Virology Profile Following Treatment With ACH-1625 Discussed in Oral Presentation at 2012 Asian Pacific Liver Conference

PRESS RELEASE

Feb. 16, 2012, 4:05 p.m. EST

NEW HAVEN, Conn., Feb 16, 2012 (GlobeNewswire via COMTEX) -- Achillion Pharmaceuticals, Inc. a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, today announced that novel preclinical and clinical virology data on ACH-1625, a Phase 2 pan-genotypic protease inhibitor, was presented in an oral presentation at the 2012 Annual Conference of the Asian Pacific Association for the Study of the Liver (APASL 2012), February 16-19, 2012, in Taipei, Taiwan.

The oral presentation, "Characterization of Hepatitis C Virus Variants Detected in vitro and in vivo After Treatment with ACH-1625, a Potent HCV NS3 Protease Inhibitor," (Abstract PS01-05) was made by Mingjun Huang, Ph.D., Vice President of Virology at Achillion, during APASL 2012 on Friday, February 17. The presentation discussed the viral resistant mutations identified in preclinical and Phase 1 clinical studies. The analyses showed that not only did wild type hepatitis C virus (HCV) profoundly decline following exposure to ACH-1625, but also that no rebound of the virus carrying the most common resistant mutations, specifically those at loci 155, 156, 168, was observed in genotype 1 HCV patients. Furthermore, the majority of resistant mutants displayed reduced replication fitness in vitro and remained sensitive to other classes of direct-acting antiviral agents.

"These data reveal a very interesting phenomenon in which following 5-day ACH-1625 monotherapy there was persistent suppression of HCV viral load observed even in the presence of pre-existing resistant variants," commented Dr. Huang. "These ad hoc study data, along with previously announced Phase 2 clinical results demonstrating significant suppression of HCV viral RNA with 100% cEVR, and an emerging virology profile that suggests a potential to suppress resistant variants, lead us to believe that ACH-1625 is well positioned to become an integral part of the future treatment of HCV in combination with other oral direct acting antiviral agents including our own NS5A inhibitors."

"As ACH-1625 continues to deliver what we believe to be a best-in-class profile for the treatment of HCV, these data further highlight the attributes of this potent, combinable, and to date very well-tolerated compound for the treatment of potentially all types of chronic hepatitis C infection," commented Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "We look forward to completing the current Phase 2 clinical trial of ACH-1625 and initiating all-oral, interferon-free combination studies with ACH-1625 later this year."

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000 begin_of_the_skype_highlighting 1-203-624-7000 end_of_the_skype_highlighting.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to: the potency, safety, tolerability, effectiveness, combinability and other characteristics of ACH-1625; Achillion's expectations regarding timing for the commencement and completion of clinical trials of ACH-1625; the potential for ACH-1625 to play an important role in the future treatment of HCV in combination with other oral direct acting antiviral agents; and the potential for ACH-1625 to be a best-in-class HCV treatment. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: replicate in later clinical trials positive results found in earlier stage clinical trials of ACH-1625 and its other product candidates; advance the development of ACH-1625 and its other drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates, and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2010 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

This news release was distributed by GlobeNewswire, www.globenewswire.com 

SOURCE: Achillion Pharmaceuticals, Inc.

Source

The Era of Direct-acting Antivirals Has Begun: The Beginning of the End for HCV?

From Seminars in Liver Disease

Marie-Louise Vachon, M.D., M.Sc.; Douglas T. Dieterich, M.D.

Posted: 02/15/2012; Semin Liver Dis. 2011;31(4):399-409. © 2011 Thieme Medical Publishers

Abstract and Introduction

Abstract

The year 2011 marks the dawn of the new era of direct-acting antivirals for hepatitis C. For the first time since 1998, the U.S. Food and Drug Administration approved two new antiviral drugs for the treatment of chronic hepatitis C virus genotype 1. Dual therapy with pegylated interferon and ribavirin is no longer the standard of care for genotype 1. The new treatment paradigm includes one direct-acting antiviral, a protease inhibitor, in combination with pegylated interferon and ribavirin. This combination nearly doubles the chances of response to treatment, but at the cost of increased toxicity. Many agents with different mechanisms of action and improved safety profiles are in clinical development. The holy grail of HCV treatment is an all oral, interferon-free treatment. The ideal regimen will be potent, well tolerated, with minimal drug-drug interactions and once daily. This article covers new concepts of treatment of hepatitis C with DAAs and gives an overview of the recent highlights in direct-acting antiviral development.

Introduction

In May 2011, telaprevir and boceprevir were approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic hepatitis C virus (HCV) genotype 1. Dual therapy with pegylated interferon (pegIFN) and ribavirin (RBV) is no longer the standard of care for genotype 1 HCV. The new treatment paradigm includes one direct-acting antiviral (DAA), a protease inhibitor (PI), in combination with pegIFN and RBV. The addition of a DAA to pegIFN/RBV nearly doubles the chances of response to treatment at the cost of increased toxicity. This is only the first wave of DAA use since many agents with different mechanisms of action and improved safety profiles are in phase I, II, and III of clinical development (Table 1 and Table 2). The use of three agents to treat HCV mirrors human immunodeficiency virus (HIV) triple combination treatment in many ways. Combination treatment seems inevitable to prevent emergence of resistance in HCV. Clinical trials are ongoing to identify the ideal regimen which would be potent, well tolerated, with minimal drug-drug interactions, once daily, all oral, and for as short a duration as possible (Table 3). Two major differences between HIV and the treatment of HCV are that treatment of HCV is for a definite duration and that HCV is curable. In this article, we examine new concepts of treatment of HCV with DAAs in general and review investigational compounds that have entered phase II of clinical development.

New Concepts of DAA Use

Several new concepts arose with the development of DAAs to treat hepatitis C. Because DAAs are true antivirals that target critical steps of HCV replication, similar to antiretrovirals inhibiting HIV, selection of resistant mutants is inevitable with monotherapy.^[1] The HCV replication cycle and the different sites at which DAAs can interfere with HCV replication are thoroughly reviewed elsewhere.^[2,3] RNA viruses like HCV inherently possess an error-prone RNA-dependent RNA polymerase that lacks the proofreading function. As a result, and with the rapid HCV viral turnover (up to 10¹² virions produced each day), it is estimated that one mutation is contained in every single genome copied.^[4] There are thus many variant populations coexisting in a given individual, the patient's quasispecies. Most of these variant populations are susceptible to DAAs because wild-type viruses usually have the advantage of fitness, but some of these preexisting variants are drug-resistant at baseline.^[5,6] When selection pressure is applied with the use of a DAA in monotherapy, these preexistent variants are rapidly selected and can become the predominant circulating population, potentially leading to treatment failure.^[7–9] Resistance profiles differ between drug classes. Some drugs have different resistance mutations within the same class. A new concept that emerged as part of PI development is the difference in resistance profile between genotype 1a and genotype 1b. For example, the R155K substitution typically emerges when HCV genotype 1a is exposed to telaprevir.^[8] Only one nucleotide change is required for the 1a subtype to develop resistance whereas two nucleotide changes must occur in genotype 1b.^[10] This is not specific to PI use and has been described with other drug classes, for example, nonnucleoside polymerase inhibitors.^[10] As a result, antiviral responses can vary between HCV genotype 1 subtypes during treatment with DAAs, while response was similar when treated with pegIFN and RBV dual therapy.

Response-guided therapy (RGT) refers to the use of on-treatment virologic response to tailor the duration of therapy for an individual patient.^[11] This concept was used with pegIFN/RBV treatment but really emerged in the era of DAAs. Both telaprevir and boceprevir can be used for a shorter treatment duration in patients who achieve HCV RNA undetectability early on in treatment.^[12,13] This is RGT. In the telaprevir studies, extended rapid virologic response (eRVR) was used to determine if RGT could be used.^[12,14] The definition of eRVR was HCV RNA <10 IU/mL at week 4 and 12. In the boceprevir studies, RGT was used when HCV RNA was less than 9.3 IU/mL at week 8 through week 24.^[13] Most phase II and III clinical trials of DAAs are exploring this possibility of shortening treatment duration in patients who achieve eRVR.

The concept of lead-in is also widely discussed in the DAA literature. Lead-in is the use of pegIFN and RBV for a short duration preceding the initiation of DAA. Lead-in was initially introduced in an attempt to lower HCV RNA levels before PI exposure to minimize the emergence of resistance. Also, by achieving proper pegIFN and RBV drug levels before the initiation of the DAA, it would avoid functional monotherapy. Studies of boceprevir used a 4-week lead-in of pegIFN and RBV. It turns out the lead-in was most useful in the assessment of interferon responsiveness. In the SPRINT-2 study evaluating boceprevir in combination with pegIFN/RBV in previously untreated patients with chronic HCV genotype 1, a decrease in the HCV RNA level by ≥1 log₁₀ IU/mL after the 4-week lead-in increased the chances of sustained virologic response (SVR; undetectable HCV RNA 24 weeks after the end of treatment) ninefold (adjusted odds ratio [AOR], 9.0; 95% confidence interval [CI], 6.3–12.8; P <.001).^[13] There was no advantage to lead-in when used with other DAAs, for example, with telaprevir and BI 201335.^[14,15]

Lower Limit of Detection (LLOD) Versus Lower Limit of Quantification (LLOQ)

The LLOD is the HCV RNA concentration at which less than 5% of the samples that contain a known amount of an RNA standard yield a signal that can be detected. The LLOQ refers to the lowest HCV RNA concentration that is within the validated quantitative range of an assay. An undetectable result indicates that HCV RNA was not detected in the sample. The limit of detection and the limit of quantification vary according to the assay used. Both the boceprevir and telaprevir phase III studies used the COBAS TaqMan HCV RNA assay, version 2.0 (Roche), with a LLOD of 10 IU/mL and a LLOQ of 25 IU/mL. Eligibility for RGT was based on the lower limit of detection (<10 IU/mL) of the assay. There is thus a range in which HCV RNA can be detectable, but falls below the level of quantification. This situation is not uncommon during HCV treatment and is associated with lower SVR rates. In the SPRINT-2 trial, 53% of the 1071 patients enrolled had at least one on-treatment result showing detectable HCV RNA, but below the level of quantification.^[13] For example, in the patients who received boceprevir and who had detectable HCV RNA at week 6 (any level), detectable HCV RNA at week 8 but below level of quantification, and undetectable HCV RNA at week 10, the SVR rate was 74%. In the patients who received boceprevir and who had detectable HCV RNA at week 6 (any level) but undetectable HCV RNA at weeks 8 and 10, the SVR rate was 86%. When assessing eligibility to response-guided therapy with DAAs, an undetectable HCV RNA (<LLOD) is not equivalent to a detectable HCV RNA that is below the limit of quantification of the assay (detectable but <LLOQ). The package inserts of telaprevir and boceprevir reflect this fact.

NS3/4A PIs

HCV NS3/4A PIs are often divided in two classes. The first generation PIs include the linear α-ketoamide derivatives, boceprevir and telaprevir. They bind the catalytic site of the enzyme covalently in a reversible reaction. Boceprevir and telaprevir are considered the first wave of the first-generation PIs. These two PIs are the first DAAs to have completed phase III clinical trials for treatment of HCV genotype 1 and to have received FDA approval. Second-wave PIs are mostly linear and macrocyclic noncovalent inhibitors of the NS3/4A enzyme. Both waves are highly potent inhibitors of the NS3/4A enzyme. The advantages of second wave PIs over first wave PIs are their convenience and improved side effect profile. Unfortunately, they share the same basic resistance mutations that are generated by the first wave of PIs. The truly second-generation PIs are the two drugs MK-5172 and the ACH-2684. They do not share the same resistance mutations and are pangenotypic. There are currently two first-generation, second-wave PIs that recently initiated phase III of clinical development: TMC435 and BI-201335.

TMC435

In phase I studies, TMC435 was generally safe and well tolerated. It showed potent anti-HCV activity. After 5 days of TMC-435 at a dose of 200 mg once daily, HCV RNA decreased by a median of 3.9 log₁₀ IU/mL in HCV genotype 1-infected patients who failed prior interferon-based therapy.^[16] The phase IIb PILLAR study is ongoing and week 24 results have recently been presented.^[17] PILLAR is investigating the use of once-daily TMC435 at two different dosages (75 mg vs 150 mg) for 12 versus 24 weeks in combination with pegIFN/RBV for 24 vs 48 weeks (vs placebo/pegIFN/RBV for 48 weeks), in 386 patients with HCV genotype 1 naïve to HCV treatment. Patients with HCV RNA less than 25 IU/mL from week 4 to week 20 were eligible for RGT and stopped treatment at week 24. Of the patients receiving TMC435, 83% achieved eRVR and 94 to 97% achieved undetectable HCV RNA at week 24 of treatment compared with a high 82% in the pegIFN/RBV control group. Of the 83% of patients who achieved eRVR and stopped therapy at week 24, 88 to 97% achieved SVR12 (undetectable HCV RNA 12 weeks after the end of treatment). Discontinuation of TMC435 or placebo occurred in 7.1% of patients receiving TMC435/pegIFN/RBV versus 7.8% of patients receiving placebo/pegIFN/RBV. The most common adverse events occurred in a similar proportion of patients receiving or not receiving TMC435. TMC435 at the 150 mg once-daily dose was associated with mild and reversible increases in direct and indirect bilirubin. Elevation in bilirubin is thought to occur through inhibition of the two transporters: organic anion transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). OATP1B1 is responsible for bilirubin uptake into hepatocytes (influx) and MRP2 is responsible for efflux into bile. No inhibition of bilirubin conjugation has been observed.^[18]

The ASPIRE study is the ongoing phase IIb study in prior partial responders (≥2 log₁₀ drop in HCV RNA at week 12 but detectable HCV RNA at week 24), prior null responders (<2 log₁₀ drop in HCV RNA at week 12 of treatment) and prior relapsers (undetectable HCV RNA at the end of treatment, but detectable HCV RNA within 24 weeks of end of treatment) to interferon-based therapy. Patients received TMC435 at doses of 100 mg versus 150 mg once daily in combination with pegIFN/RBV for 12, 24, or 48 weeks. In all seven arms of the trial, patients received pegIFN/RBV to complete 48 weeks of treatment. There was no RGT. The week 24 interim analysis showed that 92 to 96% of prior relapsers who received TMC435 had undetectable HCV RNA at week 24 compared with 83% of patients in the control group. Of the prior partial responders receiving TMC435, 83 to 89% had undetectable HCV RNA at week 24 versus 20% of the control group. Of the prior null responders, 70 to 87% had undetectable HCV RNA at week 24 versus 45% of the control group (higher than expected). The prior null responders typically have the lowest response rates to retreatment. The end of treatment and SVR data are eagerly awaited.

In summary, TMC435 is a highly potent once-daily dosing PI. Duration of treatment can be shortened to 24 weeks for the majority of patients; viral breakthroughs are low when used in combination with pegIFN and RBV. The 150 mg once-daily dose is being used in phase III trials in both patients who are naïve to HCV treatment and patients who previously relapsed to an interferon-based therapy. Patients will receive once-daily 150 mg of TMC435 during 12 weeks in combination with pegIFN/RBV for a 24 versus 48 weeks. A trial for HIV-infected patients has started enrollment in the second half of 2011.

BI 201335

BI201335 is a HCV NS3 PI given once daily currently in phase III. The phase IIb SILEN-C1 trial was conducted in patients with HCV genotype 1 naïve to HCV treatment to evaluate safety and efficacy of BI 201335 given once daily at a dose of 120 mg or 240 mg for 24 weeks in combination with pegIFN and RBV for 24 vs 48 weeks.^[14] A lead-in of pegIFN and RBV for 3 days was also evaluated in 2 of the 4 arms (with 120 mg and 240 mg once daily). In the two arms using BI 201335 at a dose of 240 mg (with and without a lead-in), patients achieving eRVR were rerandomized to either stop treatment at week 24 or continue with pegIFN/RBV for a total of 48 weeks. Patients receiving 240 mg once daily without a lead-in achieved the highest eRVR rate of 87% and were thus eligible for shortened treatment duration. As expected with this high eRVR rate, this arm also had the highest SVR rate of 83% versus 73% of patients receiving 240 mg with a lead-in and 56% of patients in the pegIFN/RBV control group. Prolonging treatment to 48 weeks in those patients achieving eRVR did not result in higher SVR rates. Of those who completed 24 weeks, 93% achieved SVR versus 90% of those who completed 48 weeks. Viral breakthroughs occurred in 2.8 to 5.8% of patients receiving BI 201335 with the highest rate in those of the 120 mg daily with lead-in arm.

The phase IIb SILEN-C2 trial evaluated BI 201335 for 24 weeks in combination with pegIFN/RBV for 24 versus 48 weeks, with or without a 3-day lead-in of pegIFN/RBV in previous partial and null responders infected with HCV genotype 1.^[19] The 240 mg once-daily dose (with and without a lead-in) was compared with 240 mg twice daily with a lead-in. Patients of the 240 mg once-daily group with lead-in achieving eRVR were rerandomized to stopping therapy or continuing 48 weeks with pegIFN/RBV. Similar to the SILEN-C1 trial, the lead-in did not appear to be useful. The 240 mg once-daily dosing without a lead-in led to the highest SVR rates. Overall, eRVR was achieved by 45% of patients and SVR was achieved by 27 to 41% of patients. The lowest SVR rate was observed in the 240 mg once daily with the lead-in arm, the one group that used RGT for those achieving eRVR. In comparison to the good results observed with 24 weeks of treatment in the naïve patients achieving eRVR in the SILEN-C1 trial,^[14] prior partial and null responders achieving eRVR in SILEN-C2 achieved lower SVR rates when stopped at week 24. Only 40% of patients achieved SVR when stopped at week 24 compared with 72% of those who completed 48 weeks of treatment. The additional 24 weeks of peg/RBV greatly impacted the relapse rate. Sixty percent of those who stopped at week 24 relapsed compared with 21% of those who completed 48 weeks of treatment. Viral breakthroughs occurred predominantly on BI 201335 compared with peg/RBV (17–28% vs 5–7%). Several adverse events were reported in a higher proportion of patients receiving BI 201335 compared with those on placebo and were dose-dependent. Jaundice, skin manifestations including rash, photosensitivity reactions, pruritus and dry skin, and gastrointestinal side effects, mostly nausea, vomiting, and diarrhea were reported in the BI 201335 arms in a proportion exceeding 10% of the placebo/peg/RBV group. Jaundice was secondary to predominantly indirect or unconjugated hyperbilirubinemia. This was dose-dependent, rapidly reversible in all cases at cessation of BI 201335, and not associated with liver injury. The mechanism of action is inhibition of hepatic uptake of uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1).^[20]

ACH-0141625 (ACH-1625)

ACH-1625 is an inhibitor of the HCV NS3 protease. ACH-1625 exhibits rapid and selective distribution to the liver and has high liver/plasma ratios. In phase Ib, 5 days of ACH-1625 monotherapy at doses ranging from 200 to 600 mg twice daily or 400 to 600 mg once daily led to mean maximal reductions in HCV RNA ranging from 3.1 log₁₀ to 4.25 log₁₀.^[21]

This PI is currently in phase IIa of clinical development to evaluate its safety, tolerability, and antiviral activity in combination with pegIFN and RBV in patients with HCV genotype 1 naïve to treatment. This study has two segments. Segment 1 compares three different dosages of ACH-1625, 200 mg, 400 mg, and 800 mg once daily with placebo in combination with pegIFN/RBV for 28 days followed by pegIFN/RBV for a total duration of 48 weeks in 64 patients with HCV genotype 1. Segment 2 compares the same three dosing regimens to placebo for 12 weeks followed by 36 weeks of pegIFN/RBV. Week 4 results of Segment 1 showed achievement of rapid virologic response (RVR) in 74 to 81% of patients compared with 20% of patients receiving placebo/pegIFN/RBV. Reductions in HCV RNA on ACH-1625 ranged from 4.63 log₁₀ to 4.96 log₁₀ IU/mL after 4 weeks of triple therapy compared with 2.25 log₁₀ IU/mL with placebo/pegIFN/RBV. It is worth noting that the majority of the patients enrolled were carriers of the unfavorable IL28B CT or TT genotypes and infected with HCV genotype 1a. The safety profile was comparable between all groups. No viral breakthroughs were observed during the first 4 weeks.

Danoprevir (RG7227/ITMN-191)

Danoprevir is a potent macrocyclic inhibitor of the HCV NS3/4A serine protease. In phase 1b studies in treatment naïve patients with HCV genotype 1, administration of danoprevir for 14 days was associated with a maximal median reduction of HCV RNA of 3.8 log₁₀ in monotherapy and 5.7 log₁₀ IU/mL in combination therapy with pegIFN and RBV.^[22] In subsequent studies, danoprevir was boosted by ritonavir, a strong inhibitor of the CYP3A4 enzyme. A phase 1b study evaluated multiple ascending doses of ritonavir-boosted danoprevir in combination with pegIFN/RBV in 30 patients with HCV genotype 1 naïve to treatment.^[23] More patients using boosted danoprevir (72%, 18/25 and 100%, 8/8 in the group receiving danoprevir 200 mg/ritonavir 100 mg twice daily) achieved undetectable HCV RNA (<15 IU/mL) at day 15 compared with patients who had previously received high-dose unboosted danoprevir (14%, 1/7) or placebo (20%, 1/5). This boosting allowed the use of a significantly lower dose of danoprevir, resulting in lower area under the curve (AUC) and maximum concentration (Cmax) of danoprevir. This reduced systemic exposure can improve the safety profile and reduce the probability of grade 4 ALT elevations, which had been seen with unboosted danoprevir at a dose of 900 mg twice daily.^[24] Danoprevir/ritonavir is now being evaluated in several phase II clinical trials. A randomized, open-label study is evaluating SVR of danoprevir/ritonavir in combination with pegIFN/RBV in treatment of naïve patients with HCV genotype 1. Week 12 results of a substudy of 24 prior null responders treated with open-label danoprevir/ritonavir 100 mg/100 mg twice daily with pegIFN and RBV were recently presented.^[25] Patients received 12 weeks of triple therapy after which they continued on pegIFN/RBV for a total of 48 weeks. At week 12, results showed a significant disparity between patients with HCV genotype 1a versus 1b. Fifty percent (50%) of patients with HCV genotype 1a achieved EVR versus 88% of those with HCV genotype 1b. Four of the eight patients with HCV genotype 1a experienced viral breakthrough with selection of the R155K mutation compared with 6% of patients with HCV genotype 1b.

A randomized open-label phase II study is evaluating SVR with danoprevir/ritonavir and RBV in combination with mericitabine (RG7128), a polymerase inhibitor, and/or pegIFN in patients with HCV genotype 1 who failed previous standard therapies. In this study, the six study arms contain RBV, but two of the six study arms are pegIFN-free.

A second phase II study, INFORM-SVR, is recruiting patients to evaluate the combination of danoprevir/ritonavir plus mericitabine with and without RBV in patients with HCV genotype 1. This is a pegIFN-free trial. In two arms, interferon-naïve patients will receive danoprevir 100 mg/ritonavir 100 mg twice daily with mericitabine 1000 mg twice daily with or without RBV for 12 weeks or 24 weeks. The third arm will enroll interferon-unable/intolerant patients who will receive an open-label combination of danoprevir/ritonavir/mericitabine plus RBV for 24 weeks. The combination of danoprevir/ritonavir with mericitabine looks promising and results of these phase II trials are awaited.

BMS-650032

One of the most important results, if not the most important, in the study of DAAs in the year 2011 was the result of the phase IIa study evaluating quadruple therapy with the PI BMS-650032 (600 mg twice daily) and BMS-790052 (an HCV NS5A replication complex inhibitor; 60 mg once daily) with and without pegIFN/RBV for 24 weeks in patients with HCV genotype 1 who were prior null responders to IFN-based therapy.^[26] Prior null responders are typically the most difficult-to-retreat patient population. In this study four (36%) of the 11 null responders who received BMS-650032 and BMS-790052 alone for 24 weeks achieved SVR. This result is proof of the concept that HCV can be cured without pegIFN/RBV. Of the 11 patients in this arm, six had a viral breakthrough and resistant variants to both drugs were detected.^[27] In four of these six, HCV RNA became undetectable when pegIFN/RBV was added at the time of viral breakthrough. All 10 patients who received the quadruple therapy were cured. There was 100% SVR12 and 90% SVR24 (one patient had SVR12, detectable HCV RNA 6 months posttreatment and undetectable HCV RNA when retested later on). These two DAAs are currently being evaluated in a phase IIb study in combination with pegIFN lambda (BMS-914143) with and without ribavirin for 24 weeks in patients with chronic HCV genotype 1 naïve to treatment. This study also compares the use of a single DAA (either BMS-650032 or BMS-790052) with RBV and either pegIFN-lambda or pegIFN-alfa. It will be very interesting to learn the role of RBV when these two DAAs are combined with pegIFN.

GS-9451 and GS-9256

GS-9451 is a potent macrocyclic HCV NS3 PI that achieved a median maximal change in HCV RNA of 3.6 log₁₀ IU/mL (range, -4.7 log₁₀ to -3.1 log₁₀ IU/mL) following 3-day monotherapy in treatment-naïve patients with HCV genotype 1 infection during phase I.^[28] It is currently being evaluated in phase II studies in combination with other DAAs. A phase IIb study with RGT will evaluate the efficacy and safety of 16 and 24 weeks of a four-drug regimen with GS-9451 and tegobuvir (a nonnucleoside HCV polymerase inhibitor) and 24 weeks of a three-drug regimen of GS-9451 without tegobuvir, all with pegIFN and RBV. Other phase II studies evaluating different DAA combinations that include the NS5A inhibitor GS-5885 are ongoing.

GS-9451 has additive to synergistic antiviral activity when combined with pegIFN, RBV, NS5A inhibitors, or polymerase inhibitors. Although a PI, GS-9451 retains activity against V36M and T54S, two NS3 mutations. However, R155K, A156T, and D168V are cross-resistant to GS-9451. The NS3 resistance mutations selected during treatment with GS-9451 are fully susceptible to other HCV inhibitor classes.^[29] This supports its use in combination with other DAAs of the company's pipeline. A new study evaluating a four all-oral drug regimen is currently recruiting patients. In this study, GS-9451 is administered with GS-5885 (a NS5A inhibitor given at two different dosages), tegobuvir, and RBV for 12 or 24 weeks in patients with chronic HCV genotype 1 infection. This type of combination could completely revolutionize HCV treatment if found potent and well tolerated.

GS-9256 is also a potent PI that was being evaluated until recently. Preliminary results of the phase II study evaluating GS-9256 in combination with tegobuvir ± RBV and ± pegIFN for 28 days have been presented.^[28] With the three oral drugs, 38% achieved RVR, 100% then achieved complete early virologic response (cEVR; undetectable HCV RNA at week 12) and maintained undetectability at week 24. With four drugs, 100% achieved RVR and were still undetectable at week 24. Without RBV and pegIFN, GS-9256 and tegobuvir led to RVR in only 7% of patients (1/15). Of these 15 patients, 12 achieved cEVR following the addition of pegIFN/RBV. All combinations were well tolerated. It was decided that GS-9256 would not be further developed, in part due to its higher potential to inhibit the transport and metabolism of bilirubin compared with GS-9451.^[30]

Nucleoside and Nucleotide NS5B Polymerase Inhibitors

The nucleoside and nucleotide analog inhibitors of the HCV polymerase target the catalytic site of the enzyme. When they incorporate in the RNA chain in lieu of the natural substrate, they cause RNA chain termination. Nucleoside analogs must be phosphorylated three times by cellular kinases to become active as the triphosphate form. Nucleotide analogs are already in the active form. Because the NS5B target is highly conserved between HCV genotypes, polymerase inhibitors usually have pangenotypic activity (Fig. 1).

Figure 1. Characteristics of the five classes of direct-acting antivirals (DAAs). *Varies with the generation. **Palm II are effective against multiple genotypes. (DAA, direct acting antiviral; NS3/4A, nonstructural 3/4A protein; PI, protease inhibitor; NS5A, nonstructural 5A protein; NS5B, nonstructural 5B protein; Nuc, nucleoside.)

PSI-352938 (PSI-938)

PSI-938 is a purine (guanosine) nucleotide analog polymerase inhibitor of HCV. In earlier phases of development, PSI-938 was shown to have pangenotypic coverage, high liver to plasma ratios, residual activity against S282T variants (substitution selected by and associated with resistance to the 2'-methyl nucleosides), and low risk of drug-drug interactions. The 14-day results of a phase II study, the NUCLEAR study, were recently presented.^[31] The NUCLEAR study compared different combinations of once daily PSI-938 plus PSI-7977 (a second polymerase inhibitor) to PSI-938 monotherapy for 14 days in treatment naïve patients with HCV genotype 1. It is the first to evaluate the combination of two nucleotide analogs for the treatment of HCV infection. Of the 24 patients who received combination treatment, 22 (92%) achieved HCV RNA <15 IU after 14 days of treatment. The two drugs are known to have complementary resistant profiles and not surprisingly, no viral breakthroughs were observed. Treatment was well tolerated. An interferon-free combination trial of PSI-938 and PSI-7977, the QUANTUM trial, has been initiated. PSI-938 was granted the fast track designation by the FDA for treatment of chronic HCV infection in August 2011.

PSI-7977

PSI-7977 is a pyrimidine (uridine) nucleotide analog active against all HCV genotypes. The dramatic results of the phase 2b study PROTON assessing safety and efficacy of PSI-7977 in combination with pegIFN/RBV against HCV genotypes 2 and 3 were presented earlier in 2011.^[32] PROTON enrolled 25 treatment-naïve patients. One patient was lost to follow-up early in the study. Among the 24 patients who completed 12 weeks of triple therapy, 24 (100%) achieved SVR. These results suggest that therapy can be significantly shortened in patients infected with HCV genotypes 2 and 3 without compromising the chances of response. A phase II study in patients with HCV genotype 2 and 3 is ongoing to explore the use of PSI-7977 in monotherapy for 12 weeks versus PSI-7977 in combination with peg/RBV for 8 weeks.

Nonnucleoside NS5B Polymerase Inhibitors

Whereas the nucleoside inhibitors bind to the polymerase's active site, the nonnucleoside inhibitors bind to allosteric sites of the enzyme. This induces conformational changes that downregulate the polymerase's activity. Different binding sites disposed in a right hand motif with the thumb (thumb 1 and thumb 2), finger and palm (palm 1 and palm 2) domains are potential targets of nonnucleoside inhibitors. As a result of different target sites, mechanism of inhibition, and potency differences, nonnucleoside inhibitors have a low genetic barrier to resistance compared with nucleoside/nucleotide analogs (Fig. 1).^[33]

SETROBUVIR (ANA598)

Setrobuvir (ANA598) is a potent nonnucleoside inhibitor and the most advanced in development. In a phase II combination study with pegIFN and RBV, 72% of patients achieved undetectable HCV RNA at week 8.^[34] It is currently in a phase IIb study for the treatment of chronic HCV infection. In this ongoing study, 133 patients naïve to HCV treatment and 141 previously treated patients (n = 133) have been enrolled to receive setrobuvir 200 mg twice daily in combination with pegIFN/RBV. Patients naïve to HCV treatment with undetectable HCV RNA at week 8 and at subsequent visits will complete treatment at week 28 (RGT). Previously treated patients will receive 48 weeks of treatment. Future trials combining ANA598 with DAAs of different classes will likely offer the best SVR results.

Nonstructural Protein 5A (NS5A) Replication Complex Inhibitors

Inhibitors of NS5A block viral production at an early stage of assembly. The exact mechanism of action of the NS5A protein is unknown.^[35] Without having an enzymatic function, this multifunctional protein is essential for replication and assembly of HCV and has no human homologs.^[36,37]

DACLATASVIR (BMS-790052)

BMS-790052 is the first NS5A inhibitor with proof-of-concept in the clinic. The results of the first placebo-controlled, multiple ascending-dose clinical study evaluate its antiviral activity, resistance profile, pharmacokinetics, safety, and tolerability in 30 patients with chronic HCV infection infected with HCV genotype 1 were recently published.^[38] Its pharmacokinetic profile supports once-daily dosing and the drug was well tolerated. Patients received BMS-790052 for 14 days. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log₁₀ IU/mL. Most patients experienced viral rebound during the first 7 days of BMS-790052 monotherapy. Viral breakthroughs were associated with mutations that had been previously found in the NS5A at baseline and at the time of resistance development.^[39,40]

Cyclophilin Inhibitors

Cyclophilin inhibitors are derived from cyclosporine A, but lack calcineurin-binding properties and thus do not exhibit immunosuppressive effects.^[41,42] Alisporivir (Debio 025) is the first-in-class cyclophilin inhibitor that recently initiated a phase III trial. It binds to cyclophilin A, an essential cofactor for HCV replication and shows additive antiviral effect with pegIFN in patients with genotype 1 and 4 HCV.^[41] Cyclophilin inhibitors are sometimes referred to as host-targeted agents, but can also be part of the DAAs because they are known to interact with the NS5A protein.

In a phase II study of patients with HCV genotype 1, 2, 3, and 4 naïve to HCV treatment, alisporivir doses of 200, 600, and 1,000 mg/day in combination with pegIFN for 4 weeks were compared with monotherapy with alisporivir 1,000 mg/day or pegIFN.^[42] In patients with genotypes 1 and 4, the 600- and 1,000-mg combination treatments reduced HCV RNA by up to 4.61 ( ± 1.88) log₁₀ IU/ml and 4.75 (±2.19) log₁₀ IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels were reduced by -5.91 (±1.11) log₁₀ IU/mL and -5.89 (±0.43) log₁₀ IU/mL at week 4, respectively, with the same treatment regimens. Alisporivir 1000 mg/day was associated with a higher incidence of isolated hyperbilirubinemia. SVR results of the phase II ESSENTIAL study were recently presented.^[43] Alisporivir (600 mg twice daily during one week followed by once-daily dosing) with pegIFN/RBV led to SVR in 76% of patients taking the triple therapy for 48 weeks compared with 55% of the control group (P = .008). Triple therapy with alisporivir for 24 weeks was as effective as pegIFN/RBV dual therapy for 48 weeks with 53% SVR compared with 55%, respectively. In the RGT arm in which patients could stop triple therapy at week 24 if they achieved RVR, the SVR rate was 69%. Alisporivir demonstrates a high barrier to resistance and interestingly, the resistance mutation identified with its use (D320E) is mainly located in the NS5A domain II. Recent findings indicate that alisporivir inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerization in domain II of NS5A.^[44] Metabolism is through cytochrome P450 3A4, which can compromise its ability to be given concomitantly with substrates, inhibitors, or inducers of this cytochrome. Cyclophilin inhibitors could be part of a potent DAA combination in patients not taking concomitant P450 3A4 medications.

Conclusion

After many years of little or no progress in the development of HCV DAAs, 2011 was a watershed year for several reasons. The most clinically significant development was the approval of boceprevir and telaprevir for the treatment of HCV genotype 1. That will revolutionize the treatment of HCV in the clinic and change the landscape of HCV treatment forever because of the dramatically increased SVR demonstrated by both drugs. The Berlin EASL meeting in March of 2011 showcased some equally dramatic and positive results of drugs in development. Among many huge advances in the field, we saw the first 100% SVR for pegIFN/RBV plus PSI-7977 for HCV genotypes 2 and 3, with a shortened course of treatment. The most revolutionary results were revealed by the combination of the PI BMS-650032 and the NS5A inhibitor BMS-790052. In previous null responders to interferon treated with quadruple therapy consisting of a PI, a NS5A inhibitor, pegIFN and RBV, 100% SVR was achieved. This alone would merit a special mention, but the truly groundbreaking results were in the other arm of the study, which combined only the PI and the NS5A compound without pegIFN/RBV. In that arm, an SVR of 36% was achieved demonstrating for first time ever, an interferon-free, RBV-free cure of HCV.

Not only did we have the first FDA, European Medicines Agency (EMEA), and Canadian approvals for the PIs telaprevir and boceprevir in 2011, but we saw the proof of principle that the Holy Grail of HCV therapy is achievable; SVR without interferon. There are dozens of new drugs in clinical development now and many will fall by the wayside, but there are clearly enough that will be approved to reassure us that the future is very bright indeed for DAA treatment of HCV.

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Source

Specialty Pharmacy Reveals Early Incivek, Victrelis Data: ‘It’s Looking Good’ for Many

Reprinted from SPECIALTY PHARMACY NEWS, a monthly newsletter designed to help health plans, PBMs, providers and employers contain costs and improve outcomes related to high-cost specialty products.

By Angela Maas, Managing Editor

February 2012Volume 9 Issue 2

When the FDA approved Incivek (telaprevir) and Victrelis (boceprevir) for the treatment of hepatitis C last May, many in the industry hailed them as game-changers. Not only are Merck & Co., Inc.’s Victrelis and Vertex Pharmaceuticals Inc.’s Incivek the first oral hepatitis C therapies and the first protease inhibitors approved for the condition (SPN 5/11, p. 1), but new data just released echo the clinical trials data that indicate the drugs also show much more promise than the previous regimen of pegylated interferon and ribavirin did of actually clearing the virus.

The drugs could cut the current 48-week treatment time down to 24 weeks for certain patients if they achieve an early viral response. However, both drugs are used with pegylated interferon and ribavirin to create a triple therapy that is fairly complicated (SPN 9/11, p. 1). People taking Incivek stop that treatment after the initial 12 weeks and continue the regimen only with pegylated interferon and ribavirin, while people on Victrelis do not take it for the initial four weeks of treatment.

Patient adherence to the rigid treatment regimen is critical to the drugs’ success, and many people are expected to clear the virus, meaning they are essentially cured. Compliance with the regimen also can have a huge impact on health plans’ bottom lines. Merck set Victrelis’ weekly price at $1,100, or $26,400 to $48,400 for a course of treatment. Vertex gave Incivek a price tag of $49,200 for a 12-week regimen. Those prices mean that treatment costs for the condition have basically doubled.

Steve Burman, CEO of Burman’s Medical Supplies and Specialty Pharmacy and president of Burman’s Pharmacy, points to a study that shows each patient in which an early viral response is identified “can save the health system a minimum of $16,200 via shortened duration of treatment. With approximately 400,000 naïve/relapsed patients in the U.S., that represents the potential of reducing the cost burden to the health system by over $4 billion. Additional saving opportunities exist when you consider identifying those less-fortunate patients by applying the FDA futility rules,” which apply when patients are not responding, and the FDA recommends halting the therapy.

With patients who were among the first to be dosed recently hitting the 24-week mark in their regimens, Burman has shared exclusive data with SPN on what his specialty pharmacy has seen so far among about 700 people it has treated with Incivek and Victrelis.

Among the people taking Incivek, “50% of referrals were for patients who were naïve” to previous hepatitis C treatment, which is exactly what Vertex had estimated, he notes. Nineteen percent were relapsers, 17% were partial responders to prior therapy, and the rest were nonresponders.

Among those taking Victrelis, “63% of the patients were naïve,” with the remainder of the patients equally divided among the other three demographic groups.

Within the naïve patient population on Victrelis, “66% achieved an early viral response; therefore, they have the opportunity for response-guided therapy,” meaning the shortened duration of treatment.

Among a sample of 77 patients taking Incivek, 75% of the naïve patients were eligible for response-guided therapy, a percentage that is “actually a little bit better than controlled studies,” he says. And 91% of prior relapsers were eligible for response-guided therapy, which is “pretty much what’s expected. Relapsers have a really great chance of clearing the virus. The only thing we can do now is compare ourselves to the clinical trials data.”

With Incivek, “if people were partial or nonresponders to previous therapy, they are not eligible for response-guided therapy and instead need to go for 48 weeks of treatment.” However, says Burman, “there are some patients who are partial responders who qualify for response-guided therapy with Victrelis.”

People treated for hepatitis C with the previous two-drug regimen have always been at risk of stopping treatment because of the dreadful flu-like symptoms they cause. Adherence is even more at risk with the addition of Incivek and Victrelis, though, which bring additional side effects.

Among those people who discontinued therapy, 30% of them discontinued Incivek due to not responding to the drug, while 44% of those patients halted therapy because they were “unable to tolerate the side effects.”

In addition, “twice as many discontinued from Victrelis due to severe anemia than Incivek,” says Burman, adding that “this is what we expected.”

“We haven’t seen any problems with patient compliance on Victrelis,” which “was an industry concern because it’s a complicated regimen,” he tells SPN.

In an interesting twist, the drugs’ rigid regimens may work in favor of patient compliance. People need to go in for lab work four weeks after starting therapy. Burman’s keeps track of the date patients start their therapy — which often may not be the same day they receive their medications — through direct communication with patients. They also have certified counselors on staff who are experts on drug and alcohol recovery for patients with a history of abuse to help them stay adherent. Then through calls, emails or text messages, the company makes sure patients come back for their four-week labs on schedule.

Following the lab results, “at four weeks, at eight weeks, they’ll have a good idea of if they will clear the virus.” Bolstered with positive results, these patients “are motivated to finish therapy.”

With clinical trials data available for only the approved regimens, some of Burman’s patients have detoured from those paths slightly but are still on the triple therapy, so he’s curious to see their final outcomes.

For example, “even though we consulted with all of the patients before they started the regimen, there were a few patients who skipped the four-week lead-in with Victrelis and started right away, but their physicians kept them on the regimen,” he says. Burman says he thinks there were two patients who did this, both naïve to prior therapy. “One was negative for the virus after four weeks,” and he is unsure of the other patient’s status.

The specialty pharmacy also had “one patient who basically had cleared the virus, and he had to go in for emergency surgery that was unrelated to the hepatitis C, which meant he had to go off the medications for one week. His doctor started him back up [on Victrelis], so it will be interesting to see what happens.”

As far as side effects of the drugs, “we have slightly more anemia with Victrelis, which was expected,” Burman says. “In most of these cases, we’ve seen physicians use ribavirin dose reductions to treat the anemia.” Ultimately, though, his specialty pharmacy has seen “a little more anemia but not as many side effects with Victrelis.”

Among people taking Incivek, “a very low percentage — less than 1% of patients — were discontinued because of a rash, although we have seen a rash on quite a few of these patients.”

One troubling trend that Burman has noticed is that “about 5% of our patients are getting triple therapy from two pharmacies.” He says he’s been told by larger PBMs that “You fill the ribavirin and interferon, and we’ll fill Incivek” — which can be $17,000 for each fill, he notes.

This kind of situation, though, can cause a “continuity of care issue,” he contends. “It doesn’t seem to be cost-effective,…and it’s disruptive to the patient.”

Burman explains that “about 25% to 30% of patients we set up and trained switched to mail order after one or two months of the six-month therapy.” But within that “complicated” six-month treatment, “there’s no room for error.”

However, some patients almost have had their adherence impacted through no fault of their own, says Burman. He tells SPN that he’s gotten calls from patients who are receiving their drugs from other PBMs through mail order but haven’t gotten their next dose as scheduled, so they’re trying to find a pharmacy that can help. Because patients cannot miss a dose, his company has driven medications to patients an hour or so away to make sure they stay compliant.

Burman expects to have final outcomes for initial patients in May or June. “The first batch of patients just finished therapy. We need to wait six months to retest them, and if they’ve still cleared the virus, we’ll consider them cured. It’s looking good for a lot of patients.…This is a new lease on life for some of these people.”

Source

Lack of donor organs and poor access to treatment mean mortality rates for liver disease destined to rise

Canada NewsWire

TORONTO, Feb. 16, 2012

TORONTO, Feb. 16, 2012 /CNW/ - When you ignore a health issue, it only tends to get worse. Liver disease has been lurking in the dark gaining strength while individuals and governments devote their attention elsewhere. Reports from Statistics Canada and most recently the Canadian Institutes for Health Information (CIHI) however are revealing glimpses of what the future may hold for liver disease patients if action is not taken soon. With rising liver cancer rates and shortages of donor organs, that future looks bleak.

"The most common forms of liver disease - hepatitis B and C, liver cancer and fatty liver disease - are chronic conditions that move slowly and may have few symptoms," says Dr. Morris Sherman, Canadian Liver Foundation Chairman and practicing hepatologist. "In some cases these diseases may not be discovered until they reach an advanced stage when a transplant is the only option. What is more disturbing however is when diseases like hepatitis B or C are diagnosed at an early stage, patients cannot access the treatment they need to avoid the need for a transplant."

According to the CIHI report on organ transplantation released this week, hepatitis C remains the leading cause of liver transplants in Canada, followed by cholestatic liver disease. Liver cancer has taken over the number 3 spot from alcoholic cirrhosis - an indication that lack of diagnosis and intervention is allowing other forms of liver disease such as hepatitis B to progress to liver cancer.

"When the country is facing a chronic shortage of donor organs, we should be looking at ways to reduce the numbers of people who need them," says Dr. Sherman. "Livers are the second most frequently transplanted organ and in 2010 74 people died on the waiting list. This is almost as many as died waiting for kidneys despite the fact that there are six times as many people waiting for kidneys. Patients with failing livers do not have an option for dialysis."

The Canadian Liver Foundation believes that improving organ donor rates is only part of the solution for liver disease patients. "We have the means to significantly reduce the demand for liver transplants," says Dr. Sherman. "We have treatments for hepatitis B that can effectively control, and in some cases cure, hepatitis B before it turns into liver cancer but in many provinces, these treatments are not accessible to patients. In the case of hepatitis C, many people are still not diagnosed. For those that are, new treatment options are available but once again it comes down to accessibility. If governments do not cover the costs of these drugs, only patients with the financial means or independent coverage will be able to afford them."

The CIHI report is further evidence that now is the time to address liver disease in Canada. "There are an estimated 600,000 Canadians living with chronic hepatitis B or C. If there are not enough donor organs now, we should be doing everything we can to keep these people off the transplant list in the future. We hope that these statistics will motivate governments to implement policies regarding screening and treatment that will not only benefit patients but help reduce the demand for liver transplants."

For more information on hepatitis or the Canadian Liver Foundation's positions on liver-related issues, visit www.liver.ca

Source

Androgen boosts hepatitis B virus replication

February 16, 2012

Androgen enhances replication of hepatitis B virus (HBV), rendering males more vulnerable than females to this virus, according to research published in the February Journal of Virology.

“Our studies allowed us to understand the gender disparity of HBV carriers, and why this virus tends to cause more severe liver disease in men than in women,” says principal investigator James Ou of the University of Southern California.

The researchers found no difference between levels of virus in prepubescent male and female mice. However, post-puberty, levels in males exceeded those in females, in some cases by more than double, says Ou. Subsequently castrating male mice reduced the viral load, but injecting castrated mice with an androgen agonist resulted in a rising viral load again.

In a third set of experiments, the researchers removed the androgen receptor by genetic knockout, once again abolishing the androgen’s effect on hepatitis B replication. Then they drilled down still further, discovering elements within the HBV genome which are recognized by the host’s activated androgen receptor, which then boosts viral gene expression and replication.

Epidemiologic studies have shown that men are three to seven times more likely than women to become HBV carriers, and male HBV carriers are more likely to develop cancer of the liver (hepatocellular carcinoma) than female carriers.

“Hepatitis B virus is one of the most important human pathogens,” says Ou. “Approximately 350 million people worldwide are chronically infected, and roughly one million die annually.”

HBV can be transmitted sexually, as well as via non-sterile needles, and perinatally. In areas where the virus is endemic, it is frequently transmitted among young children. It is present in blood (including menstrual blood), vaginal secretions, saliva, semen, breast milk, and to a lesser extent in other bodily fluids. A vaccine is available for HBV.

More information: Y. Tian, C.f. Kuo, W.-l. Chen, and J.-h.J. Ou, 2012. Enhancement of hepatitis B virus replication by androgen and its receptor in mice. J. Virol. 86:1904-1910.

Provided by American Society For Microbiology

Source

Singer Jon Secada Joins Merck and American Liver Foundation's 'Tune In to Hep C' Public Awareness Campaign

PRESS RELEASE

Feb. 16, 2012, 9:00 a.m. EST

Secada Launches Bilingual Campaign to Motivate Hispanic Americans Affected by Chronic Hepatitis C -- Joins Forces with Gregg Allman and Natalie Cole

MIAMI, Feb. 16, 2012 /PRNewswire via COMTEX/ -- Merck (known as MSD outside the United States and Canada) today announced that three-time GRAMMY® award-winning Cuban-American recording artist and songwriter Jon Secada is adding his voice to the Tune In to Hep C public health campaign to help raise awareness of chronic hepatitis C virus (HCV) infection. Secada revealed for the first time today that his father recently passed away from complications associated with chronic HCV infection, a disease that disproportionately affects the Hispanic community. He hopes that sharing his family's personal experience through this bilingual awareness campaign will activate Hispanic Americans with chronic HCV to take action and speak to their doctors about their options.

To view the multimedia content associated with this release, please click: http://www.multivu.com/players/English/54403-54403-tune-in-to-hep-c-awareness-jon-secada-joins-campaign/

Secada joins Merck, the American Liver Foundation (ALF) and fellow GRAMMY® winners Gregg Allman of The Allman Brothers Band and Natalie Cole on the Tune In to Hep C initiative, which Merck and ALF launched last year.

Chronic HCV is a viral infection of the liver that is potentially serious and can damage the liver over time and lead to cirrhosis, end-stage liver disease and liver cancer. Of the approximately 3.2 million Americans who have chronic HCV, an estimated one million are Hispanic. Research has shown that complications due to chronic HCV develop more quickly and result in more health issues in Hispanics when compared to other ethnic groups, especially considering many people infected with chronic HCV, Hispanic or non-Hispanic, do not know that they have the virus - approximately 70 to 80 percent of people newly infected with the virus do not have symptoms.

"My father chose not to tell anyone about his disease for a long time, and he chose not to take action against it for reasons I may never understand. Before he passed away, he told me that he wanted me to share his story to help other people like him who have chronic hepatitis C but aren't taking action," said Secada, who was unaware of his father's diagnosis for more than a decade. "You can't be silent with a silent disease that has consequences like chronic hepatitis C -- you need to talk to your doctor and talk to your family. Take it from me, the people who love you want to be there to help you, and want you to be there for them."

The American Liver Foundation partnered with Merck on the Tune In to Hep C campaign to help address barriers that can keep people from managing their disease, including lack of awareness and social stigma. The American Liver Foundation is a national organization advocating for those living with liver disease and their families, and provides education, support and research for the prevention, treatment and cure of liver disease.

"Chronic hepatitis C disproportionately affects the Hispanic community but, unfortunately, there is stigma and low awareness of the disease and its potential complications, so it is not widely discussed among Hispanics in the U.S.," said Newton Guerin, president and chief executive officer, American Liver Foundation. "We hope Jon's desire to turn his family's loss into a positive message for those who face this disease will encourage them to take action."

Information about chronic HCV in the Hispanic community, as well as exclusive video of Secada telling his personal story, can be found on www.HepatitisCTocaElTema.com , a Spanish-language website that launched today. Secada's story, as well as Allman and Cole's, also can be found on the campaign's English website, www.TuneInToHepC.com .

"For more than 30 years, Merck has been committed to fighting chronic HCV. That commitment extends beyond science and is part of our overall mission to help people around the world be well," said Mark Timney, president, Global Human Health - U.S. Market, Merck. "We believe Jon's message is an important one that will motivate Hispanic Americans with hepatitis C to take action and speak with their doctors, and we applaud him for his efforts in this campaign."

About Jon Secada Secada is a three-time GRAMMY award-winning Cuban-American recording artist and songwriter who has released a string of hits in both English and Spanish. He has sold more than 20 million albums since his self-titled debut album in 1992. Jon Secada (SBK/EMI) sold more than six million copies worldwide and was certified triple platinum in the U.S., where it reached No. 15 among Billboard Pop albums. He later scored a No. 5 Pop hit with the Gold single "Just Another Day," and three more top 30 hits, "Angel," "I'm Free," and "Do You Believe in Us?" The Spanish-language version of the album, Otro Dia Mas Sin Verte (EMI-Latin), became the top Latin album of 1992 earning him his first GRAMMY Award for Best Latin Pop Album.

Recently, Secada participated as a celebrity contestant on Univision's hit dance show "Mira Quien Balia" (Latin version of "Dancing with the Stars"), and he released his highly anticipated new Spanish album, Otra Vez (YME Records/Universal), in February 2011. Secada is currently working on his next English album, I'm Never Too Far Away, which is expected to be released in 2012.

Secada's father Jose was born in Cuba in 1928 and remained there until 1970 when he moved his family to the United States. After being diagnosed with chronic HCV, he waited for more than 10 years to reveal his diagnosis to his son. Jose Secada was a proud man who wanted to be strong and provide for his family. He did not feel sick initially, so he did not follow up with his doctor and never took action against his disease. Ultimately, he began to experience complications, but did not understand the potential consequences until it was too late and the damage to his liver was irreparable. Before his father passed away in November of 2011, Secada received his blessing to share their family's story to educate others about the disease.

About The American Liver Foundation The American Liver Foundation (ALF) is the nation's leading nonprofit organization promoting liver health and disease prevention. ALF provides research, education and advocacy for those affected by liver-related diseases, including hepatitis. For more information, please visit www.liverfoundation.org or call 1-800-GO-LIVER begin_of_the_skype_highlighting 1-800-GO-LIVER end_of_the_skype_highlighting. Spanish speaking operators are available.

About MerckToday's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking StatementThis news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2010 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site ( www.sec.gov ).

SOURCE Merck; The American Liver Foundation

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Vaccine discovered for hep C

Hepatitis C researcher John Law

February 16, 2012 By Jamie Hanlon

(Medical Xpress) -- A University of Alberta researcher and Canada Excellence Research Chair in Virology has made the discovery of a vaccine that will potentially help combat hepatitis C. Michael Houghton, who led the team that discovered the hepatitis C virus in 1989, announced his findings at the Canada Excellence Research Chairs Summit in Vancouver this afternoon. Currently, there are no vaccines against the disease available.

Houghton, also the Li Ka Shing Chair in Virology at the University of Alberta, says the vaccine, developed from a single strain, has shown to be effective against all known strains of the virus. It took more than 10 years to develop and started while he was working for the drug company Novartis. Following previous vaccine tests funded by the National Institutes of Health that yielded promising results, he said there remained two critical questions.

“Did the recipients actually produce antibodies that could neutralize the actual infectious virus,” he said, “and if they could, how broad was the neutralizing response?”

The challenge, Houghton said, was that hepatitis C is more virulent than HIV, thus coming up with a vaccine that would neutralize the different strains around the world was believed to be impossible. Using a vaccine developed and tested on humans in his University of Alberta lab, Houghton and his co-investigator John Law discovered that the vaccine was capable of eliciting broad cross-neutralising antibodies against all the different major strains. Houghton says that this finding bodes good news for those with hep C and those who live or travel to areas where the disease is prevalent.

“This tells us that a vaccine made from a single strain can indeed neutralize all the viruses out there,” says Houghton. “It really encourages the further development of that vaccine. This is a really a big step forward for the field of HCV vaccinology.”

With hundreds of thousands of people being infected with hepatitis C annually, and with between 20 to 30 per cent of those developing some form liver disease, this announcement brings hope. However, Houghton cautions that further testing is required, meaning that it may be five to seven years before the vaccine receives approval. And while it may make some difference in those currently suffering from hepatitis C, it is mainly a preventative measure against acquiring the disease.

The discovery of the vaccine by a University of Alberta researcher, and one of the first appointed Canada Excellence Research Chairs is proud news for both organizations.

"A breakthrough such as this one is exactly the kind of advance we believed would happen here when we created the Li Ka Shing Institute of Virology and recruited internationally renowned researchers such as Michael Houghton and his colleagues," said U of A President Indira Samarasekera.

Chad Gaffield, chair of the steering committee for Canada Excellence Research Chairs program said one of the ambitions of the program was to attract world-class talent to Canada, those whose research would be foremost in making the breakthroughs needed in the 21st century. While it may not be obvious when or where such breakthroughs will occur first, Houghton`s discovery illustrates the impact of this program on a national and international scale.

“The premise of the CERC program is that if you support top minds internationally, good things will happen,” he says. “This is a wonderful illustration of how a key problem in the world today becomes much more understandable and solutions are much closer thanks to the work of Michael Houghton.”

The breakthrough underscores the benefit of the U of A’s Li Ka Shing Institute of Virology.

"This demonstrates that the Li Ka Shing Institute is internationally competitive in important areas of virology research,” said Lorne Tyrrell, director of the institute and a leading virologist in his own right. “We are working on topics that are important to patients, and we want to translate discoveries from the lab to patient care. That has been our philosophy since day one. We have a long way to go, but this is a great step.”

The Canada Excellence Research Chairs Program supports Canadian universities in their efforts to build on Canada's growing reputation as a global leader in research and innovation. The program awards world-renowned researchers and their teams up to $10 million over seven years to establish ambitious research programs at Canadian universities. The University of Alberta is home to three of 18 CERCs in Canada. These chairs are in virology, arctic resources, and oilsands molecular engineering.

Provided by University of Alberta (news : web)

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Also See:

1. University of Alberta researchers move closer to hepatitis C vaccine
2. Alberta researchers develop vaccine to fight hep C

Conference focuses on new ideas concerning liver treatment

2012/02/16 20:58:07

Taipei, Feb. 16 (CNA) International hepatology experts advocated Thursday new ideas for the treatment of liver diseases at the 22nd Conference of the Asia Pacific Association for the Study of the Liver (APASL).

The conference, held under the banner "Advancing Hepatology in the New Era: Milestones and Perspectives," focused on new ideas for the treatment of chronic hepatitis B and C, non-alcoholic fatty liver disease and liver cancer, APASL President Kao Jia-horng said at the four-day conference in Taipei that kicked off Thursday.
It is hoped that the conference can educate medical staff and help them provide better care to patients, Kao added.

One idea to be discussed at the conference was a set of guidelines to govern noninvasive techniques to diagnose liver diseases.
New diagnosis techniques will not rely on obtaining tissue samples through liver punctures, which are deemed unnecessary, explained Academia Sinica member Liao Yun-fan.

Participants at the conference will therefore be discussing the formulation of guidelines to govern other noninvasive diagnosis methods, such as measuring virus quantities, and testing viral genes and liver fibers, Liao added.

Kaohsiung Municipal Ta-Tung Hospital President Yu Ming-lung outlined another new approach.

Future treatment for hepatitis C patients in Asia will be based on the quantity of virus genes detected, Yu said, referring to the two different types of virus strands that effect Asian people differently.
Meanwhile, a number of eminent experts have been invited by the APASL to give speeches at the four-day event.

German virologist and Nobel Prize winner Harald zur Hausen delivered a speech to explain the relationship between infections and cancer.

Liver cancer caused by hepatitis B virus infections works similarly to cervical cancer caused by human papillomavirus infections, a fact that is applicable to liver cancer studies, said zur Hausen.

Other experts invited to speak at the conference included 95-year-old Sung Juei-low, dubbed the "Father of Taiwan Liver Diseases," whose research proved that the hepatitis B virus was the main cause of liver cirrhosis and liver cancer in Taiwan.

Over 3,700 participants from 56 countries are expected to attend the conference. It has been a decade since Taiwan last hosted the event.

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University of Alberta researchers move closer to hepatitis C vaccine

John Law, a research associate, is part of a team that has made a significant discovery in the search for a vaccine against hepatitis C at the University Hospital in Edmonton. Photograph by: Ed Kaiser, Ed Kaiser

By Jodie Sinnema, Postmedia NewsFebruary 15, 2012

EDMONTON — A University of Alberta research team is one step closer to discovering a vaccine for hepatitis C that appears to work against all the major strains of the disease.

Michael Houghton, a researcher at the Li Ka Shing Institute of Virology at the university, says his discovery was unexpected. That's because there are six major strains of hepatitis C and hundreds more subtypes infecting 170 million people around the world. Hepatitis C is spread through contaminated blood and can be associated with needle-sharing, medical procedures involving unsterilized equipment or blood transfusions.

Vaccines, made with the antibodies of specific strains, tend to only work against those specific disease types. Think, for instance, about the flu vaccine and how it covers only certain strains expected to circulate during a given flu season.

Houghton said new data from the University of Alberta shows his vaccine, made from one strain of the hepatitis disease, produces antibodies that can neutralize all the hepatitis C types around the world.

"I think that's great news for our efforts to develop a vaccine for hepatitis C," said Houghton, a world-renowned expert in medical microbiology and immunology who discovered the hepatitis C virus in 1989. He presented his recent findings during Wednesday's Canada Excellence Research Chairs Summit in Vancouver. "It's a very unexpected result and it's guiding us toward the development of a successful hepatitis vaccine."

Such a vaccine was thought impossible and impractical, since hepatitis C is more heterogeneous — or has more varieties — than HIV.

"I think it's a very big step forward," he said. "I've been working on the vaccine for 15 years (and) for so many years, the field felt that antibodies would be very restricted in their neutralizing ability, that you could only neutralize the same strain that the vaccine was derived from."

John Law, Houghton's research partner, said preliminary tests show the vaccine blocked some strains from entering a person better than others, with success rates ranging from 40 per cent to 100 per cent. He said the effectiveness could be improved in clinical trials by playing with the dosage.

Houghton said while it would take five to seven years before such a vaccine could hit the market — it must be proven safe and effective in large clinical trials involving humans — he said the vaccine could also help those already infected with the disease. Of the millions who carry the infection, up to 20 per cent develop chronic illness, including cirrhosis of the liver.

A drug cocktail already on the market cures 70 per cent of those infected with hepatitis C, Houghton said. He said further research needs to determine if a combination of that antiviral with the new vaccine could increase the success rate.

"It may also be beneficial as a therapeutic vaccine," he said. "That does deserve attention in the future."

Dr. Lorne Tyrrell, a hepatitis expert and the Canadian Institutes of Health Research and GlaxoSmithKline chair in virology at the University of Alberta, said if the vaccine proves effective, it will have a global impact. In Egypt, for instance, 10 per cent of the population carries hepatitis C.

"In many parts of the world, the antiviral therapy we currently have for hepatitis C is often out of the reach of most people's affordability so having a (cheaper) vaccine that could be used to prevent the disease in those countries is particularly important," Tyrrell said.

"There's still a lot of work that needs to be done, but at least it's a clue and an indication that we can develop a potential vaccine for hepatitis C."

jsinnema@edmontonjournal.com

twitter.com/jodiesinnema

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Also See: Alberta researchers develop vaccine to fight hep C