Also See Updates On The Website
Sept 2013 - Miravirsen:
Antisense therapy for hepatitis C
COMMENTARY ON:
Treatment of HCV infection by targeting microRNA
Santaris Pharma A/S Completes Enrollment in Phase 2 Clinical Trial of Miravirsen
Santaris Pharma Miravirsen SPC3649-207-205 Enrollment.pdf
Santaris Pharma A/S Completes Enrollment in Phase 2 Clinical Trial of Miravirsen In Null Responders to Pegylated Interferon and Ribavirin for the Treatment of the Hepatitis C Virus
-- Enrollment also begins in study investigating miravirsen in combination with telaprevir and ribavirin in null responders to pegylated interferon and ribavirin --
Hørsholm, Denmark/San Diego, California, August 27, 2013 — Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, today announced the completion of enrollment of its Phase 2 miravirsen 12-week monotherapy study of miravirsen, a host-targeted, pan-HCV genotype antiviral agent, in subjects who were "null responders" to pegylated interferon alpha and ribavirin (peg-IFNα/RBV). The company also announced the enrollment of the first patient into another Phase 2 study of miravirsen in combination with telaprevir and ribavirin, also in null responders to peg-IFNα/RBV.
"The current standard of treatment for HCV is a combination of a direct acting-antiviral agent protease inhibitor with pegylated-interferon plus ribavirin. However, there remains a pressing need for therapeutic regimens that can attain high sustained virologic responses without peg-IFNα/RBV, which is poorly tolerated, and without drug-drug interactions. Miravirsen’s unique mode-of-action has shown potential in providing antiviral activity in patients who have failed previous treatment regimens for the hepatitis C virus," said Maribel Rodriguez-Torres, M.D., president of Fundacion de Investigacion and the study’s Principal Investigator. "We are excited to have completed enrollment and look forward to following the enrolled patients and reporting the data from this study. So far, the emerging viral load data suggest that miravirsen might be a unique treatment option, in combination with other antivirals, for the treatment of this type of difficult to treat patients."
The Phase 2, open-label study assesses the safety, antiviral activity and pharmacokinetics of miravirsen monotherapy over a total of 12 weeks of treatment. Patients enrolled in the study were chronically infected with HCV genotype 1 and had previously failed treatment with peg-IFNα/RBV therapy. Miravirsen was given as a total of five doses over five weeks, followed by a further four doses once every other week over seven weeks.
Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is an inhibitor of miR-122, a liver specific microRNA that the hepatitis C virus requires for replication. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the hepatitis C virus. As a result, the replication of the virus is effectively inhibited and the levels of HCV RNA are profoundly reduced.
Santaris Pharma A/S has also enrolled its first patient into another Phase 2 clinical trial that will assess the safety, tolerability and antiviral activity of miravirsen given for 12 weeks in combination with telaprevir (TVR) and ribavirin (RBV) in patients with HCV infection who are non-responders to peg-IFNα/RBV.
"We are pleased to report on the progress in the miravirsen clinical program," said Michael R. Hodges, MD, Vice President and Chief Medical Officer at Santaris Pharma A/S. "We hope that data from these two 12-week studies in the hard to treat patients will confirm the earlier promising efficacy and safety data from the four-week monotherapy study in treatment naïve patients that was recently published in the New England Journal of Medicine. We continue to believe that miravirsen given in combination with direct acting-antiviral agent(s) has the potential to cure chronic HCV infection in hard-to-treat patients."
The first series of non-clinical and clinical studies demonstrated the following key attributes for miravirsen:
Miravirsen has a novel mechanism of action, inhibits a well conserved hepatic host target thus has an high barrier to resistance with predicted activity against all HCV genotypes, is not metabolized by cytochrome P450 enzymes therefore drug interactions are unlikely
In in vitro studies, miravirsen was active against all six HCV genotypes, additive activity to direct acting antiviral agents (DAAs), active against DAA resistant virus and a showed a high barrier to resistance
In clinical trials with four weeks of monotherapy, miravirsen was well tolerated, showed dose dependent antiviral activity that can be maintained weeks after the end of therapy
In two separate drug-drug interaction clinical trials, miravirsen showed no interactions with peg-IFNα/RBV or with telaprevir
About Hepatitis C
Hepatitis C infection is a viral disease caused by the hepatitis C virus that leads to inflammation of the liver. The World Health Organization estimates that approximately 3 percent of the world’s population have been infected with HCV and that some 170 million have chronic hepatitis C and are at risk of developing liver cirrhosis and/or liver canceri. Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per yearii. In Europe, there are about 4 million carriersi. The current standard of care treatment for genotype 1 is a protease inhibitor given with pegylated-interferon α and ribavirin. This triple combination is effective in about 70-80% of those treatedii. Even though in Europe and the United States genotype 1 is the most prevalent, there are 50-70 million people worldwide that are infected with a non-genotype 1 virus. In these patients, the combination of pegylated-interferon α and ribavirin remains the currently approved standard of care treatmentiii. Patients that are not effectively treated have an increased risk for the progression of liver disease. By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billioniv.
About microRNAs
MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.
About Locked Nucleic Acid (LNA) Drug Platform
The LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the company’s proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including cardiometabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. LNA is also sometimes referred to as BNA (Bicyclic or Bridged Nucleic Acid). LNA-based drugs are a promising new class of therapeutics that enable scientists to develop drugs that work through previously inaccessible clinical pathways. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drugs candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.
About Santaris Pharma A/S
Santaris Pharma A/S is a privately held, clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Locked Nucleic Acid (LNA) Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combine the company’s proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The company’s research and development activities focus on infectious diseases and cardiometabolic disorders, while partnerships with major pharmaceutical companies address a range of therapeutic areas including cancer, cardiovascular disease, infectious and inflammatory diseases, and rare genetic disorders. The company has strategic partnerships with RaNA Therapeutics, Bristol-Myers Squibb, miRagen Therapeutics, Shire, Pfizer, GlaxoSmithKline, and Enzon Pharmaceuticals. As part of its broad patent estate, the company holds exclusive worldwide rights to manufacture and sell products that comprise LNA as active ingredient for studies performed with a view to obtaining marketing approval. Santaris Pharma A/S, founded in 2003, is headquartered in Denmark with operations in the United States. Please visit www.santaris.com for more information.
Santaris Pharma A/S® is a registered trademark of Santaris Pharma A/S. SantarisTM, Santaris PharmaTM, CureonTM and LNA-antimiR™ are trademarks of Santaris Pharma A/S.
Media Contacts: Liz Narrillos Roux, Edelman (liz.narrillosroux@edelman.com) - Office: (323)202-1074
Showing posts with label Miravirsen. Show all posts
Showing posts with label Miravirsen. Show all posts
Tuesday, August 27, 2013
Thursday, June 6, 2013
Miravirsen-Treating hepatitis C by blocking a cellular microRNA
Podcast: Download TWiV 235
Treating hepatitis C by blocking a cellular microRNA
Miravirsen is a drug that binds to and blocks the function of a cellular microRNA called miR-122 that is required for the replication of hepatitis C virus (HCV). Treatment of chimpanzees chronically infected with HCV with this drug leads to suppression of viral replication. The results of a phase 2b human clinical trial in HCV infected humans indicate that Miravirsen reduces levels of viral RNA without evidence for viral resistance. I asked virologist Stan Lemon (who appeared recently on TWiV 235) his opinion of these findings.
Are you surprised that the antiviral effect of Miravirsen is long lasting?
The Janssen study published in NEJM basically recapitulated what Lanford had observed in HCV-infected chimps treated with the compound, with a very slow onset of antiviral effect, and then a very slow rebound as well. This probably reflects the pharmacokinetics and very high stability of the locked nucleic acid compound, and the time required to sequester endogenous miR-122 – changes in serum cholesterol also move very slowly. I think this is why the antiviral effect (and cholesterol effect) are long-lasting.
Is it surprising that no resistance to Miravirsen was observed?
As for the lack of resistance, it doesn’t surprise me much. This was observed in the chimps as well. The virus is really dependent upon miR-122 for its replication, and can’t readily mutate around it – the requirement for miR-122 reflects more than just the stabilizing effect of miR-122 on the viral genome, as we showed in a recent PNAS paper (Li et al., Proc. Nat’l. Acad. Sci U.S.A., 110:1881-6, 2013) written in follow-up to our earlier demonstration of the stabilizing effect of the miRNA on the HCV genome (Shimakami et al., Proc. Nat’l. Acad. Sci U.S.A. 109: 941-6, 2012, that you reviewed in TWIV 180) – what we know and don’t know about the mechanism of action is summarized in an “opinion” piece now in press in RNA Biology.
Do you think this drug will ultimately get FDA approval?
Given issues of resistance, relapse, and poor pan-genotype coverage with direct-acting antivirals for HCV, all of this should bode well for Miravirsen. However, it has issues like almost all the new therapies under evaluation.
First, the spaghetti plots in the Janssen paper show large variation in the response of individual patients, with some having little effect when receiving Miravirsen. This is unlike studies with enzyme inhibitor antivirals, and I am not aware of any good reason for it other than potential variation in endogenous miR-122 abundance.
A second and greater issue is the cancer concern. Most hepatocellular carcinomas (except those associated with HCV, interestingly enough) demonstrate significant reductions in miR-122 abundance, and miR-122 can reverse some malignancy-associated features of transformed hepatocytes in vitro – thus, miR-122 seems to act much like a tumor suppressor in the liver. miR-122 knockout mice develop normally but have a high incidence of hepatocellular carcinoma. I think this poses real problems for the development of Miravirsen. While one could reasonably argue that short-term exposure to the antagomir is very different than gene knockout, the patients being treated are those at the highest risk for HCC – particularly if there is advanced fibrosis or cirrhosis, which characterizes those most in need of treatment. It is also clear that HCC can manifest itself in patients AFTER therapeutic elimination of the virus. The risk is most certainly greatly reduced, but it is not zero (HCC develops very slowly, and in a multi-centric fashion), and with the evidence that the drug has relatively long-lasting effects on cholesterol (as well as the virus), I think the developers of Miravirsen may find it difficult to defend against future claims that the drug contributed to the development of HCC in some cases. There isn’t a good way to de-risk this, to show that this theoretical concern is not real, and this must be worrying the regulatory authorities – especially since there are now many alternative therapies under evaluation that don’t carry this risk, some of which are looking very good in combination with each other (e.g., advanced NS3 inhibitors, NS5A inhibitors, and nucs).
Source - http://www.virology.ws/
Podcast: Download TWiV 235
Wednesday, May 15, 2013
Hepatitis C Therapy Update 2013-What About Interferon-free Regimens?
Hepatitis C Virus Therapy Update 2013
Lisa C. Casey, William M. Lee
Curr Opin Gastroenterol. 2013;29(3):243-249.
Medscape Today
Abstract and Introduction
Abstract
Purpose of review: We review here the
recent literature regarding hepatitis C virus (HCV) therapy through
January 2013. We discuss current therapies, targets for new therapies,
and what might be expected in this rapidly changing field.
Recent findings: Boceprevir-based and telaprevir-based triple therapy with pegylated interferon and ribavirin marked the beginning of a new era in HCV therapy for genotype 1 patients. New direct-acting antivirals (DAAs) are being developed and new antiviral drug targets are being explored. New combination treatment regimens are expected to emerge soon and there is hope for interferon-free regimens.
Summary: The standard of care for treatment of HCV genotype 1 changed dramatically with the approval of two new DAA drugs – telaprevir and boceprevir – for use in pegylated interferon-based and ribavirin-based triple therapy in mid-2011. Experience has shown improved response rates and treatment durations for many patients with genotype 1 HCV infection. However, persistent limitations to HCV treatment still exist for patients with prior treatment failure and comorbid conditions and patients on newer therapies suffer additional therapy-limiting side effects and drug–drug interactions. Genetic testing may provide some guidance but additional options for therapy are still needed for HCV. Many new drugs are currently under investigation and there is hope that effective and well tolerated interferon-free regimens may become a part of future therapy.
Introduction
An estimated 130–170 million people are infected with hepatitis C worldwide leading to significant morbidity, mortality, and financial burden on healthcare.[1] Out of 100 people who contract the infection, 75–85% will develop chronic infection, 60–70% will develop chronic liver disease, 5–20% will develop cirrhosis over the course of their chronic infection, and 1–5% will die of complications including hepatocellular carcinoma (HCC).[1,2] The majority of the infected population in the United States, an estimated 3.2–3.7 million people, are believed to have been born between 1945 and 1965 and likely contracted the virus when transmission rates were highest in the 1970s and 1980s.[3,4] Hepatitis C virus (HCV) has a long and relatively symptom-free incubation period prior to causing serious illness. Although the contribution of blood product screening, disposable medical equipment, and public health education efforts over the years has led to a decrease in the incidence of HCV in the United States, an estimated 65–75% of currently infected individuals in the United States are unaware of their infection. The consequences of these undiagnosed and untreated chronic infections are expected to be staggering as this population ages with predictive models suggesting a two-fold increase in HCV-related deaths with direct medical costs exceeding $6.7 billion between 2010 and 2019[5] and, without intervention, a four-fold rise in the incidence of end-stage liver disease related to hepatitis C within the next 20 years.[6] An effort to capture these patients has led to the recent Centers for Disease Control and Prevention recommendations for birth cohort screening of the population born between 1945 and 1965 in the United States.[4]
Outside of the United States, many other countries worldwide face significant HCV infection rates. Despite aggressive programs toward education, care, and treatment over the last 10 years, Egypt faces the largest burden of HCV infection in the world with a 10% prevalence of chronic hepatitis C infection among persons aged 15–59 years, predominantly genotype 4.[7] In many parts of the world the virus remains unchecked because of continued unsafe medical practices, lack of public health education, and lack of funding for research and treatment. Perz et al. [8] looked at 11 WHO-based regions in 2006 and estimated that globally 27% of cirrhosis was attributable to HCV and 25% of HCC was attributable to HCV. In many countries and populations, only a small number of patients with known infection actually receive treatment and yet successful treatment has been shown to have a significant impact on outcomes.[6,9] A sustained virological response (SVR) to hepatitis C therapy reduces liver-related as well as all-cause mortality for patients with hepatitis C[3,8] including a 70–80% reduction in overall liver-related mortality and hepatic decompensation and a 75% reduction in risk of HCC at all stages of fibrosis.[4,10]
Until 2011, the historically accepted standard therapy with pegylated interferon and ribavirin produced an SVR rate of approximately 40–50% for genotype 1 patients and higher rates up to 80% for alternate genotypes after 24–48 weeks of therapy.[11] The limitations of this therapy are well recognized. Pregnant patients or those with advanced renal disease are contraindicated from using ribavirin. Likewise, interferon therapy excludes patients with autoimmune diseases, uncontrolled depression and mental illness, decompensated liver disease (child turcotte pugh > 6) or decompensated cardiac or pulmonary disease. Patients experienced frequent side effects and those failing therapy due to relapse, non or null response had few options. This led to aggressive research into additional treatment targets and ways to predict patient response to treatment.
Viral Structure
What was first known as non-A, non-B hepatitis was designated hepatitis C in 1989 by Michael Houghton and scientists at Chiron Corporation while searching for the blood-borne cause of hepatitis in transfusion recipients (see Fig. 1).[12] Hepatitis C is a single-stranded RNA flavivirus of the hepacivirus genus. Of the six genotypes, genotype 1 is the most prominent in the United States and Europe. The virus lacks proofreading ability leading to significant genetic variation, historically making drug development against the virus challenging. When the virus enters a liver cell, it releases its RNA and is translated into a poly-protein containing structural and nonstructural regions. The poly-protein is processed by proteases into several polypeptides with different functional roles in the virus life cycle. The virus is replicated with the help of a polymerase and then assembled, transported, and released from the cell. The nonstructural region codes for the polypeptides NS2, NS3, NS4A, NS4B, NS5A, and NS5B. All are potential targets for drug therapy. Initial cleavage of the poly-protein is performed by the NS3/NS4A protease, which seems to be highly conserved across most strains, and, without which, the HCV life cycle cannot proceed.[13] This region became the first therapeutic target for direct-acting antiviral (DAA) therapy, the NS3/NS4 protease inhibitors telaprevir and boceprevir.
Viral
structure and genome demonstrating potential therapeutic targets.
Reproduced with permission from.[12] HCV, hepatitis C virus.
The Era of Triple Therapy
The creation of the new standard 'triple
therapy' with the DAA medications has led to significant improvements in
the response rates for patients with genotype 1 HCV, with SVR rates as
high as 63–75% and reduction in duration of therapy by half for many
patients based on response-guided therapy (RGT). The first Food and Drug
Administration (FDA)-approved protease inhibitors, telaprevir and
boceprevir, are designed to mimic the natural NS3/NS4A protease
substrate in genotype 1 HCV, therefore inhibiting the onset of the
replication process. The successes, failures, and new challenges of
triple therapy have become well known. Although the advent of triple
therapy has dramatically improved outcomes for many, therapeutic options
for HCV are still far from optimal. Many new side effects have been
encountered with creative management strategies developed, drug
interactions have taken on new importance and issues with resistance and
intolerance persist. With the explosion of research and development of
newer DAA and additional therapeutic targets, we are at the very
beginning of a new era in HCV therapy. A review of the lessons learned
from the beginning will be important as we move forward.
First-generation Protease Inhibitors: Lessons From Telaprevir and Boceprevir
Telaprevir efficacy was initially proven in multiple large multicenter trials including protease inhibition for viral evaluation-1 (PROVE-1), PROVE-2, PROVE-3, ADVANCE, REALIZE, and illustrating the effects of combinatherapy with telaprevir (ILLUMINATE).[13–16] The importance of ribavirin was confirmed by demonstration of significant viral breakthrough and relapse after therapy in patients in a pegylated interferon and telaprevir study arm without ribavirin. These early trials developed and confirmed the utility of RGT, suggesting that a shortened duration of therapy was acceptable for patients meeting certain criteria and 24 weeks of telaprevir-based therapy was noninferior to 48 weeks of triple therapy in patients meeting appropriate criteria. Differences have been observed in treatment failure rates between genotypes 1a and 1b and in various difficult-to-treat groups. African–Americans, those with high-viral loads, bridging fibrosis or cirrhosis demonstrated somewhat improved rapid viral response with new agents but responses are still decreased compared with those observed in naive, noncirrhotic patients.[14–17]
Conceptually, the Peg-interferon/ribavirin lead-in was introduced to bring the baseline viral load down prior to starting boceprevir and, in turn, decrease the emergence of drug-resistant mutations. SVR was similar in the 28-week and 48-week groups that demonstrated at least a 1.5 log drop in viral load after the 4-week lead-in therapy phase. Patients in the 28-week triple therapy arm that did not demonstrate the 1.5 log drop after lead-in showed a poor SVR of 30% or less at 28 weeks compared with the corresponding 48-week group. The overall conclusion was that RGT based on 4-week lab values would help predict the best duration of treatment.[18] Serine protease inhibitor therapy trial-2 (SPRINT-2) stratified black and non-black patients into different arms and again demonstrated persistently lower SVR rates for black patients versus non-blacks, suggesting interferon resistance continued to play a role.[19] Additional studies suggest that the use of interleukin (IL)-28 genotyping (rs 12979860) may also identify patients who are more likely to qualify for shorter treatment durations in RGT with boceprevir.[19,20] Thus, interferon responsiveness is important in prediction of response to triple therapy; patients with a poor response to interferon might be best served by waiting for improved future therapies.
Limitations of First-generation Direct-acting Antiviral Therapy
Although the advent of triple therapy with boceprevir and telaprevir has improved response rates and treatment durations for many patients with genotype 1 disease, the phase 3 clinical trials demonstrated that many still do not achieve SVR. In addition, drug–drug interactions limit use, the high pill burden makes compliance difficult and resistance is still a real threat with unclear future implications. New rashes and anorectal symptoms are seen with telaprevir and moderate-to-severe anemia is common in both regimens.[16,19,21] In December 2012, a black box warning was added to telaprevir labeling in light of some rashes resulting in death.[22]
What is Needed: Goals for the Future
Traditionally HCV therapy has been nonspecific in its therapeutic target. Interferon activates the immune system and inhibits viral replication whereas ribavirin is a nonspecific antiviral that may inhibit viral replication but also aid in viral clearance though its true function against HCV is elusive.[23,24] Newer therapies directed against specific viral and host targets appear to have greater potential for success.
Epidemiologists have produced a long list of barriers to HCV treatment including goals for future HCV medications including: improved tolerance, high potency, favorable safety profile, high barrier to resistance, all oral regimen, pan-genotypic, favorable pill burden, short duration, few drug interactions, available for cirrhosis, HIV, mental illness, and affordable.[5,9] For the first time, ongoing research suggests that many of these goals may be realistic.
Understanding Direct-acting Antiviral Resistance is Important for the Future
Drug resistance was noted in some form with both telaprevir and boceprevir in the early protease inhibitor trials, impacting the final structure of treatment protocols. Specifically, ribavirin use is required by all protocols and genotypic subtypes 1a and 1b demonstrate a recognizable difference in rates of SVR. The findings are explained by the very low genetic barrier to resistance of protease inhibitors as a class, defined as the number of amino acid substitutions required to confer full resistance to a drug.[25,26] In general, DAAs with a low genetic barrier to resistance require only 1–2 amino acid substitutions for high resistance and DAAs with a high barrier to resistance usually require 3–4 amino acid substitutions in the same region. Telaprevir resistance is recognized to most frequently be represented by mutation R155K. The R-K change requires only one nucleotide change in genotype 1a, whereas genotype 1b requires two nucleotide changes. The amino acid target sequence of the NS3 region differs significantly between HCV genotypes (explaining why telaprevir and boceprevir have efficacy limited to genotype 1) and resistance can develop easily with few mutations.[25] The barrier to genetic resistance of DAA in development will be a critical factor in the success of future regimens.
Resistance-associated amino acid variants (RAVs) have been found in treatment-naive HCV as well as after drug exposure, thought to result from genetic variation inherent in the virus itself and selective pressure from drugs. Given as monotherapy, most DAAs rapidly select for HCV variants with reduced drug susceptibility resulting in virological failure and treatment rebound.[27] Although protocols instruct against monotherapy, reaffirmation of the mandate that these drugs not be used alone is important. Cross-reactivity has been shown in RAV between telaprevir and boceprevir and there is the theoretical risk for development of resistance to several protease inhibitors with injudicious use of one of the current regimens. Careful monitoring of stopping rules is essential in current therapies, particularly in the setting of treatment of prior null responders.[28] Fortunately, there are multiple different targets for therapy with differing genetic barriers to resistance. On the basis of what we have learned to this point, combination therapy will be the rule in the future.
New Drugs in Development
In addition to boceprevir and telaprevir, many new DAA and host-targeted drugs are in development
Protease Inhibitors: The Next Generation
Despite their limitations, protease inhibitors have high antiviral efficacy and will play an important role in future therapies. Newer protease inhibitors in development: asunaprevir, danoprevir, vaniprevir, MK-5172, BI-201335, and simeprevir are expected to have improved tolerance and safety profiles and will likely be used in combination with pegylated interferon and ribavirin or in newer DAA combination regimens in the future.
Polymerase Inhibitors: NS5B
Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. Their success has been demonstrated extensively in phase 1 and 2 trials, and they are expected to play an important role in newer DAA combination therapy regimens. The class comprises two types – nucleos(t)ide inhibitors and non-nucleotide inhibitors (NNIs). Nucleos(t)ide analogue inhibitors are active site inhibitors that mimic the natural substrates of the polymerase, being incorporated into the RNA chain and causing direct chain termination. As the active site of NS5B is highly conserved, these are potentially active against all the different genotypes. In addition, as amino acid substitutions in every position of the active site may result in loss of function, resistance to nucleos(t)ide analogue inhibitors is usually low. Mericitabine and sofosbuvir both have demonstrated convincing data in clinical trials.
Non-nucleoside inhibitors, on the contrary, bind to several discrete sites outside of the polymerase active center, which results in a conformational protein change before the elongation complex is formed – essentially inhibiting the polymerase from a distance. Resistance is more frequent with NNIs as NS5B is structurally organized into multiple different domains with at least four different binding sites. Mutations at the individual binding sites do not necessarily cause loss of function of the polymerase.[25] Drugs in this category are tegobuvir, filibuvir, BI-207127, VX-222, ANA598, ABT-333.
NS5A Inhibitors
NS5A is a membrane-associated phosphoprotein involved in HCV virion production and the viral life cycle. Daclatasvir, the first in its class NS5A inhibitor, exhibits high potency and is expected to have a broad range of genotypic coverage; it is synergistic with other DAAs. Several others are in development including ABT-267, GS-5885, PPI-461.[25,28]
Host-targeted Therapies
Several drugs are in development against host
targets. Cyclophilin inhibitors such as the cyclophilin A binding
molecule alisporivir appear to have potent anti-HCV activity and have
broad genotype activity for types 1–4. Alisporivir appears to inhibit
HCV viral replication by interfering with the interaction between
cyclophilin A and NS5A. In early trials with pegylated interferon and
ribavirin, an SVR rate into the 70% range was seen with 24 weeks of once
daily therapy and benefits have been confirmed in genotypes 2 and 3,
with particular success against genotype 3 and a very high barrier to
resistance.[23]
An additional host-targeted agent is the subcutaneously administered
drug, mirvirsen, which specifically targets the liver-specific micro-RNA
miR-122 that is involved in gene expression and HCV viral replication,
producing dramatic suppression of HCV viremia without evidence of RAV or
significant side effects in early trials. New interferons have also
been explored. Native human interferon lambda proteins are generated by
the immune system in response to viral infection. This interferon family
has been found to have antiviral activity against HCV. The interferon
and its receptor are both expressed at high levels by hepatocytes but
not all tissues suggesting that this reagent could have tissue specific
effects, potentially equating to reduced toxicity compared to current
experience with α-interferon.[23] This could be a better tolerated alternative to interferon α until oral regimens are available.
What About Interferon-free Regimens?
Interferon-free regimens are widely being tested in clinical trials with encouraging results. The following selected trials demonstrate how rapidly progress is being made. Beginning in 2010, studies demonstrated the potential for antiviral efficacy of an all-oral regimen using combinations of drugs with different targets.
Interferon-free regimen for the management of HCV-1 (INFORM-1) was a phase 1 proof of concept study from 2010 using combination DAA without interferon.[27] Danoprevir, an NS3/4A protease inhibitor, and RG7128 (later named mericitabine), a NS5B nucleoside polymerase inhibitor, were given for up to 13 days in multiple different dosing arms to assess the ability of an interferon-free regimen to suppress viral load. After the treatment period, all patients subsequently were given standard of care pegylated interferon and ribavirin for 48 weeks. Overall, the DAA combination therapy was well tolerated, and there were no treatment-related study withdrawals or dose reductions during the treatment period. Most common adverse event was headache. The DAA combination regimen showed very potent activity against HCV in all participants, including previous null responders giving encouragement that interferon-free all DAA regimens are possible. Of note, patients with cirrhosis were excluded.
SOUND-1 and SOUND-2 trials included an NS3/4A protease inhibitor (BI-201335) and an NNI NS5B polymerase inhibitor (BI-207127) and ribavirin to demonstrate proof of potent antiviral activity against HCV with rapid viral response rates of 73–100% dependent on dosing. Genotype 1b responded more favorably than 1a and the ribavirin-sparing arm in the later trial showed reasonable but substantially lower response rates. Final results were presented in abstract form at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting 2012.[29] Patient results were randomized by genotype 1a versus 1b and by IL-28 genotype CC/CT/TT. Ribavirin arms with variable DAA dosing demonstrated a range in SVR12 (SVR after only 12 weeks off therapy), of 52–69% but only 39% in ribavirin-free arms. Genotype 1b responded better than 1a and IL-28 appeared to be an independent predictor of SVR. All IL-28 genotype of 1b and IL-28 CC 1a patients demonstrated SVR 12 rates as high as 84% with the all-oral regimen.
More recently, exciting results from the phase 2 ELECTRON trial were reported.[30] Sofosbuvir (formerly known as GS-7977) NS5B polymerase inhibitor in a once daily dose was combined with ribavirin for 12 weeks, pegylated interferon and ribavirin for 4, 8, or 12 weeks in naive patients with genotypes 2 or 3 or sofosbuvir monotherapy for 12 weeks in naive patients with genotypes 2 or 3. An additional group of 35 genotype 1 patients was enrolled, 25 naive patients and 10 prior nonresponders who were also treated with sofosbuvir and ribavirin for 12 weeks. After 24 weeks of therapy, all naive genotype 2 and 3 patients on combination therapy had an SVR at 24 weeks (100%). SVR was seen in only 60% of the genotype 2 and 3 patients on monotherapy. Among genotype 1, treatment-naive patients demonstrated 84% SVR and prior nonresponders fared less well with an SVR of only 10%. Sofosbuvir appears to be well tolerated and to have a high barrier to resistance. This study suggests a new DAA option may soon be available for naive patients with genotype 1, 2, and 3; however, ribavirin still plays a role in maintenance of an antiviral response.[30]
Another new phase 2 clinical trial was found to show even better responses in genotype 1 patients. ABT-450 (an NS3 protease inhibitor) combined with low-dose ritonavir, ABT-333 (a non-nucleoside NS5B polymerase inhibitor), and ribavirin were used in varying doses in treatment-naive and experienced patients excluding those with cirrhosis for 12 weeks. Treatment-naive patients demonstrated an SVR12 of 93–95% depending on dose and treatment experienced patients an SVR12 of 47%. Some viral breakthrough and resistance was noted during treatment in the prior nonresponder population and the study suggests this population will need a modified DAA regimen as extending duration would not have changed outcome. Overall, this 12-week combination therapy may be an effective future therapy for HCV genotype 1.[31]
Conclusion
We are once again preparing for a dramatic paradigm shift in approach to HCV infection. Worldwide, the epidemic proportions of HCV are coming to light both in the efforts of healthcare workers and governments in the underdeveloped world and in the burden from untreated and undiagnosed disease in the developed world. Numerous new drugs targeting various aspects of the HCV life cycle and the host are in development and clinical trials. Overall, combination therapies will be the rule. New combinations of DAA have synergistic effects, decrease the risk of resistance, and improve antiviral efficacy, are effective in different genotypes and have a favorable safety profile. Despite universal hope for all-oral regimens, pegylated-IFN is still in the literature. Many phase 1 and 2 clinical trials are still designed to demonstrate the safety of new DAA in combination with a pegylated interferon and ribavirin backbone and though the best response rates in interferon containing regimens still tend to be in favorable genotypes or IL-28 CC patients, the important benefit in these combinations is much shorter treatment duration of 12 weeks. Interferon-free combination regimens appear to be on the horizon, providing a new option in particular for patients with non-genotype 1 HCV, but there will still be treatment failures and resistance issues to be overcome, particularly in the treatment experienced population.
http://www.medscape.com/viewarticle/802844_1
Recent findings: Boceprevir-based and telaprevir-based triple therapy with pegylated interferon and ribavirin marked the beginning of a new era in HCV therapy for genotype 1 patients. New direct-acting antivirals (DAAs) are being developed and new antiviral drug targets are being explored. New combination treatment regimens are expected to emerge soon and there is hope for interferon-free regimens.
Summary: The standard of care for treatment of HCV genotype 1 changed dramatically with the approval of two new DAA drugs – telaprevir and boceprevir – for use in pegylated interferon-based and ribavirin-based triple therapy in mid-2011. Experience has shown improved response rates and treatment durations for many patients with genotype 1 HCV infection. However, persistent limitations to HCV treatment still exist for patients with prior treatment failure and comorbid conditions and patients on newer therapies suffer additional therapy-limiting side effects and drug–drug interactions. Genetic testing may provide some guidance but additional options for therapy are still needed for HCV. Many new drugs are currently under investigation and there is hope that effective and well tolerated interferon-free regimens may become a part of future therapy.
Introduction
An estimated 130–170 million people are infected with hepatitis C worldwide leading to significant morbidity, mortality, and financial burden on healthcare.[1] Out of 100 people who contract the infection, 75–85% will develop chronic infection, 60–70% will develop chronic liver disease, 5–20% will develop cirrhosis over the course of their chronic infection, and 1–5% will die of complications including hepatocellular carcinoma (HCC).[1,2] The majority of the infected population in the United States, an estimated 3.2–3.7 million people, are believed to have been born between 1945 and 1965 and likely contracted the virus when transmission rates were highest in the 1970s and 1980s.[3,4] Hepatitis C virus (HCV) has a long and relatively symptom-free incubation period prior to causing serious illness. Although the contribution of blood product screening, disposable medical equipment, and public health education efforts over the years has led to a decrease in the incidence of HCV in the United States, an estimated 65–75% of currently infected individuals in the United States are unaware of their infection. The consequences of these undiagnosed and untreated chronic infections are expected to be staggering as this population ages with predictive models suggesting a two-fold increase in HCV-related deaths with direct medical costs exceeding $6.7 billion between 2010 and 2019[5] and, without intervention, a four-fold rise in the incidence of end-stage liver disease related to hepatitis C within the next 20 years.[6] An effort to capture these patients has led to the recent Centers for Disease Control and Prevention recommendations for birth cohort screening of the population born between 1945 and 1965 in the United States.[4]
Outside of the United States, many other countries worldwide face significant HCV infection rates. Despite aggressive programs toward education, care, and treatment over the last 10 years, Egypt faces the largest burden of HCV infection in the world with a 10% prevalence of chronic hepatitis C infection among persons aged 15–59 years, predominantly genotype 4.[7] In many parts of the world the virus remains unchecked because of continued unsafe medical practices, lack of public health education, and lack of funding for research and treatment. Perz et al. [8] looked at 11 WHO-based regions in 2006 and estimated that globally 27% of cirrhosis was attributable to HCV and 25% of HCC was attributable to HCV. In many countries and populations, only a small number of patients with known infection actually receive treatment and yet successful treatment has been shown to have a significant impact on outcomes.[6,9] A sustained virological response (SVR) to hepatitis C therapy reduces liver-related as well as all-cause mortality for patients with hepatitis C[3,8] including a 70–80% reduction in overall liver-related mortality and hepatic decompensation and a 75% reduction in risk of HCC at all stages of fibrosis.[4,10]
Until 2011, the historically accepted standard therapy with pegylated interferon and ribavirin produced an SVR rate of approximately 40–50% for genotype 1 patients and higher rates up to 80% for alternate genotypes after 24–48 weeks of therapy.[11] The limitations of this therapy are well recognized. Pregnant patients or those with advanced renal disease are contraindicated from using ribavirin. Likewise, interferon therapy excludes patients with autoimmune diseases, uncontrolled depression and mental illness, decompensated liver disease (child turcotte pugh > 6) or decompensated cardiac or pulmonary disease. Patients experienced frequent side effects and those failing therapy due to relapse, non or null response had few options. This led to aggressive research into additional treatment targets and ways to predict patient response to treatment.
Viral Structure
What was first known as non-A, non-B hepatitis was designated hepatitis C in 1989 by Michael Houghton and scientists at Chiron Corporation while searching for the blood-borne cause of hepatitis in transfusion recipients (see Fig. 1).[12] Hepatitis C is a single-stranded RNA flavivirus of the hepacivirus genus. Of the six genotypes, genotype 1 is the most prominent in the United States and Europe. The virus lacks proofreading ability leading to significant genetic variation, historically making drug development against the virus challenging. When the virus enters a liver cell, it releases its RNA and is translated into a poly-protein containing structural and nonstructural regions. The poly-protein is processed by proteases into several polypeptides with different functional roles in the virus life cycle. The virus is replicated with the help of a polymerase and then assembled, transported, and released from the cell. The nonstructural region codes for the polypeptides NS2, NS3, NS4A, NS4B, NS5A, and NS5B. All are potential targets for drug therapy. Initial cleavage of the poly-protein is performed by the NS3/NS4A protease, which seems to be highly conserved across most strains, and, without which, the HCV life cycle cannot proceed.[13] This region became the first therapeutic target for direct-acting antiviral (DAA) therapy, the NS3/NS4 protease inhibitors telaprevir and boceprevir.
Figure 1.
The Era of Triple Therapy
First-generation Protease Inhibitors: Lessons From Telaprevir and Boceprevir
Telaprevir efficacy was initially proven in multiple large multicenter trials including protease inhibition for viral evaluation-1 (PROVE-1), PROVE-2, PROVE-3, ADVANCE, REALIZE, and illustrating the effects of combinatherapy with telaprevir (ILLUMINATE).[13–16] The importance of ribavirin was confirmed by demonstration of significant viral breakthrough and relapse after therapy in patients in a pegylated interferon and telaprevir study arm without ribavirin. These early trials developed and confirmed the utility of RGT, suggesting that a shortened duration of therapy was acceptable for patients meeting certain criteria and 24 weeks of telaprevir-based therapy was noninferior to 48 weeks of triple therapy in patients meeting appropriate criteria. Differences have been observed in treatment failure rates between genotypes 1a and 1b and in various difficult-to-treat groups. African–Americans, those with high-viral loads, bridging fibrosis or cirrhosis demonstrated somewhat improved rapid viral response with new agents but responses are still decreased compared with those observed in naive, noncirrhotic patients.[14–17]
Conceptually, the Peg-interferon/ribavirin lead-in was introduced to bring the baseline viral load down prior to starting boceprevir and, in turn, decrease the emergence of drug-resistant mutations. SVR was similar in the 28-week and 48-week groups that demonstrated at least a 1.5 log drop in viral load after the 4-week lead-in therapy phase. Patients in the 28-week triple therapy arm that did not demonstrate the 1.5 log drop after lead-in showed a poor SVR of 30% or less at 28 weeks compared with the corresponding 48-week group. The overall conclusion was that RGT based on 4-week lab values would help predict the best duration of treatment.[18] Serine protease inhibitor therapy trial-2 (SPRINT-2) stratified black and non-black patients into different arms and again demonstrated persistently lower SVR rates for black patients versus non-blacks, suggesting interferon resistance continued to play a role.[19] Additional studies suggest that the use of interleukin (IL)-28 genotyping (rs 12979860) may also identify patients who are more likely to qualify for shorter treatment durations in RGT with boceprevir.[19,20] Thus, interferon responsiveness is important in prediction of response to triple therapy; patients with a poor response to interferon might be best served by waiting for improved future therapies.
Limitations of First-generation Direct-acting Antiviral Therapy
Although the advent of triple therapy with boceprevir and telaprevir has improved response rates and treatment durations for many patients with genotype 1 disease, the phase 3 clinical trials demonstrated that many still do not achieve SVR. In addition, drug–drug interactions limit use, the high pill burden makes compliance difficult and resistance is still a real threat with unclear future implications. New rashes and anorectal symptoms are seen with telaprevir and moderate-to-severe anemia is common in both regimens.[16,19,21] In December 2012, a black box warning was added to telaprevir labeling in light of some rashes resulting in death.[22]
What is Needed: Goals for the Future
Traditionally HCV therapy has been nonspecific in its therapeutic target. Interferon activates the immune system and inhibits viral replication whereas ribavirin is a nonspecific antiviral that may inhibit viral replication but also aid in viral clearance though its true function against HCV is elusive.[23,24] Newer therapies directed against specific viral and host targets appear to have greater potential for success.
Epidemiologists have produced a long list of barriers to HCV treatment including goals for future HCV medications including: improved tolerance, high potency, favorable safety profile, high barrier to resistance, all oral regimen, pan-genotypic, favorable pill burden, short duration, few drug interactions, available for cirrhosis, HIV, mental illness, and affordable.[5,9] For the first time, ongoing research suggests that many of these goals may be realistic.
Understanding Direct-acting Antiviral Resistance is Important for the Future
Drug resistance was noted in some form with both telaprevir and boceprevir in the early protease inhibitor trials, impacting the final structure of treatment protocols. Specifically, ribavirin use is required by all protocols and genotypic subtypes 1a and 1b demonstrate a recognizable difference in rates of SVR. The findings are explained by the very low genetic barrier to resistance of protease inhibitors as a class, defined as the number of amino acid substitutions required to confer full resistance to a drug.[25,26] In general, DAAs with a low genetic barrier to resistance require only 1–2 amino acid substitutions for high resistance and DAAs with a high barrier to resistance usually require 3–4 amino acid substitutions in the same region. Telaprevir resistance is recognized to most frequently be represented by mutation R155K. The R-K change requires only one nucleotide change in genotype 1a, whereas genotype 1b requires two nucleotide changes. The amino acid target sequence of the NS3 region differs significantly between HCV genotypes (explaining why telaprevir and boceprevir have efficacy limited to genotype 1) and resistance can develop easily with few mutations.[25] The barrier to genetic resistance of DAA in development will be a critical factor in the success of future regimens.
Resistance-associated amino acid variants (RAVs) have been found in treatment-naive HCV as well as after drug exposure, thought to result from genetic variation inherent in the virus itself and selective pressure from drugs. Given as monotherapy, most DAAs rapidly select for HCV variants with reduced drug susceptibility resulting in virological failure and treatment rebound.[27] Although protocols instruct against monotherapy, reaffirmation of the mandate that these drugs not be used alone is important. Cross-reactivity has been shown in RAV between telaprevir and boceprevir and there is the theoretical risk for development of resistance to several protease inhibitors with injudicious use of one of the current regimens. Careful monitoring of stopping rules is essential in current therapies, particularly in the setting of treatment of prior null responders.[28] Fortunately, there are multiple different targets for therapy with differing genetic barriers to resistance. On the basis of what we have learned to this point, combination therapy will be the rule in the future.
New Drugs in Development
In addition to boceprevir and telaprevir, many new DAA and host-targeted drugs are in development
| NS3/4A protease inhibitors | NS5A | NS5B polymerase nucleos(t)ide | NS5B | NNI Host targets |
|---|---|---|---|---|
| Asunaprevir | Daclatasvir | Mericitabine | Tegobuvir | Alisporovir |
| Vaniprevir | ABT-267 | Sofasbuvir | Filibuvir | Mirvirsen |
| Danoprevir | GS-5885 | IDX184 | BI-207127 |  |
| MK-5172 | PPI-461 | PSI-938 | VX-222 | lambda IFN |
| BI-201335 | BMS791325 | Setrobuvir | | |
| Simeprevir | | ABT-333 | | |
| Tibotec | INX-189 | | | |
| ABT-450 | | | | |
Protease Inhibitors: The Next Generation
Despite their limitations, protease inhibitors have high antiviral efficacy and will play an important role in future therapies. Newer protease inhibitors in development: asunaprevir, danoprevir, vaniprevir, MK-5172, BI-201335, and simeprevir are expected to have improved tolerance and safety profiles and will likely be used in combination with pegylated interferon and ribavirin or in newer DAA combination regimens in the future.
Polymerase Inhibitors: NS5B
Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. Their success has been demonstrated extensively in phase 1 and 2 trials, and they are expected to play an important role in newer DAA combination therapy regimens. The class comprises two types – nucleos(t)ide inhibitors and non-nucleotide inhibitors (NNIs). Nucleos(t)ide analogue inhibitors are active site inhibitors that mimic the natural substrates of the polymerase, being incorporated into the RNA chain and causing direct chain termination. As the active site of NS5B is highly conserved, these are potentially active against all the different genotypes. In addition, as amino acid substitutions in every position of the active site may result in loss of function, resistance to nucleos(t)ide analogue inhibitors is usually low. Mericitabine and sofosbuvir both have demonstrated convincing data in clinical trials.
Non-nucleoside inhibitors, on the contrary, bind to several discrete sites outside of the polymerase active center, which results in a conformational protein change before the elongation complex is formed – essentially inhibiting the polymerase from a distance. Resistance is more frequent with NNIs as NS5B is structurally organized into multiple different domains with at least four different binding sites. Mutations at the individual binding sites do not necessarily cause loss of function of the polymerase.[25] Drugs in this category are tegobuvir, filibuvir, BI-207127, VX-222, ANA598, ABT-333.
NS5A Inhibitors
NS5A is a membrane-associated phosphoprotein involved in HCV virion production and the viral life cycle. Daclatasvir, the first in its class NS5A inhibitor, exhibits high potency and is expected to have a broad range of genotypic coverage; it is synergistic with other DAAs. Several others are in development including ABT-267, GS-5885, PPI-461.[25,28]
Host-targeted Therapies
What About Interferon-free Regimens?
Interferon-free regimens are widely being tested in clinical trials with encouraging results. The following selected trials demonstrate how rapidly progress is being made. Beginning in 2010, studies demonstrated the potential for antiviral efficacy of an all-oral regimen using combinations of drugs with different targets.
Interferon-free regimen for the management of HCV-1 (INFORM-1) was a phase 1 proof of concept study from 2010 using combination DAA without interferon.[27] Danoprevir, an NS3/4A protease inhibitor, and RG7128 (later named mericitabine), a NS5B nucleoside polymerase inhibitor, were given for up to 13 days in multiple different dosing arms to assess the ability of an interferon-free regimen to suppress viral load. After the treatment period, all patients subsequently were given standard of care pegylated interferon and ribavirin for 48 weeks. Overall, the DAA combination therapy was well tolerated, and there were no treatment-related study withdrawals or dose reductions during the treatment period. Most common adverse event was headache. The DAA combination regimen showed very potent activity against HCV in all participants, including previous null responders giving encouragement that interferon-free all DAA regimens are possible. Of note, patients with cirrhosis were excluded.
SOUND-1 and SOUND-2 trials included an NS3/4A protease inhibitor (BI-201335) and an NNI NS5B polymerase inhibitor (BI-207127) and ribavirin to demonstrate proof of potent antiviral activity against HCV with rapid viral response rates of 73–100% dependent on dosing. Genotype 1b responded more favorably than 1a and the ribavirin-sparing arm in the later trial showed reasonable but substantially lower response rates. Final results were presented in abstract form at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting 2012.[29] Patient results were randomized by genotype 1a versus 1b and by IL-28 genotype CC/CT/TT. Ribavirin arms with variable DAA dosing demonstrated a range in SVR12 (SVR after only 12 weeks off therapy), of 52–69% but only 39% in ribavirin-free arms. Genotype 1b responded better than 1a and IL-28 appeared to be an independent predictor of SVR. All IL-28 genotype of 1b and IL-28 CC 1a patients demonstrated SVR 12 rates as high as 84% with the all-oral regimen.
More recently, exciting results from the phase 2 ELECTRON trial were reported.[30] Sofosbuvir (formerly known as GS-7977) NS5B polymerase inhibitor in a once daily dose was combined with ribavirin for 12 weeks, pegylated interferon and ribavirin for 4, 8, or 12 weeks in naive patients with genotypes 2 or 3 or sofosbuvir monotherapy for 12 weeks in naive patients with genotypes 2 or 3. An additional group of 35 genotype 1 patients was enrolled, 25 naive patients and 10 prior nonresponders who were also treated with sofosbuvir and ribavirin for 12 weeks. After 24 weeks of therapy, all naive genotype 2 and 3 patients on combination therapy had an SVR at 24 weeks (100%). SVR was seen in only 60% of the genotype 2 and 3 patients on monotherapy. Among genotype 1, treatment-naive patients demonstrated 84% SVR and prior nonresponders fared less well with an SVR of only 10%. Sofosbuvir appears to be well tolerated and to have a high barrier to resistance. This study suggests a new DAA option may soon be available for naive patients with genotype 1, 2, and 3; however, ribavirin still plays a role in maintenance of an antiviral response.[30]
Another new phase 2 clinical trial was found to show even better responses in genotype 1 patients. ABT-450 (an NS3 protease inhibitor) combined with low-dose ritonavir, ABT-333 (a non-nucleoside NS5B polymerase inhibitor), and ribavirin were used in varying doses in treatment-naive and experienced patients excluding those with cirrhosis for 12 weeks. Treatment-naive patients demonstrated an SVR12 of 93–95% depending on dose and treatment experienced patients an SVR12 of 47%. Some viral breakthrough and resistance was noted during treatment in the prior nonresponder population and the study suggests this population will need a modified DAA regimen as extending duration would not have changed outcome. Overall, this 12-week combination therapy may be an effective future therapy for HCV genotype 1.[31]
Conclusion
We are once again preparing for a dramatic paradigm shift in approach to HCV infection. Worldwide, the epidemic proportions of HCV are coming to light both in the efforts of healthcare workers and governments in the underdeveloped world and in the burden from untreated and undiagnosed disease in the developed world. Numerous new drugs targeting various aspects of the HCV life cycle and the host are in development and clinical trials. Overall, combination therapies will be the rule. New combinations of DAA have synergistic effects, decrease the risk of resistance, and improve antiviral efficacy, are effective in different genotypes and have a favorable safety profile. Despite universal hope for all-oral regimens, pegylated-IFN is still in the literature. Many phase 1 and 2 clinical trials are still designed to demonstrate the safety of new DAA in combination with a pegylated interferon and ribavirin backbone and though the best response rates in interferon containing regimens still tend to be in favorable genotypes or IL-28 CC patients, the important benefit in these combinations is much shorter treatment duration of 12 weeks. Interferon-free combination regimens appear to be on the horizon, providing a new option in particular for patients with non-genotype 1 HCV, but there will still be treatment failures and resistance issues to be overcome, particularly in the treatment experienced population.
http://www.medscape.com/viewarticle/802844_1
Thursday, March 28, 2013
Watch - Miravirsen: First microRNA-targeted drug effective for hepatitis C
Uploaded Mar 27 - UMassMedicalSchool·
Miravirsen, the first microRNA-targeted drug to enter human clinical trials, successfully reduced hepatitis C (HCV) RNA levels in patients with chronic HCV infection in a phase 2a trial, according to results published March 27 in the New England Journal of Medicine. The development opens the door to a potential new treatment for the disease.
“This is particularly exciting for patients with chronic hepatitis infection,” said Gyongyi Szabo, MD, PhD, professor of medicine and a translational scientist studying chronic hepatitis C infection and liver function, who was not involved in the trial. “This may represent a new type of therapy that has the potential for future treatments in patients with the most difficult hepatitis C type to treat—genotype 1. Especially when one considers that current treatments have many side effects and limited efficacy.”
Globally, as many as 170 million people are estimated to suffer from HCV infection. Chronic HCV is a major cause of liver cirrhosis, liver failure, hepatocellular carcinoma and is the leading cause of liver transplants in the United States.
Inside the liver, the hepatitis C virus uses a liver-specific microRNA-122 (miR-122) molecule normally important for cholesterol metabolism to replicate. Miravirsen, developed by Santaris Pharma, works by sequestering and effectively inhibiting miR-122 so the virus can’t use it to propagate.
In the study, a total of 36 patients with chronic HCV genotype 1 received various doses of Miravirsen over a 29-day period. Two weeks after treatment, five patients receiving the two highest doses of the drug showed no observable signs of HCV RNA.
Essential for turning genes on and off, microRNA was discovered in 1993 by Victor R. Ambros, PhD, the Silverman Chair in Natural Sciences and professor of molecular medicine.
Additional Information-
Miravirsen- Hepatitis C drug goes after patients’ RNA
Results - New England Journal of Medicine
Wednesday, March 27, 2013
Miravirsen- Hepatitis C drug goes after patients’ RNA
Hepatitis C drug goes after patients’ RNA
Experimental Drug May Work Against Hepatitis C
Miravirsen greatly reduced virus in patients in small study
March 27, 2013
By Maureen Salamon HealthDay Reporter
WEDNESDAY, March 27 (HealthDay News) -- An experimental therapy for hepatitis C -- a "silent killer" linked to liver cancer and cirrhosis -- has shown promise in tamping down virus levels in early trials. Experts caution, however, that it's too soon to know if the injectable drug will someday gain a standing among emerging oral medications against the disease.
New research suggests that the drug, miravirsen, could potentially be part of a drug "cocktail" that manages the hepatitis C virus in much the same way as similar combinations have transformed HIV/AIDS from a death sentence into a chronic, manageable condition. Miravirsen suppresses molecules the hepatitis C virus needs to reproduce.
The drug decreased viral loads by about 500-fold at the highest doses used in a small, phase 2 study by an international group of researchers. Drug resistance, a common problem with other hepatitis C medications, did not develop among patients taking miravirsen. A phase 2 trial evaluates a drug's effectiveness while continuing to assess its safety.
"This is the first real clinical study of this approach and the results are encouraging," said Dr. Judy Lieberman, chairwoman of cellular and molecular medicine at Boston Children's Hospital. "What's exciting to me is that there doesn't seem to be any drug resistance developing. If there's a way to develop a drug cocktail that doesn't require a half a year of treatment ... that would be really exciting, but it's too early to tell."
Lieberman was not involved in the research but co-wrote an editorial accompanying the new study in the March 27 issue of the New England Journal of Medicine.
Hepatitis C is one form of liver disease and affects about 170 million people worldwide, according to study background information. It's transmitted by shared needles or, less frequently, through sex.
Often symptomless, the infection is a major cause of liver cancer and cirrhosis, or scarring of the liver.
Led by Dr. Harry Janssen, a professor of medicine at the University of Toronto and Erasmus University Rotterdam in the Netherlands, researchers split 36 patients with hepatitis C into four groups.
Nine patients in each of the first three groups received a dose of either 3 milligrams (mg), 5 mg or 7 mg of miravirsen per kilogram of body weight for 29 days, while the last nine patients received a placebo. All were followed for 18 weeks. The so-called viral load of patients receiving the highest dose decreased by about 500-fold, Lieberman said, and the hepatitis C virus was below detectable levels in four of nine patients.
Meanwhile, the treatment caused no significant toxic effects in any patients, aside from mild injection-site reactions and a brief increase in liver enzyme levels. Calling the study "interesting," Dr. David Bernstein, chief of the division of hepatology at North Shore University Hospital in Manhasset, N.Y., said that as an injectable drug, miravirsen would be less desirable among patients than other new drugs for hepatitis C that can be taken orally.
"It's a novel concept, but it's only 36 patients and a phase 2 study," Bernstein said. "It's impressive that their viral loads came down, but most suffered a recurrence of the virus."
More information
The U.S. Centers for Disease Control and Prevention has more about hepatitis C.
Copyright © 2012 HealthDay. All rights reserved.
Research Published in the New England Journal of Medicine Demonstrates Marked and Long-Lasting Antiviral Activity Against HCV for Santaris Pharma A/S' Miravirsen, the First MicroRNA-Targeted Drug to Enter Clinical Trials
Final Phase 2a results show dose-dependent, prolonged antiviral activity in Hepatitis C patients --
HOERSHOLM, Denmark and SAN DIEGO, March 27, 2013 /PRNewswire via COMTEX/ --
Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, today announced the publication of study results online in the New England Journal of Medicine (NEJM). The publication highlights the potential benefits of miravirsen, a host-targeted, pan-HCV genotype anti-viral agent and the first microRNA-targeted drug to enter clinical trials for the treatment of Hepatitis C virus (HCV). In the study, miravirsen, given as a four-week monotherapy treatment, provided robust dose-dependent antiviral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA (log10 IU/mL). The effect was sustained well beyond the end of therapy.
Clinical data from the Phase 2a study demonstrated the following:
-- Miravirsen was safe, well tolerated and provided prolonged antiviral activity well after the last dose of miravirsen monotherapy (x5 weekly injections)
-- There were no signs of viral resistance
-- Adverse events were infrequent, mild and did not lead to study drug discontinuation
-- There were no dose limiting toxicities or discontinuations due to adverse events
-- Miravirsen was associated with dose-dependent reductions in HCV RNA that were sustained well beyond the end of the four-week dosing period
-- Four out of nine patients treated at the highest dose (7 mg/kg) with miravirsen became HCV RNA undetectable with just five weekly doses of miravirsen monotherapy
"We are excited because the data show that miravirsen offers long-lasting suppression of HCV RNA, a high barrier to viral resistance, a favorable tolerability and dosing profile, a low propensity for drug interactions and a very long duration of action. All of these properties suggest that miravirsen's unique mechanism-of-action may offer a potential cure for Hepatitis C patients, either in combination with other antiviral agents or as a monotherapy," said Harry Janssen, M.D., Head of the Liver Clinic at Toronto Western and Toronto General Hospital and lead author of the NEJM publication. "Due to its ability to target the host factor miR-122, miravirsen has the potential to change the way Hepatitis C is treated. This study is also the first to prove that blocking microRNA can be effective in treating Hepatitis C in humans without limiting side effects. This trial is a landmark study for new therapeutic modalities in many other diseases where microRNA's play a role, such as in cardiovascular disease, cancer and metabolic disorders."
Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is an inhibitor of miR-122, a liver specific microRNA that the Hepatitis C virus requires for replication. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the Hepatitis C virus. As a result, the replication of the virus is effectively inhibited and the level of Hepatitis C virus is profoundly reduced.
"This is a seminal moment for the microRNA community as miravirsen is the first microRNA targeted drug to show efficacy in clinical trials, and we are honoured that such a prestigious journal as the New England Journal of Medicine has published this work," said Henrik Stage, Chief Executive Officer at Santaris Pharma A/S. "It's amazing to think that the journey from bench to bedside has occurred over such a short span of time. Recall that human microRNAs were only discovered in 2001, and miR-122's role in the HCV lifecycle determined in 2005. Based on the published results, microRNA targeted therapy has shown its potential to become a new important class of drugs, and the LNA platform has demonstrated its role as the chemistry of choice for RNA targeted therapies."
The randomized, double-blind, placebo-controlled, ascending multiple-dose Phase 2a study assessed the safety and tolerability of miravirsen in treatment-naive patients with chronic HCV genotype 1 infection. Patients were enrolled sequentially to one of three cohorts (9 active:3 placebo per cohort) at doses of 3, 5 and 7 mg/kg. Miravirsen was given as a total of 5 weekly subcutaneous injections over 29 days.
"These study results are the culmination of over 6 years of microRNA research at Santaris Pharma A/S," said Michael R. Hodges, MD, Vice President and Chief Medical Officer at Santaris Pharma A/S. "The results of this study highlight miravirsen's exceptional high barrier to resistance, long duration of action and good tolerability. Miravirsen would be especially suitable for treatment of hard-to-treat patients, for example those patients who have already failed treatment with pegylated-interferon and ribavirin combination or protease inhibitor triple therapy." Dr. Hodges continued, "Longer treatment durations of miravirsen are currently being tested in clinical trials in subjects who have failed initial therapy for HCV infection."
About Hepatitis CHepatitis C infection is a viral disease caused by the Hepatitis C virus that leads to inflammation of the liver. The World Health Organization estimates that approximately 3 percent of the world's population have been infected with HCV and that some 170 million have chronic hepatitis C and are at risk of developing liver cirrhosis and/or liver cancer[i]. Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per year[ii]. In Europe, there are about 4 million carriers[i]. The current standard of care treatment for genotype 1 is a protease inhibitor given with pegylated-interferon a and ribavirin. This triple combination is effective in about 70-80% of those treated[ii]. Patients that are not effectively treated have an increased risk for the progression of liver disease. By 2029, total annual medical costs in the United States for people with Hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion[iii].
About microRNAsMicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.
About Locked Nucleic Acid (LNA) Drug PlatformThe LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including cardiometabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. LNA-based drugs are a promising new class of therapeutics that are enabling scientists to develop drug candidates to work through previously inaccessible clinical pathways. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drugs candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.
About Santaris Pharma A/SSantaris Pharma A/S is a privately held clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Locked Nucleic Acid (LNA) Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combine the company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The company's research and development activities focus on infectious diseases and cardiometabolic disorders, while partnerships with major pharmaceutical companies include a range of therapeutic areas including cancer, cardiovascular disease, infectious and inflammatory diseases, and rare genetic disorders. The company has strategic partnerships with miRagen Therapeutics, Shire plc., Pfizer, GlaxoSmithKline, and Enzon Pharmaceuticals. As part of its broad patent estate, the company holds exclusive worldwide rights to manufacture and sell products that comprise LNA as active ingredient for studies performed with a view to obtaining marketing approval. Santaris Pharma A/S, founded in 2003, is headquartered in Denmark with operations in the United States. Please visit www.santaris.com for more information.
Santaris Pharma A/S® is a registered trademark of Santaris Pharma A/S. Santaris(TM) and LNA-antimiR(TM) are trademarks of Santaris Pharma A/S.
[i] World Health Organization - http://www.who.int/csr/disease/hepatitis/Hepc.pdf ii] Jacobson IM. Telaprevir for previously untreated chronic hepatitis C virus infection. NEJM 2011;364:2405-16[iii] Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx.
SOURCE Santaris Pharma A/S
Compound targets genetic material that virus uses for replicating
By Nathan Seppa
Web edition: March 27, 2013
No matter what medications doctors throw at hepatitis C, it continues to defy treatment in some patients. But a new compound offers an approach quite apart from the rest: It assaults a kind of RNA that is implicated in allowing the virus to gain a foothold.
In most of a small group of patients who took the experimental drug, virus levels were knocked down, sometimes below the threshold of detection. The drug does this by targeting genetic material in the liver called microRNA-122. The hepatitis virus normally attaches to this RNA, gaining the stability it needs to propagate while hiding from immune system patrols.
The new drug, called miravirsen, binds to microRNA-122, sequesters it and indirectly thwarts viral replication, says study coauthor Harry Janssen, a hepatologist and physician at the University of Toronto. Janssen and colleagues report the findings March 27 in the New England Journal of Medicine.
Miravirsen greatly reduced virus in patients in small study
March 27, 2013
By Maureen Salamon HealthDay Reporter
WEDNESDAY, March 27 (HealthDay News) -- An experimental therapy for hepatitis C -- a "silent killer" linked to liver cancer and cirrhosis -- has shown promise in tamping down virus levels in early trials. Experts caution, however, that it's too soon to know if the injectable drug will someday gain a standing among emerging oral medications against the disease.
New research suggests that the drug, miravirsen, could potentially be part of a drug "cocktail" that manages the hepatitis C virus in much the same way as similar combinations have transformed HIV/AIDS from a death sentence into a chronic, manageable condition. Miravirsen suppresses molecules the hepatitis C virus needs to reproduce.
The drug decreased viral loads by about 500-fold at the highest doses used in a small, phase 2 study by an international group of researchers. Drug resistance, a common problem with other hepatitis C medications, did not develop among patients taking miravirsen. A phase 2 trial evaluates a drug's effectiveness while continuing to assess its safety.
"This is the first real clinical study of this approach and the results are encouraging," said Dr. Judy Lieberman, chairwoman of cellular and molecular medicine at Boston Children's Hospital. "What's exciting to me is that there doesn't seem to be any drug resistance developing. If there's a way to develop a drug cocktail that doesn't require a half a year of treatment ... that would be really exciting, but it's too early to tell."
Lieberman was not involved in the research but co-wrote an editorial accompanying the new study in the March 27 issue of the New England Journal of Medicine.
Hepatitis C is one form of liver disease and affects about 170 million people worldwide, according to study background information. It's transmitted by shared needles or, less frequently, through sex.
Often symptomless, the infection is a major cause of liver cancer and cirrhosis, or scarring of the liver.
Led by Dr. Harry Janssen, a professor of medicine at the University of Toronto and Erasmus University Rotterdam in the Netherlands, researchers split 36 patients with hepatitis C into four groups.
Nine patients in each of the first three groups received a dose of either 3 milligrams (mg), 5 mg or 7 mg of miravirsen per kilogram of body weight for 29 days, while the last nine patients received a placebo. All were followed for 18 weeks. The so-called viral load of patients receiving the highest dose decreased by about 500-fold, Lieberman said, and the hepatitis C virus was below detectable levels in four of nine patients.
Meanwhile, the treatment caused no significant toxic effects in any patients, aside from mild injection-site reactions and a brief increase in liver enzyme levels. Calling the study "interesting," Dr. David Bernstein, chief of the division of hepatology at North Shore University Hospital in Manhasset, N.Y., said that as an injectable drug, miravirsen would be less desirable among patients than other new drugs for hepatitis C that can be taken orally.
"It's a novel concept, but it's only 36 patients and a phase 2 study," Bernstein said. "It's impressive that their viral loads came down, but most suffered a recurrence of the virus."
More information
The U.S. Centers for Disease Control and Prevention has more about hepatitis C.
Copyright © 2012 HealthDay. All rights reserved.
Original Article-New England Journal of Medicine
Treatment of HCV Infection by Targeting MicroRNA
March 27, 2013DOI: 10.1056/NEJMoa1209026
Background
The
stability and propagation of hepatitis C virus (HCV) is dependent on a
functional interaction between the HCV genome and liver-expressed
microRNA-122 (miR-122). Miravirsen is a locked nucleic acid–modified DNA
phosphorothioate antisense oligonucleotide that sequesters mature
miR-122 in a highly stable heteroduplex, thereby inhibiting its
function.
Methods
In
this phase 2a study at seven international sites, we evaluated the
safety and efficacy of miravirsen in 36 patients with chronic HCV
genotype 1 infection. The patients were randomly assigned to receive
five weekly subcutaneous injections of miravirsen at doses of 3 mg, 5
mg, or 7 mg per kilogram of body weight or placebo over a 29-day period.
They were followed until 18 weeks after randomization.
Results
Miravirsen
resulted in a dose-dependent reduction in HCV RNA levels that endured
beyond the end of active therapy. In the miravirsen groups, the mean
maximum reduction in HCV RNA level (log10 IU per milliliter)
from baseline was 1.2 (P=0.01) for patients receiving 3 mg per kilogram,
2.9 (P=0.003) for those receiving 5 mg per kilogram, and 3.0 (P=0.002)
for those receiving 7 mg per kilogram, as compared with a reduction of
0.4 in the placebo group. During 14 weeks of follow-up after treatment,
HCV RNA was not detected in one patient in the 5-mg group and in four
patients in the 7-mg group. We observed no dose-limiting adverse events
and no escape mutations in the miR-122 binding sites of the HCV genome.
Conclusions
The
use of miravirsen in patients with chronic HCV genotype 1 infection
showed prolonged dose-dependent reductions in HCV RNA levels without
evidence of viral resistance. (Funded by Santaris Pharma;
ClinicalTrials.gov number, NCT01200420.)
Research Published in the New England Journal of Medicine Demonstrates Marked and Long-Lasting Antiviral Activity Against HCV for Santaris Pharma A/S' Miravirsen, the First MicroRNA-Targeted Drug to Enter Clinical Trials
Final Phase 2a results show dose-dependent, prolonged antiviral activity in Hepatitis C patients --
HOERSHOLM, Denmark and SAN DIEGO, March 27, 2013 /PRNewswire via COMTEX/ --
Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, today announced the publication of study results online in the New England Journal of Medicine (NEJM). The publication highlights the potential benefits of miravirsen, a host-targeted, pan-HCV genotype anti-viral agent and the first microRNA-targeted drug to enter clinical trials for the treatment of Hepatitis C virus (HCV). In the study, miravirsen, given as a four-week monotherapy treatment, provided robust dose-dependent antiviral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA (log10 IU/mL). The effect was sustained well beyond the end of therapy.
Clinical data from the Phase 2a study demonstrated the following:
-- Miravirsen was safe, well tolerated and provided prolonged antiviral activity well after the last dose of miravirsen monotherapy (x5 weekly injections)
-- There were no signs of viral resistance
-- Adverse events were infrequent, mild and did not lead to study drug discontinuation
-- There were no dose limiting toxicities or discontinuations due to adverse events
-- Miravirsen was associated with dose-dependent reductions in HCV RNA that were sustained well beyond the end of the four-week dosing period
-- Four out of nine patients treated at the highest dose (7 mg/kg) with miravirsen became HCV RNA undetectable with just five weekly doses of miravirsen monotherapy
"We are excited because the data show that miravirsen offers long-lasting suppression of HCV RNA, a high barrier to viral resistance, a favorable tolerability and dosing profile, a low propensity for drug interactions and a very long duration of action. All of these properties suggest that miravirsen's unique mechanism-of-action may offer a potential cure for Hepatitis C patients, either in combination with other antiviral agents or as a monotherapy," said Harry Janssen, M.D., Head of the Liver Clinic at Toronto Western and Toronto General Hospital and lead author of the NEJM publication. "Due to its ability to target the host factor miR-122, miravirsen has the potential to change the way Hepatitis C is treated. This study is also the first to prove that blocking microRNA can be effective in treating Hepatitis C in humans without limiting side effects. This trial is a landmark study for new therapeutic modalities in many other diseases where microRNA's play a role, such as in cardiovascular disease, cancer and metabolic disorders."
Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is an inhibitor of miR-122, a liver specific microRNA that the Hepatitis C virus requires for replication. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the Hepatitis C virus. As a result, the replication of the virus is effectively inhibited and the level of Hepatitis C virus is profoundly reduced.
"This is a seminal moment for the microRNA community as miravirsen is the first microRNA targeted drug to show efficacy in clinical trials, and we are honoured that such a prestigious journal as the New England Journal of Medicine has published this work," said Henrik Stage, Chief Executive Officer at Santaris Pharma A/S. "It's amazing to think that the journey from bench to bedside has occurred over such a short span of time. Recall that human microRNAs were only discovered in 2001, and miR-122's role in the HCV lifecycle determined in 2005. Based on the published results, microRNA targeted therapy has shown its potential to become a new important class of drugs, and the LNA platform has demonstrated its role as the chemistry of choice for RNA targeted therapies."
The randomized, double-blind, placebo-controlled, ascending multiple-dose Phase 2a study assessed the safety and tolerability of miravirsen in treatment-naive patients with chronic HCV genotype 1 infection. Patients were enrolled sequentially to one of three cohorts (9 active:3 placebo per cohort) at doses of 3, 5 and 7 mg/kg. Miravirsen was given as a total of 5 weekly subcutaneous injections over 29 days.
"These study results are the culmination of over 6 years of microRNA research at Santaris Pharma A/S," said Michael R. Hodges, MD, Vice President and Chief Medical Officer at Santaris Pharma A/S. "The results of this study highlight miravirsen's exceptional high barrier to resistance, long duration of action and good tolerability. Miravirsen would be especially suitable for treatment of hard-to-treat patients, for example those patients who have already failed treatment with pegylated-interferon and ribavirin combination or protease inhibitor triple therapy." Dr. Hodges continued, "Longer treatment durations of miravirsen are currently being tested in clinical trials in subjects who have failed initial therapy for HCV infection."
About Hepatitis CHepatitis C infection is a viral disease caused by the Hepatitis C virus that leads to inflammation of the liver. The World Health Organization estimates that approximately 3 percent of the world's population have been infected with HCV and that some 170 million have chronic hepatitis C and are at risk of developing liver cirrhosis and/or liver cancer[i]. Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per year[ii]. In Europe, there are about 4 million carriers[i]. The current standard of care treatment for genotype 1 is a protease inhibitor given with pegylated-interferon a and ribavirin. This triple combination is effective in about 70-80% of those treated[ii]. Patients that are not effectively treated have an increased risk for the progression of liver disease. By 2029, total annual medical costs in the United States for people with Hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion[iii].
About microRNAsMicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.
About Locked Nucleic Acid (LNA) Drug PlatformThe LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including cardiometabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. LNA-based drugs are a promising new class of therapeutics that are enabling scientists to develop drug candidates to work through previously inaccessible clinical pathways. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drugs candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.
About Santaris Pharma A/SSantaris Pharma A/S is a privately held clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Locked Nucleic Acid (LNA) Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combine the company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The company's research and development activities focus on infectious diseases and cardiometabolic disorders, while partnerships with major pharmaceutical companies include a range of therapeutic areas including cancer, cardiovascular disease, infectious and inflammatory diseases, and rare genetic disorders. The company has strategic partnerships with miRagen Therapeutics, Shire plc., Pfizer, GlaxoSmithKline, and Enzon Pharmaceuticals. As part of its broad patent estate, the company holds exclusive worldwide rights to manufacture and sell products that comprise LNA as active ingredient for studies performed with a view to obtaining marketing approval. Santaris Pharma A/S, founded in 2003, is headquartered in Denmark with operations in the United States. Please visit www.santaris.com for more information.
Santaris Pharma A/S® is a registered trademark of Santaris Pharma A/S. Santaris(TM) and LNA-antimiR(TM) are trademarks of Santaris Pharma A/S.
[i] World Health Organization - http://www.who.int/csr/disease/hepatitis/Hepc.pdf ii] Jacobson IM. Telaprevir for previously untreated chronic hepatitis C virus infection. NEJM 2011;364:2405-16[iii] Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx.
SOURCE Santaris Pharma A/S
Thursday, April 19, 2012
EASL-Final Phase 2a Study Results For Miravirsen Showing Dose-dependent, Prolonged Antiviral Activity In Hepatitis C Patients
Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, will present final data from a Phase 2a trial showing that miravirsen given as a four-week monotherapy treatment provided robust dose-dependent anti-viral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA (log10 IU/mL) that was sustained well beyond the end of therapy. These final clinical data are being presented at the International Liver Congress™ 2012, the annual meeting of the European Association for the Study of the Liver (EASL), taking place on April 18 - 22 in Barcelona, Spain.
Clinical data from the Phase 2a study will be presented in an oral presentation on April 20, 2012 at 5:15 p.m. CEST, titled "Final Results: Randomized, Double-Blind, Placebo-Controlled Safety, Anti-Viral Proof-of-Concept Study of Miravirsen, an Oligonucleotide Targeting miR-122, in Treatment-Naive Patients with Genotype 1 Chronic HCV Infection." Study results demonstrated the following:
"These data provide clinical evidence that miravirsen's unique mechanism-of-action offers a high barrier to viral resistance and the potential for cure with monotherapy. Due to its ability in targeting miR-122, miravirsen has the potential to change the way hepatitis C is treated," said Dr. Henk Reesink, Academic Medical Center, University of Amsterdam, who is presenting the data at EASL. "These data show that longer duration of miravirsen monotherapy has the potential to produce sustained virological responses."
The mean of the maximum decline from baseline in HCV RNA (log10 IU/mL) over the 18 week study was 1.2, 2.9, 3.0 in the 3, 5 and 7 mg/kg miravirsen dose groups respectively vs. 0.4 in the placebo group (Table 1).
Table 1: Mean of the Maximum HCV RNA (Log10 IU/mL) Change from Baseline in all 3 Cohorts
p-value (t) MIR Dose Group Mean Maximum HCV RNA decline IU/mL (SEM) vs. placebo Pooled placebo 0.4 (0.4) --- Miravirsen 3 mg/kg 1.2 (0.6) 0.011 Miravirsen 5 mg/kg 2.9 (1.7) 0.003 Miravirsen 7 mg/kg 3.0 (1.6) 0.002
"We are pleased that the final data set reinforces that miravirsen, the first microRNA-targeted drug to be given to patients, provides long-lasting suppression of HCV RNA, has a high barrier to viral resistance and favorable tolerability and dosing profiles," said Michael R. Hodges, MD, Vice President and Chief Medical Officer at Santaris Pharma A/S. "Miravirsen has the potential to be used in combination with direct acting anti-viral agents as part of an interferon-free, dosing regimen in patients with all types of HCV genotypes."
The randomized, double-blind, placebo-controlled, ascending multiple-dose Phase 2a study assessed the safety and tolerability of miravirsen in treatment-naïve patients with chronic HCV genotype 1 infection. Patients with chronic HCV genotype 1 infection were enrolled sequentially to one of three cohorts (9 active: 3 placebo per cohort) at doses of 3, 5 and 7 mg/kg. Miravirsen was given as a total of 5 weekly subcutaneous injections over 29 days.
Additional data supporting the final results in the miravirsen Phase 2a study will also be presented in posters demonstrating evidence of its high barrier to resistance and favorable dosing schedule:
Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is an inhibitor of miR-122, a liver specific microRNA that the Hepatitis C virus requires for replication. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the Hepatitis C virus. As a result, the replication of the virus is effectively inhibited and the level of Hepatitis C virus is profoundly reduced.
About Hepatitis C
Hepatitis C infection is a viral disease caused by the Hepatitis C virus that leads to inflammation of the liver. The World Health Organization estimates about 3% of the world's population has been infected with HCV and that some 170 million have chronic hepatitis C and are at risk of developing liver cirrhosis and/or liver cancer[1]. Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per year[2]. In Europe, there are about 4 million carriers[1]. Treatment with pegylated interferon in combination with ribavirin is effective in only about 50% of those treated[2]. Patients that are not effectively treated have an increased risk for the progression of liver disease. By 2029, total annual medical costs in the United States for people with Hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion[3].
About microRNAs
MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.
About Locked Nucleic Acid (LNA) Drug Platform
The LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including cardiometabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. LNA-based drugs are a promising new class of therapeutics that are enabling scientists to develop drug candidates to work through previously inaccessible clinical pathways. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drugs candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.
NOTES:
[1] World Health Organization - http://www.who.int/csr/disease/hepatitis/Hepc.pdf [http://www.who.int/csr/disease/hepatitis/Hepc.pdf]
[2] American Association for the Study of Liver Diseases - http://www.aasld.org/patients/Pages/LiverFastFactsHepC.aspx [http://www.aasld.org/patients/Pages/LiverFastFactsHepC.aspx]
[3] Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-St... [http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx].
Source
Clinical data from the Phase 2a study will be presented in an oral presentation on April 20, 2012 at 5:15 p.m. CEST, titled "Final Results: Randomized, Double-Blind, Placebo-Controlled Safety, Anti-Viral Proof-of-Concept Study of Miravirsen, an Oligonucleotide Targeting miR-122, in Treatment-Naive Patients with Genotype 1 Chronic HCV Infection." Study results demonstrated the following:
"These data provide clinical evidence that miravirsen's unique mechanism-of-action offers a high barrier to viral resistance and the potential for cure with monotherapy. Due to its ability in targeting miR-122, miravirsen has the potential to change the way hepatitis C is treated," said Dr. Henk Reesink, Academic Medical Center, University of Amsterdam, who is presenting the data at EASL. "These data show that longer duration of miravirsen monotherapy has the potential to produce sustained virological responses."
The mean of the maximum decline from baseline in HCV RNA (log10 IU/mL) over the 18 week study was 1.2, 2.9, 3.0 in the 3, 5 and 7 mg/kg miravirsen dose groups respectively vs. 0.4 in the placebo group (Table 1).
Table 1: Mean of the Maximum HCV RNA (Log10 IU/mL) Change from Baseline in all 3 Cohorts
p-value (t) MIR Dose Group Mean Maximum HCV RNA decline IU/mL (SEM) vs. placebo Pooled placebo 0.4 (0.4) --- Miravirsen 3 mg/kg 1.2 (0.6) 0.011 Miravirsen 5 mg/kg 2.9 (1.7) 0.003 Miravirsen 7 mg/kg 3.0 (1.6) 0.002
"We are pleased that the final data set reinforces that miravirsen, the first microRNA-targeted drug to be given to patients, provides long-lasting suppression of HCV RNA, has a high barrier to viral resistance and favorable tolerability and dosing profiles," said Michael R. Hodges, MD, Vice President and Chief Medical Officer at Santaris Pharma A/S. "Miravirsen has the potential to be used in combination with direct acting anti-viral agents as part of an interferon-free, dosing regimen in patients with all types of HCV genotypes."
The randomized, double-blind, placebo-controlled, ascending multiple-dose Phase 2a study assessed the safety and tolerability of miravirsen in treatment-naïve patients with chronic HCV genotype 1 infection. Patients with chronic HCV genotype 1 infection were enrolled sequentially to one of three cohorts (9 active: 3 placebo per cohort) at doses of 3, 5 and 7 mg/kg. Miravirsen was given as a total of 5 weekly subcutaneous injections over 29 days.
Additional data supporting the final results in the miravirsen Phase 2a study will also be presented in posters demonstrating evidence of its high barrier to resistance and favorable dosing schedule:
Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is an inhibitor of miR-122, a liver specific microRNA that the Hepatitis C virus requires for replication. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the Hepatitis C virus. As a result, the replication of the virus is effectively inhibited and the level of Hepatitis C virus is profoundly reduced.
About Hepatitis C
Hepatitis C infection is a viral disease caused by the Hepatitis C virus that leads to inflammation of the liver. The World Health Organization estimates about 3% of the world's population has been infected with HCV and that some 170 million have chronic hepatitis C and are at risk of developing liver cirrhosis and/or liver cancer[1]. Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per year[2]. In Europe, there are about 4 million carriers[1]. Treatment with pegylated interferon in combination with ribavirin is effective in only about 50% of those treated[2]. Patients that are not effectively treated have an increased risk for the progression of liver disease. By 2029, total annual medical costs in the United States for people with Hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion[3].
About microRNAs
MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.
About Locked Nucleic Acid (LNA) Drug Platform
The LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including cardiometabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. LNA-based drugs are a promising new class of therapeutics that are enabling scientists to develop drug candidates to work through previously inaccessible clinical pathways. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drugs candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.
NOTES:
[1] World Health Organization - http://www.who.int/csr/disease/hepatitis/Hepc.pdf [http://www.who.int/csr/disease/hepatitis/Hepc.pdf]
[2] American Association for the Study of Liver Diseases - http://www.aasld.org/patients/Pages/LiverFastFactsHepC.aspx [http://www.aasld.org/patients/Pages/LiverFastFactsHepC.aspx]
[3] Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-St... [http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx].
Source
Sunday, November 13, 2011
AASLD: MicroRNA Drug Safe in Ongoing HCV Study
By Michael Smith, North American Correspondent, MedPage Today
Published: November 12, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
Action Points
SAN FRANCISCO -- A novel hepatitis C virus (HCV) drug targeting genetic material in the liver was safe and well tolerated in a small, dose-finding clinical trial, a researcher said here.
Primary source: Hepatology
Source reference:
Janssen HL, et al. "A Randomized, Double - blind, Placebo ( PLB ) Controlled Safety and Anti - viral Proof of Concept Study of Miravirsen ( MIR ) , an Oligonucleotide Targeting miR - 122, In Treatment Naive Patients with Genotype 1 ( GT1 ) Chronic HCV Infection" Hepatology 2011; Abstract LB-6.
http://www.medpagetoday.com/MeetingCoverage/AASLD/
Published: November 12, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- Explain that a novel hepatitis C virus drug (miravirsen) targeting genetic material in the liver was safe and well tolerated in a small, dose-finding clinical trial.
- Point out that in all of the doses evaluated, the drug resulted in a significant decrease in hepatitis C RNA levels, compared with placebo.
SAN FRANCISCO -- A novel hepatitis C virus (HCV) drug targeting genetic material in the liver was safe and well tolerated in a small, dose-finding clinical trial, a researcher said here.
Given as monotherapy, the compound, dubbed miravirsen, induced rapid dose-dependent reductions in the hepatitis C viral load, according to Harry Janssen, MD, of Erasmus Medical Center in Rotterdam, the Netherlands.
The reductions were sustained for more than a month after the end of therapy, Janssen reported at a late-breaker session during the annual meeting of the American Association for the Study of Liver Diseases.
Miravirsen "has the potential to eradicate" hepatitis C virus either alone or as part of an interferon-free regimen, Janssen concluded.
The compound blocks a host microRNA -- miR-122 -- that is critical to hepatitis C accumulation in the liver, Janssen said. MicroRNAs play important roles in gene regulation and expression and Janssen said miravirsen is the first drug to exploit a microRNA target for therapy.
Indeed, of the research presented at the late-breaker session, this study is " the most exciting because it is a whole new class of drug," said Norah Terrault, MD, of the University of California San Francisco, who was not part of the study but who was one of the moderators of the session.
For the study, Janssen said, researchers enrolled 36 patients with the difficult-to-treat genotype 1 of hepatitis C and assigned them to placebo or one of three doses of the drug -- 3, 5, and 7 mg/kg.
The patients, none of whom had been previously treated with pegylated interferon and ribavirin, were given five subcutaneous injections of the drug over four weeks and then followed for another 14 weeks.
The primary endpoint was safety and tolerability, Janssen said, with viral response as a second endpoint. Not all patients have completed the study, so the researchers reported data up to week 10, six weeks after the final dose.
Adverse events, he said, were "very much balanced" among the arms and over all "there were not a lot of side effects seen here." Most such events were mild and none led to stopping treatment, he added.
The only serious adverse event, in a patient receiving the high dose of the drug, was not considered related to treatment, he said.
In all three arms, the drug resulted in a significant drop in hepatitis C RNA levels, compared with placebo. Specifically:
- The low dose (3 mg/kg) led to a 0.57 IU/mL decline in in viral load, which was significant at P=0.0334.
- The medium dose (5 mg/kg) yielded a drop of 2.16 IU/mL, which was significant at P=0.007.
- The high dose (7 mg/kg) led to a decline of 2.73 IU/mL, significant at P<0.001.
Although some patients in the low- and medium-dose arms had been allowed to begin treatment with peginterferon and ribavirin three weeks after their last dose of miravirsen, those taking the high dose were not allowed standard therapy until week 10.
Janssen said the drop in viral load seen with the high dose at week 10 "is a pure effect of miravirsen."
The down side of the drug, Terrault told MedPage Today, is that "it has to be given by injection, and that's always a challenging form of treatment."
On the other hand, it appears well tolerated and safe, with good efficacy, so "it might still be part of the mix" of treatment options. "I clearly get the sense it isn't going to be used solo," she said.
The study was supported by Santaris Pharma. Janssen reported financial links with the company and one author was employed by the company.
Terrault reported financial links with Gilead, Pfizer, Genentech, Roche, SciClone, BMS, Novartis, Essai, and Vertex.
Primary source: Hepatology
Source reference:
Janssen HL, et al. "A Randomized, Double - blind, Placebo ( PLB ) Controlled Safety and Anti - viral Proof of Concept Study of Miravirsen ( MIR ) , an Oligonucleotide Targeting miR - 122, In Treatment Naive Patients with Genotype 1 ( GT1 ) Chronic HCV Infection" Hepatology 2011; Abstract LB-6.
http://www.medpagetoday.com/MeetingCoverage/AASLD/
Saturday, November 5, 2011
AASLD-Santaris Phase 2a Data of Miravirsen Shows Dose-Dependent, Prolonged Viral Reduction of 2-3 Logs HCV RNA After Four-Week
Santaris Pharma A/S Phase 2a Data of Miravirsen Shows Dose-Dependent, Prolonged Viral Reduction of 2-3 Logs HCV RNA After Four-Week Treatment in Hepatitis C Patients
These new clinical data as well as the data in the abstract are being presented in a late-breaking oral presentation on November 7 at 4p.m., at The Liver Meeting® 2011, the 62nd annual meeting of the AASLD, in San Francisco, California
HOERSHOLM, Denmark & SAN DIEGO, November 5, 2011 /PRNewswire/ --
- New Phase 2a clinical data to be presented in late-breaking oral presentation at AASLD -
- Miravirsen given as a four-week monotherapy treatment provided robust, dose-dependent antiviral activity with a mean reduction of 2 to 3 logs from baseline in Hepatitis C Virus (HCV) RNA (log10 IU/mL) that was maintained for more than four weeks beyond the end of therapy
- Four out of nine patients treated at the highest dose with miravirsen became HCV RNA undetectable during the study, providing clinical evidence that miravirsen's unique mechanism-of-action offers high barrier to viral resistance and the potential for treatment cures with monotherapy
- Miravirsen, the first microRNA-targeted drug to enter clinical trials, works by inhibiting miR-122, a microRNA required for HCV accumulation, was well tolerated in patients with chronic HCV infection- Miravirsen's long-lasting suppression of HCV RNA, high barrier to viral resistance, low propensity for drug interactions and favorable tolerability profile holds promise as pivotal new treatment option given as monotherapy or in combination with direct acting antiviral agents as an interferon-free treatment to eradicate chronic HCV infection in multiple genotypes
Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, presents new data from the Phase 2a trial showing that miravirsen given as a four-week monotherapy treatment provided robust dose-dependent anti-viral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA (log10 IU/mL) that was maintained for more than four weeks beyond the end of therapy. These new clinical data as well as the data in the abstract are being presented in a late-breaking oral presentation on November 7 at 4p.m., at The Liver Meeting® 2011, the 62nd annual meeting of the AASLD, in San Francisco, California(1).
New clinical data from the Phase 2a study demonstrate that four out of nine patients treated at the highest dose (7 mg/kg) with miravirsen became HCV RNA undetectable with just four weeks of dosing. These data provide clinical evidence that miravirsen's unique mechanism-of-action offers high barrier to viral resistance and the potential for cure with monotherapy. Miravirsen was also well tolerated in patients with HCV, signaling a possible advantage over standard of care treatment.
"The miravirsen Phase 2a data is very promising considering that with only four weeks of treatment, miravirsen provided robust antiviral activity and throughout the study there was no sign of viral resistance," said Harry Janssen, M.D. Ph.D., Head of Liver Unit at the Erasmus MC University Hospital Rotterdam, The Netherlands and Lead Clinical Investigator of the study, who is presenting the data at AASLD. "These data, taken together with the observation that four patients became HCV RNA undetectable at the highest dose, show that longer duration of miravirsen monotherapy has the potential to produce sustained virological responses."
Data from the Phase 2a study show that the mean change from baseline in HCV RNA (log10 IU/mL) at 10 weeks after initiation of therapy was -0.57, -2.16, -2.73 in the 3, 5 and 7 mg/kg miravirsen dose groups, respectively vs. -0.01 in the placebo group (Table 1).
These new clinical data as well as the data in the abstract are being presented in a late-breaking oral presentation on November 7 at 4p.m., at The Liver Meeting® 2011, the 62nd annual meeting of the AASLD, in San Francisco, California
HOERSHOLM, Denmark & SAN DIEGO, November 5, 2011 /PRNewswire/ --
- New Phase 2a clinical data to be presented in late-breaking oral presentation at AASLD -
- Miravirsen given as a four-week monotherapy treatment provided robust, dose-dependent antiviral activity with a mean reduction of 2 to 3 logs from baseline in Hepatitis C Virus (HCV) RNA (log10 IU/mL) that was maintained for more than four weeks beyond the end of therapy
- Four out of nine patients treated at the highest dose with miravirsen became HCV RNA undetectable during the study, providing clinical evidence that miravirsen's unique mechanism-of-action offers high barrier to viral resistance and the potential for treatment cures with monotherapy
- Miravirsen, the first microRNA-targeted drug to enter clinical trials, works by inhibiting miR-122, a microRNA required for HCV accumulation, was well tolerated in patients with chronic HCV infection- Miravirsen's long-lasting suppression of HCV RNA, high barrier to viral resistance, low propensity for drug interactions and favorable tolerability profile holds promise as pivotal new treatment option given as monotherapy or in combination with direct acting antiviral agents as an interferon-free treatment to eradicate chronic HCV infection in multiple genotypes
Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, presents new data from the Phase 2a trial showing that miravirsen given as a four-week monotherapy treatment provided robust dose-dependent anti-viral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA (log10 IU/mL) that was maintained for more than four weeks beyond the end of therapy. These new clinical data as well as the data in the abstract are being presented in a late-breaking oral presentation on November 7 at 4p.m., at The Liver Meeting® 2011, the 62nd annual meeting of the AASLD, in San Francisco, California(1).
New clinical data from the Phase 2a study demonstrate that four out of nine patients treated at the highest dose (7 mg/kg) with miravirsen became HCV RNA undetectable with just four weeks of dosing. These data provide clinical evidence that miravirsen's unique mechanism-of-action offers high barrier to viral resistance and the potential for cure with monotherapy. Miravirsen was also well tolerated in patients with HCV, signaling a possible advantage over standard of care treatment.
"The miravirsen Phase 2a data is very promising considering that with only four weeks of treatment, miravirsen provided robust antiviral activity and throughout the study there was no sign of viral resistance," said Harry Janssen, M.D. Ph.D., Head of Liver Unit at the Erasmus MC University Hospital Rotterdam, The Netherlands and Lead Clinical Investigator of the study, who is presenting the data at AASLD. "These data, taken together with the observation that four patients became HCV RNA undetectable at the highest dose, show that longer duration of miravirsen monotherapy has the potential to produce sustained virological responses."
Data from the Phase 2a study show that the mean change from baseline in HCV RNA (log10 IU/mL) at 10 weeks after initiation of therapy was -0.57, -2.16, -2.73 in the 3, 5 and 7 mg/kg miravirsen dose groups, respectively vs. -0.01 in the placebo group (Table 1).
"Due to its unique mechanism of action in targeting miR-122, miravirsen has the potential to change the way Hepatitis C is treated," said Stefan Zeuzem, M.D., Professor of Medicine and Chief of the Department of Medicine at the JW Goethe University Hospital, Frankfurt, Germany and Lead Clinical Investigator of the trial.
Click Table To Enlarge
The randomized, double-blind, placebo-controlled, ascending multiple-dose Phase 2a study assessed the safety and tolerability of miravirsen in treatment-naive patients with chronic HCV genotype 1 infection. Patients with chronic HCV genotype 1 infection were enrolled sequentially to one of three cohorts (9 active: 3 placebo per cohort) at doses of 3, 5 and 7 mg/kg. Miravirsen was given as a total of 5 weekly subcutaneous injections over 29 days.
Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is an inhibitor of miR-122, a liver specific microRNA critical for Hepatitis C virus RNA accumulation in the liver. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the Hepatitis C virus. As a result, the level of Hepatitis C virus is profoundly reduced.
Hepatitis C infection is a viral disease caused by the Hepatitis C virus that leads to inflammation of the liver. The World Health Organization estimates about 3% of the world's population has been infected with HCV and that some 170 million have chronic Hepatitis C and are at risk of developing liver cirrhosis and/or liver cancer(2). Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per year(3). In Europe, there are about 4 million carriers(1). Treatment with pegylated interferon in combination with ribavirin is effective in only about 50% of patients with genotype 1 HCV(2). Although the addition of one of the recently approved protease inhibitors has led to an improvement in virological response rates, not all patients can effectively be treated with triple therapy and they will continue to have an increased risk for the progression of liver disease(4). By 2029, total annual medical costs in the United States for people with Hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion(5).
MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.
About Locked Nucleic Acid (LNA) Drug PlatformThe LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the Company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including infectious and inflammatory diseases, cardiometabolic disorders, cancer and rare genetic disorders. LNA-based drugs are a promising new class of therapeutics that are enabling scientists to develop drug candidates to work through previously inaccessible clinical pathways. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drug candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.
Santaris Pharma A/S is a privately held clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Locked Nucleic Acid (LNA) Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combine the Company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The Company's research and development activities focus on infectious diseases and cardiometabolic disorders, while partnerships with major pharmaceutical companies include a range of therapeutic areas including cancer, cardiovascular disease, infectious and inflammatory diseases, and rare genetic disorders. The Company has strategic partnerships with miRagen Therapeutics, Shire plc, Pfizer, GlaxoSmithKline, and Enzon Pharmaceuticals. As part of its broad patent estate, the Company holds exclusive worldwide rights to manufacture, have manufactured and sell products that comprise LNA as active ingredient for studies performed with a view to obtaining marketing approval. Santaris Pharma A/S, founded in 2003, is headquartered in Denmark with operations in the United States. Please visit www.santaris.com for more information.
(1) A Randomized, Double-blind, Placebo Controlled Safety and Anti-viral Proof of Concept Study of Miravirsen, an Oligonucleotide Targeting miR-122, In Treatment Naive Patients with Genotype 1 Chronic HCV Infection, Abstract AASLD
(2) World Health Organization - http://www.who.int/csr/disease/hepatitis/Hepc.pdf
(3) American Association for the Study of Liver Diseases - http://www.aasld.org/patients/Pages/LiverFastFactsHepC.aspx
(4) Ghany, et. al. An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. HEPATOLOGY, Vol. 54, No. 4, 2011. http://www.aasld.org/practiceguidelines/Documents/2011UpdateGenotype1HCVbyAASLD24641.pdf
(5) Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx.
SOURCE Santaris Pharma A/S
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