, which proves to be patient friendly. The program is presented in an enjoyable TV news format with a look at treating HCV in persons with cirrhosis using lovely Kimberly as a patient case study. I enjoyed the question and answer segment, along with the slide set. Check out who the news anchor is and the field reporter, not to mention the news desk reporter, loving it!

Begin here.... 

RG-101 - Decreased viral load in patients with various HCV genotypes

Commentary @ Healio

Oct 23

Potential drug decreased viral load in patients with various HCV genotypes
Interim results from an ongoing clinical trial revealed that a microRNA therapeutic was well-tolerated and safe for the treatment of hepatitis C virus infection, according to a company release from Regulus Therapeutics.

In the trial, currently taking place in the Netherlands, RG-101 (Regulus Therapeutics), a GalNac-conjugated anti-miR targeting microRNA-122, was dosed at 2 mg/kg and given to 14 patients with HCV and various genotypes. This treatment resulted in significant and sustained reductions in HCV RNA among the patients, including those with difficult to treat genotypes and experienced viral relapse after a prior interferon-based regimen, according to the release. 

Continue reading @ Healio

Investment Commentary
Regulus Gets Seat at Hep C Table With Today's Impressive Drug Results 

By Adam Feuerstein
Oct 22
But you're getting way ahead of the facts if you think Regulus has a game-changing hepatitis C therapy in its grasp already. There's a lot more questions to be answered.
Continue reading @ TheStreet.com

Press Release

A Single Subcutaneous Dose of 2mg/kg of RG-101, Regulus' Wholly-Owned, GalNac-Conjugated anti-miR Targeting microRNA-122, Demonstrates 4.1 log10 Mean Viral Load Reduction as Monotherapy at Day 29 in Patients with Varied HCV Genotypes and Treatment History

- Interim Results from Ongoing Study Demonstrate Human Proof-of-Concept and Underscore the Value of Regulus' microRNA Platform -
- Conference Call Today at 8:30 a.m. EDT to Discuss Results -

LA JOLLA, Calif., Oct. 22, 2014 /PRNewswire/ -- Regulus Therapeutics Inc. (NASDAQ:RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced that it has demonstrated human proof-of-concept with a microRNA therapeutic from an ongoing clinical study evaluating RG-101, a wholly-owned, GalNac-conjugated anti-miR targeting microRNA-122 ("miR-122"), for the treatment of hepatitis C virus infection ("HCV"). Interim results from the ongoing clinical study demonstrate that treatment with a single subcutaneous dose of 2 mg/kg of RG-101 as monotherapy resulted in significant and sustained reductions in HCV RNA in a varied group of patients, including difficult to treat genotypes and patients who experienced viral relapse after a prior IFN-containing regimen. Additionally, RG-101 was safe and well tolerated and has demonstrated a very favorable pharmacokinetic profile to date, which may allow for combination with oral direct-acting antiviral ("DAA") agents to treat HCV.

Interim results from the ongoing clinical study are summarized below:

In the first dose cohort of part IV of the ongoing study, 16 HCV patients were enrolled with multiple genotypes, 10 GT1s, 5 GT3s, and 1 GT4. 14 patients, 8 naïve and 6 patients who experienced viral relapse after a prior IFN-containing regimen, received a single subcutaneous dose of 2 mg/kg of RG-101 as monotherapy while 2 patients received placebo.

In the 14 HCV treated patients, there was a mean viral load reduction of 4.1 log10 at day 29 (range -5.8 log10 to -2.3 log10).

6 out of 14 patients had HCV RNA levels below the limit of quantification at day 29 and the 3 patients from this group who have reached day 57 still have HCV RNA levels below the limit of quantification.
Viral load reduction occurs within the first 96 hours and virologic response is not influenced by IL-28 genotype.
Due to the long-lasting and sustained virologic effect seen, the ongoing study protocol has been amended to follow patients for up to six months after dosing to evaluate the possibility for certain patients to achieve viral cure after a single dose of RG-101.

There were no drug-drug interactions from part III of the ongoing study in which RG-101 was combined with simeprevir (OLYSIO™), an approved oral DAA (protease inhibitor), and the combination had no effect on the pharmacokinetic profile of RG-101 or simeprevir (OLYSIO™).
RG-101 is safe and well tolerated with no serious adverse events reported to date.

"We are very excited to have demonstrated our first human proof-of-concept results with a microRNA therapeutic from the ongoing study of RG-101, which is a significant milestone in Regulus' history, and represents a key achievement under our 'Clinical Map Initiative'," said Kleanthis G. Xanthopoulos, Ph.D., President and Chief Executive Officer of Regulus. "We believe these interim data are exceptional and provide strong evidence to support the rapid advancement of RG-101 into future clinical studies, while presenting a clear opportunity for a potentially disruptive therapy to the current HCV treatment paradigm."

"RG-101 is the first microRNA therapeutic in clinical development to combine the most advanced RNA technologies from three leading RNA therapeutics companies; chemistry 2.5 from Isis, GalNAc conjugate from Alnylam, and Regulus' unique and proprietary chemistry including the novel linker that facilitates the release of the parent oligonucleotide after hepatocyte uptake," said Neil W. Gibson, Ph.D., Chief Scientific Officer. "We believe the innovative design of RG-101 has led to achievement of our first human proof-of-concept results, and hope these findings will advance the growth of our microRNA therapeutics pipeline."

"We are very pleased and encouraged with the interim results and believe these findings strongly support the rapid advancement of RG-101 into Phase II development," said Paul Grint, M.D., Regulus' Chief Medical Officer. "Currently, we plan to file an Investigational New Drug Application with the U.S. Food and Drug Administration in the first quarter of 2015 and plan to initiate a Phase II DAA combination study of RG-101 in HCV patients in the second quarter of 2015. In addition, we look forward to reporting additional data from the ongoing study in the first half of next year."

"The efficacy and sustained viral response seen with a single dose of RG-101 is very promising and it was encouraging to see response across a diversity of genotypes and treatment experience in this clinical trial. Additionally, all patients in the first cohort on active therapy demonstrated a viral response to RG-101, which is also very encouraging," said Dr. Eric Lawitz, M.D., Vice President, Scientific and Research Development, The Texas Liver Institute, and Clinical Professor of Medicine, University of Texas Health Science Center in San Antonio. "These findings suggest the clinical benefit of utilizing a unique mechanism of action to potentially treat difficult patient populations. There may be an opportunity to improve upon the current real world compliance issues with therapies such as RG-101 that may be administered subcutaneously by a clinician. I look forward to seeing RG-101 advance into future clinical trials."

Conference Call & Webcast Information

Regulus will host a conference call and webcast at 8:30 a.m. Eastern Daylight Time today to discuss its interim results from the ongoing clinical study of RG-101 for the treatment of HCV. A live webcast of the call will be available online at www.regulusrx.com. To access the call, please dial (877) 257-8599 (domestic) or (970) 315-0459 (international) and refer to conference ID 24374685. To access the telephone replay of the call, dial (855) 859-2056 (domestic) or (404) 537-3406 (international), passcode ID 24374685. The webcast and telephone replay will be archived on the company's website for ninety days following the call.

About RG-101 for HCV

RG-101 is a wholly-owned, GalNAc-conjugated anti-miR targeting miR-122 for the treatment of HCV. Regulus is currently evaluating RG-101 in an ongoing study being conducted in the Netherlands. The study has the following four parts: (I) a single ascending-dose study in which healthy volunteer subjects receive a single subcutaneous dose of RG-101, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg and 8 mg/kg or placebo; (II) a multiple-ascending dose study in which healthy volunteer subjects receive a monthly single subcutaneous dose for four months of RG-101 or placebo; (III) a single-dose drug-drug interaction study in which healthy volunteer subjects receive a single subcutaneous dose of RG-101 in combination with simeprevir, an approved DAA; and (IV) a single-dose study in which HCV patients receive either a single subcutaneous dose of RG-101 or placebo at two doses, 2 mg/kg of RG-101 (the first dose cohort) or 4 mg/kg of RG-101 (the second dose cohort), to assess the safety and viral load reduction. The primary objective is to evaluate safety and tolerability and the secondary objectives are to evaluate pharmacokinetics, viral load reduction and any impact an oral DAA, such as simeprevir, may have on the pharmacokinetics of RG-101. Up to 100 healthy volunteer subjects and HCV patients with multiple HCV genotypes and treatment history are planned to be enrolled.

Today, Regulus reported interim results from the above study and plans to report additional results from the ongoing study in 2015.

About microRNAs

The discovery of microRNAs in humans during the last decade is one of the most exciting scientific breakthroughs in recent history. microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length, that do not encode proteins but instead regulate gene expression. More than 800 microRNAs have been identified in the human genome, and over two-thirds of all human genes are believed to be regulated by microRNAs. A single microRNA can regulate entire networks of genes. As such, these molecules are considered master regulators of the human genome. microRNA expression, or function, has been shown to be significantly altered or dysregulated in many disease states, including oncology, fibrosis, metabolic diseases, immune-inflammatory diseases and HCV. Targeting microRNAs with anti-miRs, chemically modified, single-stranded oligonucleotides, offers a unique approach to treating disease by modulating entire biological pathways and may become a new and major class of drugs with broad therapeutic application.

About Hepatitis C Virus Infection (HCV)

Hepatitis C is a result of a hepatocyte specific infection induced by the virus known as HCV. Chronic HCV may lead to significant liver disease, including chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Up to 170 million people are chronically infected with HCV worldwide, and more than 350,000 people die from HCV annually. The CDC estimates that there are currently approximately 3.2 million persons infected with HCV in the United States. HCV shows significant genetic variation in worldwide populations due to its frequent rates of mutation and rapid evolution. There are six genotypes of HCV, with several subtypes within each genotype, which vary in prevalence across the different regions of the world. The response to treatment varies from individual to individual underscoring the inadequacy of existing therapies and highlights the need for combination therapies that not only target the virus but endogenous host factors as well, such as microRNA-122.

Regulus believes that its' miR-122 antagonist, RG-101, may be a useful agent in emerging combination regimens to address difficult-to-treat genotypes and to potentially expand upon the current therapies available to clinicians treating HCV patients.

Update to the 'Clinical Map Initiative'

Launched in February 2014, Regulus' 'Clinical Map Initiative' outlines certain corporate goals to advance its microRNA therapeutics pipeline over the next several years. In October 2014, Regulus demonstrated human proof-of-concept with a microRNA therapeutic, RG-101, a wholly-owned, GalNac-conjugated anti-miR targeting microRNA-122 for the treatment of HCV. The company plans to rapidly advance RG-101 in clinical development and expects to initiate a Phase II DAA combination study in HCV patients in the second quarter of 2015. In addition, Regulus expects to initiate a Phase I clinical study of RG-012 for the treatment of Alport syndrome, nominate a third microRNA candidate for clinical development by the end of 2014, and maintain a strong financial position and end 2014 with at least $75.0 million in cash, cash equivalents and short-term investments.

About Regulus

Regulus Therapeutics Inc. (NASDAQ:RGLS) is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is uniquely positioned to leverage a mature therapeutic platform that harnesses the oligonucleotide drug discovery and development expertise of Alnylam Pharmaceuticals, Inc. and Isis Pharmaceuticals, Inc., which founded the company. Regulus has a well-balanced microRNA therapeutics pipeline entering clinical development, an emerging microRNA biomarkers platform to support its therapeutic programs, and a rich intellectual property estate to retain its leadership in the microRNA field. Regulus intends to focus its proprietary efforts on developing microRNA therapeutics for oncology indications and orphan diseases and is currently advancing several programs toward clinical development in oncology, fibrosis and metabolic diseases. Specifically, Regulus is developing RG-012, an anti-miR targeting microRNA-21 for the treatment of Alport syndrome, a life-threatening kidney disease driven by genetic mutations with no approved therapy, and RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122 for the treatment of chronic hepatitis C virus infection. Regulus' commitment to innovation and its leadership in the microRNA field have enabled the formation of strategic alliances with AstraZeneca and Sanofi and a research collaboration with Biogen Idec focused on microRNA biomarkers. In addition, the Company has established Regulus microMarkers™, a division focused on identifying microRNAs as biomarkers of human disease, which is designed to support its therapeutic pipeline, collaborators and strategic partners.

For more information, please visit http://www.regulusrx.com.

Forward-Looking Statements

Statements contained in this presentation regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including the expected ability of Regulus to undertake certain activities and accomplish certain goals with respect to RG-101, the projected timeline of clinical development activities related to RG-101, and expectations regarding future therapeutic and commercial potential with respect to RG-101. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "intends," "will," "goal," "potential" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Regulus' current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. These and other risks concerning Regulus' are described in additional detail in Regulus filings with the Securities and Exchange Commission. All forward-looking statements contained in this presentation speak only as of the date on which they were made. Regulus undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

OLYSIO™ is a registered trademark of Janssen Therapeutics.

To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/a-single-subcutaneous-dose-of-2mgkg-of-rg-101-regulus-wholly-owned-galnac-conjugated-anti-mir-targeting-microrna-122-demonstrates-41-log10-mean-viral-load-reduction-as-monotherapy-at-day-29-in-patients-with-varied-hcv-genoty-248366539.html

SOURCE Regulus Therapeutics Inc.

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NATAP-Treatment of Chronic Hepatitis C: The Revolution!

Treatment of Chronic Hepatitis C: The Revolution!

Jules Levin founder and executive director of National AIDS Treatment Advocacy Project (NATAP) reports on the European AIDS Conference which took place in Belgium from October 16-19.

Mr. Levin offers commentary and slides from Dr. Wedemeyer's presentation; Treatment of Chronic Hepatitis C: The Revolution! which reviews data on new HCV oral IFN-free drug regimens and direct acting activirals in clinical development.

Here are a few sample slides and a bit of commentary, view complete presentation @  NATAP

Treatment of Chronic Hepatitis C: The Revolution!

Heiner Wedemeyer
Hannover Medical School
Germany

Commentary From Jules Levin:  

The FDA hearings on Oct 24/25 reviewed Simeprevir+PR for 24 weeks and Sofosbuvir +PR for 12 weeks, and as expected the panels voted unanimously to approve both 19-0 & 15-0. This is just the prelude to next year when the first 2 IFN-free regimens will be considered for approval by the FDA in the early part of 2014 & of course approval is expected, they are Gilead's Sofosbuvir+Ledipasvir & Abbvie's ABT450+ABT267+ABT333 both with and/or without RBV, phase 3 studies are......

Continue reading here............

 

"All oral therapy will lead to a change in treatment paradigm"
 

"The number of treatable patients will dramatically increase! Interferon-Free"
 

"There is an association between SVR & all-cause mortality & liver-related mortality"

 

 

Complete Coverage

EACS - European AIDS Conference - Oct 16-19 Brussels, Belgium

 

 

Watch-Hepatitis C: The Pace of Progress/Interferon-Free Treatment Still Searching

Medscape Gastroenterology

Hepatitis C: The Pace of Progress

Digestive Disease Week (DDW) 2013

 

Progress in Treating Hepatitis C Infection

Hello. I am Dr. Bill Balistreri, Professor at Cincinnati Children's Hospital. I am here at Digestive Disease Week (DDW) in Orlando, reporting for Medscape.

A major focus of the research and the state-of-the-art summaries presented here at DDW has been the pace of progress in developing new treatment strategies for hepatitis C. Speakers highlighted the fact that the agents and approaches for treatment of hepatitis C virus (HCV) infection are in constant change and may, in fact, be in for an upgrade.

The standard of care for several years consisted of a combination of pegylated interferon and ribavirin. With advanced understanding of the biology of HCV came the identification of specific proteins involved in its replication and the understanding that these proteins can be targeted by protease and polymerase inhibitors.

Last year, the US Food and Drug Administration approved 2 NS3 protease inhibitors -- telaprevir and boceprevir -- for the treatment of HCV genotype 1 in combination with standard therapy. Clinical trials of the 2 agents showed significantly improved sustained virologic response (SVR) rates in treatment-naive patients. Therefore, the American Association for the Study of Liver Diseases guidelines were altered to recommend triple therapy consisting of a protease inhibitor (either telaprevir or boceprevir) plus peginterferon and ribavirin.....

 

Continue reading/watch video