October 1, 2012

Hepatitis C Therapy in Non-genotype 1 Patients: The Near Future

From Journal of Viral Hepatitis

C. Wartelle-Bladou; G. Le Folgoc; M. Bourlière; L. Lecomte

Posted: 07/27/2012; J Viral Hepat. 2012;19(8):525-536. © 2012 Blackwell Publishing

Abstract and Introduction

Summary. Worldwide, 50–70 million subjects are infected with an hepatitis C virus (HCV) genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin remains the currently approved standard-of-care treatment. The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A protease inhibitors (PIs), nucleos(t)ide (NIs) and non-nucleoside inhibitors of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-protein-directed antiviral agents are cyclophilin inhibitors and silibinin. Whereas the launch of first-generation PIs was a major landmark in the management of genotype 1 (GT-1)-infected patients, these drugs are inactive in most non-GT-1-infected patients. Several of these and other drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds and combinations.


There are approximately 170–200 million people chronically infected with hepatitis C virus (HCV) worldwide. Chronic hepatitis C can lead to cirrhosis and its subsequent complications such as hepatocellular carcinoma with more than 350 000 people dying each year from hepatitis C–related liver disease. Clearance of the virus is associated with improved histological outcomes, morbidity and mortality. The therapeutic goal is therefore to achieve a sustained virological response (SVR) defined as undetectable HCV RNA 6 months after cessation of therapy. Among the six identified HCV genotypes, genotype 1 (GT-1) is the most prevalent and was, until the approval in 2011 of two-first-generation NS3/4A protease inhibitors (PIs) in combination with pegylated interferon (PEG-INF)-α and ribavirin, the most difficult to cure. The launch in 2011 of boceprevir and telaprevir was a major landmark in the management of GT-1-infected patients. In association with PEG-INF and ribavirin, these two drugs increase the chances of cure by 30% with SVR rates in the range of 66–75% in naïve patients.[1–3] The benefit appears to be even more important in treatment-experienced patients in whom the chances of cure increase by 50–60% in relapsers, 40–45% in partial responders and 25% in null responders.[4,5]

However, this major advance benefits only GT-1 patients while there remains worldwide 50–70 million subjects infected with an HCV genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin (PR) remains the currently approved standard-of-care treatment (SOC). HCV genotypes present specific geographical distribution (Fig. 1), leading to a quasi-mono-genotypic HCV infection in some parts of the world such as Egypt, where the HCV infection prevalence reaches 15% in the general population with an almost exclusive GT-4 distribution. In such a country, chronic hepatitis C will exert an increasing substantial disease burden without more effective treatments.


Figure 1. Hepatitis C virus (HCV) genotype distribution worldwide (courtesy of S. Locarnini).

The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A PIs, nucleos(t)ide (NIs) and non-nucleoside inhibitors (NNIs) of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-proteins-directed antiviral agents are cyclophilin inhibitors and silibinin. Several drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds.

Current Standard-of-care Treatment Treatment Results in Non-GT-1 HCV Infection

The recommended first-line treatment for non-GT-1 chronic hepatitis C is based on the use of any of the two pegylated IFN-α available administered weekly subcutaneously and daily oral ribavirin.[6] PEG-IFN-α2a should be used at a dose of 180 μg once per week, whereas PEG-IFN-α2b should be used at a weight-based dose of 1.5 μg/kg per week. The ribavirin dose depends on the HCV genotype. Patients infected with GT-4, GT-5 or GT-6 should receive a weight-based dose of ribavirin of 15 mg/kg body weight per day. Patients infected with GT-2 or GT-3 can be treated with a flat dose of 800 mg of ribavirin daily; however, those with baseline factors predictive of a low responsiveness should receive a weight-based dose of ribavirin similar to GT-4, GT-5 and GT-6. Although initially the duration of treatment was fixed, 24 weeks for GT-2 and GT-3 and 48 weeks for GT-4, GT-5 and GT-6, the treatment duration should now be tailored to the on-treatment virological response in most non-GT-1 HCV patients.

Patients infected with GT-2 or GT-3 are not a homogenous population. There is now mounting evidence that these two genotypes should be distinguished from one another and not be anymore labelled together as the 'easy-to–treat' group. Indeed, SVR rates with a SOC 24-week treatment range from 75% to 97% and 62% to 92% in GT-2 and GT-3 patients, respectively.[7] Shortening the duration of treatment without compromising the chances of cure has been investigated in GT-2/GT-3 patients with conflicting results. A meta-analysis concluded that in rapid virological responders (RVR, defined as undetectable HCV RNA at 4 weeks), shortening of treatment duration to 16 weeks is possible in GT-2 patients or in GT-3 patients with an optimal weight-based ribavirin dose. Whatever the genotype, shortening of treatment duration is not recommended in cirrhotic patients. Extension of the treatment to 48 weeks is suggested in the absence of an RVR and/or in the presence of predictive factors of lower SVR such as advanced liver fibrosis or high BMI.[6] The impact of the IL28B polymorphism is unclear in GT-2/GT-3 patients. While some studies have failed to demonstrate any clear association between IL28B polymorphism and SVR,[8,9] others have reported a positive association between the favourable rs12979860 CC or rs8099917 TT genotype, respectively, with RVR, but not SVR,[10] suggesting an increased rate of relapse in this population along with higher pretreatment viral loads and ALT levels. Finally, two European studies showed that CC genotype is associated with SVR.[11,12] In an Italian study, IL28B CC genotype is highly predictive of SVR among non-RVR patients.[12]

In patients infected with GT-4, despite the lack of data validating the response-guided therapy concept, it has been suggested by an international panel that a response-guided approach similar to the one used in GT-1 patients may be considered.[13] Thus, RVR are highly likely to achieve SVR and are candidate to 24-week regimens in the absence of poor baseline predictive factor of response. Patients with RVR and pejorative predictive factors and complete early virological responders (EVR defined as undetectable HCV RNA at week 12) should be treated for 48 weeks. Patients with partial EVR (detectable HCV RNA but >2 log10 drop at week 12 and undetectable HCV RNA at week 24) may be considered for treatment prolongation to 72 weeks.[13] IL28B polymorphism is an important baseline predictive factor of response in GT-4 patients. Genotype CC in the SNP rs12979860 is associated with SVR but not with liver severity in these patients.[14,15] However, its predictive weight is lower than in GT-1 patients, and RVR remains the strongest predictive factor of response.[14]

In patient infected with GT-6, two studies evaluated response-guided therapy in a pilot trial and a randomized trial.[16,17] They demonstrated that patients with RVR could be treated for 24 weeks. However, those without RVR had very low SVR.[16] In GT-5-infected patients, there are no data on response-guided therapy, and 48-week regimens should therefore be recommended.

Apart from clinical trials, observation cohorts provide us with real-life results. In the PROPHESYS cohort, 37% of the 7163 patients included were infected with a non-GT-1 HCV. The observed SVR rates after SOC treatment were of 41%, 61%, 68% and 71% in GT-4, GT-3, GT-5/GT-6 and GT-2 patients, respectively.[18] In the German cohort, which included 23 893 patients, 39 patients were infected with GT-5 and 39 patients with GT-6. SVR after 48 weeks of treatment was 58% and 59% for GT-5 and GT-6, respectively.[19]

Current results of SOC treatment in non-GT-1 patients are not optimal especially in GT-4 and GT-3 patients.

Standard-of-care treatment will not be successful in 30–60% of patients. A second course of PEG-INF and ribavirin for a longer duration with an optimal dose of ribavirin is currently the only available option. This leads to unsatisfactory results with poor SVR rates ranging from 19% to 34% in previous nonresponders to 46% in relapsers.[6] Therefore, new treatments are urgently needed in this population.

Telaprevir and Boceprevir in Non-genotype 1 Hepatitis C Virus Infection

Telaprevir and boceprevir are orally available, first-generation PIs. Combined with PEG-IFN and ribavirin, both drugs have recently been approved for the treatment of naïve and treatment-failure GT-1-infected patients.

The antiviral activity of telaprevir against GT-2 and GT-3 HCV was investigated in a randomized, partially blinded study. The study design allowed evaluation of the intrinsic antiviral potency of the drug in the 9 GT-2 patients and 8 GT-3 patients randomized to an initial 2-week course of telaprevir monotherapy. A significant reduction in the HCV viral load (median HCV decrease – 3.27 log10 IU/L) was observed at day 3 in GT-2 patients compared with SOC. However, a virological breakthrough was observed in six of the nine patients within 15 days. Telaprevir monotherapy had no activity in GT-3 patients, with only a slight decrease in the HCV RNA levels (−0.54 log10 IU/L at day 3 and 15, respectively).[20] Triple therapy with telaprevir for 2 weeks induced a greater reduction in HCV RNA level compared with the SOC arm in GT-2 patients, but not in GT-3 patients.[20] Boceprevir monotherapy was evaluated in a phase I study in 40 GT-2/GT-3 patients in a 2-week dosing period. The maximum decrease in the viral load during the treatment period was observed in the 400 mg q.8 h arm in GT-3 patients with a mean – 1.71 log10 UI HCV RNA from baseline comparable with the viral drop seen in GT-1 patients.[21]

In a phase IIa study conducted in 24 GT-4 patients, triple therapy with telaprevir for 2 weeks induced a greater reduction in the HCV RNA level compared with the SOC arm. However, following triple regimen, PR for 46 weeks did not lead to a greater SVR compared with PR (62% in both groups).[22]

While telaprevir in association with PR demonstrated antiviral effectiveness in GT-2 patients, leading to an ongoing phase III trial in treatment-experienced patients, triple regimen with first-generation PI elicits no or limited antiviral effectiveness in GT-3 and GT-4 chronic hepatitis, confirming the need for more potent combinations.

Beyond Triple Therapy with First-generation Protease Inhibitors

The main compounds in clinical stage development for non-GT-1 HCV infection comprise DAAs, host-targeting antiviral agents and PEG-INF-λ.

Most second-wave PIs are macrocyclic. Their antiviral potency is similar or slightly better than first-generation PIs, but they exhibit a more favourable resistance profile and are easier to administrate.[23] TMC-435 inhibits HCV replication across all genotypes in preclinical protease biochemical assays, with an IC50 value below 13 nm except for GT-3a protease.[24] Danoprevir (DNV) has equipotent activity against HCV genotypes 1, 4 and 6 in vitro.[23] MK 5172 is a highly effective second-generation PI with subnanomolar in vitro IC50 values across all HCV genotypes. It is effective in vitro against the majority of first-generation PI resistance–associated variants and is the first pan-genotypic PI.[25] The safety profile of both second-wave and second-generation PIs appears to be good so far.

NS5B polymerase inhibitors comprise nucleoside(-tide) inhibitors (NIs) and non-nucleotide inhibitors (NNIs).[26] NIs binds to the NS5B active sites, causing chain termination and/or an increased number of errors when incorporated into a growing RNA chain. The NS5B's active site being well conserved, NIs tend to have a similar efficacy across all genotypes and present the highest barrier of resistance of all DAAs to date. In contrast, NNIs have shown a restricted spectrum of activity against the various HCV genotypes. They are mainly active against HCV GT-1 and present the lowest barrier of resistance. NS5B NIs appear therefore to be among the most promising pan-genotypic drugs.

Hepatitis C virus NS5A is a critically important viral protein in the virus replication, whose function is still not clearly elucidated.[27] BMS-790052 (Daclatasvir) is a first-in-class NS5A inhibitor which potently inhibits replicons representative of all six major genotypes with EC50 of <1 nm without overt cytotoxicity to host cells.[28]

Drugs targeting host proteins essential for the HCV replication may provide a greater barrier to resistance than DAAs. The first host-targeting compounds to emerge were the cyclophilin inhibitors, cyclophilin A being the putative protein involved. Debio 025 (alisporivir, ALV) is a selective cyclophilin inhibitor whose antiviral activity against HCV GT-1, 3 and 4 was demonstrated in a proof-of-concept study with no overt sign of upcoming resistance.[29] Seven-day intravenous treatment (20 mg/kg/day) with silibinin, whose mechanism of action is not yet completely understood, resulted in a mean decrease of 3 log10 IU/mL in HCV RNA in GT-1 patients. No data are available on the specific antiviral activities for non-GT-1 genotypes.[30]

Pegylated interferon lambda is a type III interferon with a marked antiviral C activity and a restricted distribution of receptors, mostly in the liver, leading to less hematopoietic side effects than PEG-IFN-α This was confirmed in a phase 2b study in terms of reduction in side effects, even in cirrhotic patients.[31–33] A recent study suggested that vitamin D could increase the response to PR treatment in HCV GT-1 patients.[34] This should be confirmed in other trials and in other HCV genotypes.

Where Are We Now in Clinic With New Compounds?
Genotype 2 and Genotype 3 Future Treatment

Second-Wave and Second-Generation Protease Inhibitors TMC 435 monotherapy 200 mg daily for 7 days was investigated in GT-2–6 patients in a phase IIa study. The study confirmed the absence of activity observed in vitro in GT-3 infection and demonstrated a weak activity of the compound against GT-2.[35] In a phase 1 study with MK-5172 monotherapy 400 mg daily for 7 days, a maximum mean HCV RNA reduction from baseline of 5.4 and 3.98 log 10 UI/mL was observed in GT-1 and GT-3 patients, respectively.[36] Studies assessing MK-5172 with PR for 12 or 24 weeks are currently ongoing in GT-2/GT-3 patients (Table 1).

NS5B Nucleos(t)ide Inhibitors Mericitabine (RG7128) is a nucleoside analogue, whose antiviral activity was demonstrated in vitro across HCV genotypes. Mericitabine was evaluated in GT-2/GT-3 treatment-failure patients. After a 4-week triple combination, RG7128 1500 mg bid was discontinued and PR resumed for 20–44 weeks. Week 4 RVR rate was 95% in RG7128-treated patients vs 60% in the PR arm, demonstrating the antiviral potency of the molecule. In the absence of an RVR, no patient presented SVR whereas 68% of RVR patients were cured. SVR rates were less impressive, due to the short duration of the triple regimen (4 weeks), and did not differ among GT-2 and GT-3 RG7128 treated patients: 63% and 67%, respectively.[37] In patients treated with RG7128, SVR was higher in those treated for 48 weeks (90%) than in those treated for 24 weeks (67%).[37]

PSI-7977 (now GS-7977) is a pyrimidine nucleotide analogue with a high antiviral activity across all genotypes and a high genetic barrier to resistance. It is safe, well tolerated and administrated once daily. PSI(GS)-7977 was evaluated in 25 naïve GT-2/GT-3 patients in the PROTON study. A 12-week triple combination of PSI(GS)-7977 400 mg once daily plus PEG-INF and weight-based ribavirin yielded a 100% SVR rate 24 weeks after the end of therapy.[38] Furthermore, in the ELECTRON study, an 8-week triple combination of PSI(GS)-7977 400 mg/day plus PEG-IFN and weight-based ribavirin yielded a 100% SVR rate 12 weeks after the end of therapy in the 10 treatment-naive GT-3 patients included.[39] Combination of PSI(GS)-7977 with ribavirin was further evaluated in the ELECTRON study with a 12-week treatment duration. The trial conducted in 40 treatment-naïve GT-2/GT-3 patients comprised one triple regimen arm, two INF-sparing arms and one INF-free arm.[40] SVR rates 12 weeks after cessation of treatment were 100% in all arms. Ten patients were enrolled in an additional 12-week PSI(GS)-7977 monotherapy. Whereas the EOT rate was 100%, four patients relapsed within the month following cessation of therapy, outlining the importance of ribavirin. There was no virological breakthrough identified and no premature discontinuation of treatment due to adverse events.[40] In subsequent arms of the ELECTRON study, 25 treatment-experienced GT-2/GT-3 patients were treated for 12 weeks with PSI(GS)-7977 and ribavirin. Whereas the EOT rate was 100%, three patients relapsed within the month following cessation of therapy, and SVR rates 4 weeks after cessation of treatment was 80%.[39] Other potent guanosine nucleotide polymerase inhibitors INX-189, active against GT-1, GT-2 and GT-3, are currently beginning phase II trial in naive GT-2 or GT-3 patients.

NS5A Inhibitors (NS5A Is) Daclatasvir (BMS-790052) is, in vitro, a potent inhibitor of viral replication in all six major genotypes. There are two ongoing phase II studies in GT-2/GT-3 patients. The first one conducted in naive patients assesses the benefit of a triple regimen with daclatasvir 60 mg daily plus PR given for 16 or 24 weeks. The second study is being conducted in treatment-experienced patients and evaluates the benefit of a quadruple regimen comprising daclatasvir 60 mg daily, asunaprevir (NS3/4 PI) and PR given for 24 weeks (Table 1).

Cyclophilin Inhibitors Alisporivir (Deb025) was investigated in GT-2/GT-3 naïve patients in a double blind, placebo controlled escalating dose-ranging with or without PEG-INF for 29 days in a phase II study.[41] HCV RNA levels at week 4 were reduced by −5.91 and −5.89 log10 IU/mL in the 600 and 1000 mg combination arms, respectively. Five of six patients in both groups had undetectable HCV RNA at the end of treatment, and one patient had a SVR after 28 days of Deb025.[41,42] In the phase II VITAL study, 346 GT-2/GT-3 naïve patients were randomized in five groups: (1) ALV 1000 mg qd; (2)ALV 800 mg qd + RBV 800 mg/day; (3) ALV 600 mg qd + RBV 800 mg/day; (4) ALV 600 mg qd + PEG-INFα-2a 180 μg/week; and (5) PEG-IFNα-2a 180 μg/week + RBV 800 mg/day.[43] All treatments were given for 24 weeks. In all ALV arms, patients received a leading dose of ALV 600 mg bid during the first treatment week. In each arm, in the absence of an RVR, patients were treated from week 6 to week 24 with a triple regimen ALV 600 mg qd + PEG-IFNα-2a 180 μg/week + RBV 800 mg/day. Whatever the ALV dose, SVR rates 12 weeks after the end of therapy were significantly higher in ALV-treated patients ranging in ITT analysis from 77% to 83%vs 58% in the control arm. Among the three IFN-free arms, 22%, 23% and 34% of patients in ALV 1000, 600 and 800 mg arm, respectively, reached RVR and were therefore maintained on the IFN-free regimen until week 24. The SVR rate 12 weeks after cessation of treatment was 82%, 93% and 91% in ALV 1000, 600 and 800 mg groups, respectively.[43] However, despite those encouraging results, the development of the molecule wad stopped due to the occurrence of six cases of acute pancreatitis including one fatal case.

IFN-free Regimen With Direct Antiviral Agents Combination With or Without Ribavirin The ELECTRON study has demonstrated that a 12-week IFN-free regimen with PSI(GS)-7977 + RBV was able to cure ten naive GT-2/GT-3 patients without advanced disease. Moreover, the same regimen was able to cure '80% (SVR4)' of a larger cohort of treatment-experienced GT-2/GT-3 patients again without advanced fibrosis.[39]

The second IFN-free regimen phase II trial assessed the antiviral efficacy of daclatasvir (NS5A. I) in combination with GS-7977 (NS5B. NI) with or without ribavirin for 24 weeks in naive GT-2/GT-3 patients without advanced fibrosis.[44] There were three arms: (i) a first week of GS-7977 followed by 23 weeks of daclatasvir in combination with GS-7977, (ii) 24 weeks of daclatasvir and GS-7977 combination, (iii) 24 weeks of triple combination of daclatasvir, GS-7977 and ribavirin 800 mg/day. Combination was well tolerated, and early SVR rate 4 weeks after the end of therapy was 91% (40/44 patients). Two patients were lost to follow-up, one patient had a breakthrough and one patients relapsed 4 week after the end of therapy.

A third ongoing IFN-free regimen phase II trial assesses the antiviral efficacy of a regimen associating ABT-267 (NS5A. I) and ABT-450r, a ritonavir-boosted protease inhibitor, with or without ribavirin in naive GT-2/GT-3 patients (Table 1).

Interferon Lambda Final data for GT-2/GT-3 patients of the EMERGE phase II study suggest a beneficial impact of PEG-INF-λ in GT-3 patients.[45] There were 60 GT-2 and 58 GT-3 patients enrolled in this trial evaluating different doses of PEG-IFN-λ (120, 180 and 240 μg) in association with RBV for 24 weeks. Whatever the PEG-IFN-λ dose, SVR rates 24 weeks after the EOT were numerically greater in GT-3 patients receiving PEG-INF-λ compared with the control SOC group (PEG-INFα-2a 180 μg plus ribavirin). SVR rates in GT-2 patients were similar in PEG-INF-λ and control arms. Flu-like symptoms, myalgia and pyrexia were significantly lower in PEG-INF-λ-treated patients. No reduction in the dose of ribavirin was needed in the PEG-INF-λ 180 μg group vs 23% in those treated with PEG-INFα-2a 180 μg.[45]

In Summary The recently reported clinical results suggest that (i) an oral 'PEG-INF-free' 12-week treatment (GS-7977 with ribavirin for 12 weeks) can lead to definitive clearance of the virus in most naive and treatment-experienced GT-2/GT-3 HCV infection with mild or moderate fibrosis; (ii) ribavirin still matters in combinations including a single DAA; (iii) an oral, 'IFN-free', 'RBV-free' DAAs combination (daclatasvir and GS-7977 for 24 weeks) may achieve eradication of the virus in more than 90% of naive GT-2/GT-3. The high SVR rate, 4 weeks after EOT, needs to be confirmed with a longer follow-up, particularly in the absence of ribavirin in the regimen. Moreover, all these very encouraging results for IFN-free regimens need to be confirmed in patients with more advanced fibrosis and in null-responders to SOC. Meanwhile, triple regimen with GS-7977 plus PEG-IFN and ribavirin for 12 weeks appears to be conclusive, but must be confirmed in the most-difficult-to-treat patients. Candidate compounds, currently available for an oral, IFN-free combination in this population, are second-generation PI (MK-5172) as second-wave PI exerts no efficacy on GT-3, NS5A inhibitors, NS5B nucleoside or nucleotide inhibitors (Mericitabine, GS-7977) and cyclophilin inhibitors (ALV); however, this last compound is on hold due to toxicity. The association would ideally comprise at least one compound with a high barrier to resistance.

Several therapeutic combinations (triple combinations with PR, INF-free combinations and INF-free, ribavirin-free DAAs combinations) are currently evaluated both in naïve and in prior nonresponders GT-2/GT-3 patients (Table 1). Those studies need to address more rapidly the most-difficult-to-treat population.

Finally, switching from PEG-INFα to PEG-INF-λ may be an interesting alternative in GT-2/GT-3 patients. The lesser hematopoietic side effects with no need for RBV dose reduction may be of particular interest in GT-3 patients as an optimal dose of RBV appears essential in this subgroup to prevent relapse.

Genotype 4

Second-Wave and Second-Generation Protease Inhibitors TMC 435 was investigated in 8 GT-4 patients during an 11-day monotherapy course. Mean viral decrease was −3.43 log10 UI/mL at day 3 and −3.52 at day 8.[35] A phase III study assessing the efficacy of triple regimen with TMC435 150 mg qd plus PR for 12 weeks fallowed by 12 or 24 weeks of PR is ongoing in naive and treatment-experienced GT-4 patients.

Danoprevir is also active against GT-4. Different doses of DNV boosted with ritonavir (DNVr 200/100, 100/100, 50/100 mg bid) for 24 weeks and DNVr100/100 for 12/24 weeks (response-guided arm) were evaluated in combination with PR in the DAUPHINE trial.[46] Thirty-three GT-4 patients were enrolled in this open-label, active-controlled phase IIb study. All DNVr-treated GT-4 patients achieved an SVR12, independently of the DNVr dose and the treatment duration. There were no DNVr-related grade 3/4 AE. Diarrhoea was the only side effect that occured in all DNVr arms with an 10% higher incidence than in the control group.

Asunaprevir, a second-wave PI, is studied in an ongoing trial in combination with PR for various duration – 24 to 48 weeks – in naïve GT-4 patients.

Lastly, among PIs, second-generation PI (as MK-5172) may be a good candidate for triple therapy; however, studies are pending.

NS5B Nucleos(t)ide Inhibitors Mericitabine was evaluated in the 28 naive GT-4 patients who were included in the PROPEL study. This phase II, controlled trial evaluated an initial 8- or 12-week triple combination of mericitabine with PR followed by 12–36 weeks of PR. RVR and cEVR were higher among patients treated with mericitabine, but SVR and relapse rates were comparable to the PEG-IFN and ribavirin control arm.[47] This is due to the short duration of triple regimen. In the JUMP phase 2b study, five naive GT-4 patients alongside 166 GT-1 naive patients were randomized to SOC for 48 weeks or to triple therapy with mericitabine during 24 weeks, followed by 24 weeks of PR in those without eRVR.[48] In this study SVR rate was always superior in triple regimen arms compared with SOC. However, the 57% SVR rate is lower to what we reach with other triple regimens. Therefore, mericitabine may be more interesting as a compound used in a DAAs association than in a triple regimen with PEG-IFN and ribavirin.

GS-7977 in combination with PEG-IFN and ribavirin exhibits a rapid and drastic viral decay within the first 4 weeks of treatment similar across all genotypes.[49] Eleven GT-4 patients were included in the ATOMIC study and treated with GS-7977 400 mg once daily plus PEG-IFN and ribavirin for 24 weeks. All 11 patients were HCV RNA undetectable at week 4. At interim analysis, the eight patients evaluable 12 weeks post-treatment (three patients pending) had remained HCV RNA negative.[50]

NS5A Inhibitor Daclatasvir (BMS-790052) is, in vitro, a potent inhibitor of viral replication in all six major genotypes. Daclatasvir in association with PEG-IFN and ribavirin was evaluated in 30 GT-4 patients. Preliminary data reported that all 12 patients in the daclatasvir 60 mg qd arm had undetectable HCV RNA at week 12 compared with 58% in the 20 mg arm and 50% in the placebo arm.[51]

Cyclophilin Inhibitor (CI) Four naïve GT-4 patients presented a viral decay of more than 2 log10 UI at week 4 in a phase 2a dose-ranging study of 29 days of the cyclophilin inhibitor ALV.[41] This weak antiviral activity preclude further study; however, due to this different mode of action, CI could be part of DAAs combination regimen. Unfortunately, the molecule was on hold due to toxicity.

Direct Antiviral Agents Combination With PEG-IFN and Ribavirin There are two ongoing studies evaluated in treatment-experienced GT-4 patients: the combination of daclatasvir (NS5A inhibitor) plus asunaprevir (PI) and PEG-IFN plus ribavirin for 24 weeks in the first study; and ritonavir-boosted DNV (PI) plus mericitabine (NS5B NI) and PEG-IFN plus ribavirin for 24 weeks in the second study (Table 1).

Nitazoxanide Nitazoxanide (NTZ) is an antiparasitic drug efficient against cryptosporidium, giardia Lamblia and clostridium difficile. The postulated antiviral C mechanism of NTZ is believed to be through selective induction of a host protein kinase.[52] The STEALTH C trial was conducted in 96 GT-4 patients in two Egyptian centres. The SVR rate increased from 50% in the control SOC 48 weeks group to 79% in patients receiving 12 weeks lead-in phase of NTZ 500 mg twice daily followed by 36 weeks of triple combination.[53] Although these results are promising, the number of patients was small and the percentage of patients with advanced liver disease was low. Thus, further studies are needed to investigate NTZ in GT-4.

In Summary Clinical results with DAAs are sparse for GT-4 patients, mostly derived from trials enrolling GT-1–4 patients with small numbers of GT-4 subjects included. However, the reported results are promising, demonstrating: (i) 100% RVR rates with a triple combination (GS-7977 + PR); (ii) high SVR rates with short 12-week combination regimens (GS-7977 + PR, DAN/r + PR). (iii) The efficiency of second-wave PIs in GT-4 HCV infection.

Potential INF-free therapeutic options consist in a combination of GS-7977 with RBV or a combination of two DAAs with or without ribavirin. Candidate DAAs are second-wave (DNV/r, TMC 435) and second-generation PIs (MK-5172), NS5A inhibitor (daclatasvir), NS5B NIs (mericitabine, GS-7977) and new cyclophilin inhibitor if available.

Genotype 5 and 6

Clinical results of the use of DAAs for GT-5 and GT-6 HCV infection are limited.

TMC 435 monotherapy induced a significant mean viremia decrease of −4.35 log10 UI/mL after 8 days in the GT-6 patients studied whereas the mean change was only – 2.19 in GT-5 patients (−2.71 at day 3).[35]

Five GT-6 patients were included in the ATOMIC study and treated with GS 797 400 mg once daily plus PEG-INF plus ribavirin for 24 weeks. The RVR rate at week 4 and the SVR rate 12 weeks after the end of the treatment were both 100%.[50]


Current results of SOC treatment in non-GT-1 patients are not optimal, especially in GT-4 and GT-3 patients.

New treatments are urgently needed in this subgroup. While telaprevir in association with PR has demonstrated antiviral effectiveness in GT-2 patients, the current available first-generation PIs (telaprevir and boceprevir) are not active against non-GT-1 HCV infection.

Evaluation of many promising molecules such as second-generation PIs, NS5A I and NS5B NIs, some with pan-genotypic activity, have begun, demonstrating potent viral efficacy with good safety profile in easy-to-treat patients. An all-oral PEG-INF-free regimen for 12 weeks was able to cure nearly all naive and treatment-experienced GT-2/GT-3 HCV infection with mild or moderate fibrosis. IFN- and RBV-free DAAs combination also appears very efficient in this population. These data need to be confirmed in treatment-experienced and advanced liver fibrosis populations.

Meanwhile, triple regimens with DAAs plus PEG-IFN and ribavirin appear to be very conclusive although results must be confirmed in difficult-to-treat patients. Whether or not PEG-IFN and/or ribavirin will remain in some patients the backbone of future DAAs combinations remains an open and unsolved issue.

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Medical research funding tied to advocacy, study finds


A new study argues that funding priorities at the National Institutes of Health have changed because of efforts by advocacy groups. (Mark Wilson / Newsmakers)

By Jon Bardin

October 1, 2012, 11:14 a.m.

The way medical research is funded in the United States has been vastly altered over the last 20 years by advocates asking that research be focused on particular diseases, according to a new study.

Since the 1980s, a growing number of health advocacy groups have lobbied Washington for research dollars. As these groups have grown in size, the new study says, they have begun to influence how the federal government, in particular the National Institutes of Health, allocates its dollars.

In the new report, published Sunday in the American Sociological Review, sociologist Rachel Best analyzed funding for 53 diseases over 19 years, looking to see whether there was any clear relationship between advocacy and funding. Unsurprisingly, she found that there were clear effects: The more advocacy, the more research dollars for specific diseases, such as HIV/AIDS and breast cancer.

But because there is only so much money in the NIH budget, research funding tends to be a zero-sum game. So Best also found that the overall portfolio of NIH funding moved toward those with the money to lobby, and away from groups that did not. The biggest losers were diseases that primarily affected women, such as cervical cancer, and the African American community, such as sickle cell anemia. (The exception to the rule was breast cancer, which has very well organized lobbying efforts.)

Best also found that the changes had system-wide effects on funding that trickled down to the practice of science as well. In particular, Best argues that the efforts of particular groups to focus research efforts on particular diseases motivated the government to move the NIH away from research projects that were general, basic-science projects with the potential to affect many diseases to ones that were focused on single diseases or disease groups, such as diabetes or cancer.

Though the NIH resisted this push in the name of scientific independence, Best's analysis showed that, over time, funding came more in line with a particularly morbid-sounding metric: "dollars-per-death." According to Best, the phrase grew out of some disease advocates' objections to a focus on HIV/AIDS research after AIDS activists’ great successes in garnering NIH funding in the early 1980s.

While HIV/AIDS was viewed as a deadly disease greatly in need of a cure, many advocates for other ailments believed it was receiving too much funding. In 1984, for example, Rose Kushner, advocating on behalf of breast cancer research, pointed out that the NIH was spending about $11,000 in research dollars per HIV/AIDS patient, compared to $400 per breast cancer patient.

Best writes that such "dollars-per-death" lobbying led to an increased NIH focus on funding diseases with high mortality. And her statistics back it up: Best found an increasingly strong relationship over time between mortality and funding.

But this focus on mortality only went so far, Best found. Stigmatized diseases, such as lung cancer (which many connect to smoking) and liver cancer (which many connect to alcohol abuse) increased in funding far less than would be expected from their mortality alone.

According to Best, those data show how even erudite organizations such as the NIH can be shaped by social pressure. "Once patients were viewed as beneficiaries of medical research funding," Best writes, "disease stigma became increasingly relevant to NIH priority-setting."

You can read a summary of the study here.

Return to the Booster Shots blog.


Home Access Health launches educational website for at-home HIV tests


New website www.HIVhometestfacts.com provides clarity about all FDA-approved over-the-counter HIV test products on the market

HOFFMAN ESTATES, Ill., Oct. 1, 2012 /PRNewswire/ -- Home Access Health Corporation, manufacturer of at-home laboratory test services, today announced the launch of www.HIVhometestfacts.com, a new website providing vital facts about all FDA-approved over-the-counter HIV tests currently on the market.

"We believe HIVhometestfacts.com will be an important resource for those interested in choosing an at-home HIV test," said Mary Vogt, President of Home Access Health Corporation. "At-home testing options increase overall testing rates, add to the body of knowledge surrounding risk factors for HIV, and reduce the rates of transmission of this dangerous virus. But the products on the market differ widely, and the public deserves to know the key distinctions that each offers."

The website is designed to help the public understand the two at-home testing options –and more importantly– their differences, especially as they relate to accuracy, Vogt said.

Two FDA-approved, over-the-counter at-home HIV tests are available to the public today without the need to see a doctor or visit a clinic: the Home Access® Express HIV-1 Test System, on the shelves since 1996, and the OraSure Technologies' OraQuick® In-Home HIV Test, which received FDA approval in July 2012.

www.HIVhometestfacts.com provides a clear comparison of the products, offers answers to frequently asked questions, explains how the tests work, and supplies additional resources on HIV/AIDS education and support.

The completely anonymous Home Access ® Express HIV-1 Test System is greater than 99.9 percent accurate, gives users next-day results, provides confirmation of preliminary positive results, and offers counseling by degreed professionals, Vogt said. The Home Access® Express HIV-1 Test System may be purchased through major retailers such as Walgreens, CVS and Rite-Aid, through various online retailers including Drugstore.com and directly from Home Access (www.homeaccess.com).

The Home Access® Express HIV-1 Test System uses a self-collected fingerstick blood sample, which is sent to the certified Home Access laboratory via FedEx® overnight delivery. The laboratory tests the sample for presence of antibodies to HIV-1. Results are available the day the sample is received by the testing lab, by telephone, using the anonymous 1-800 number included with the test and referencing the unique PIN associated with the blood sample.

The OraQuick® In-Home HIV Test relies on self-collected oral fluid. The user places the oral fluid sample collection stick in a test tube of developer solution and waits 20 – 40 minutes for results. The test user interprets the test validity and the presence of antibodies to HIV-1 and HIV-2 by reading the lines on the test stick. No control line represents an invalid test. A preliminary positive result must be confirmed, typically requiring a visit to a clinical laboratory or health department.

Medical literature reports that blood-based HIV tests have a shorter "window" period -- the time period that individuals who are positive will test negative, but can still infect others -- than oral fluid tests. According to the Centers for Disease Control and Prevention, the "window" period can range from 4-6 weeks up to 6 months; most HIV tests can detect antibodies within 2 months. Blood-based testing will detect antibodies earlier than oral fluid testing. If a person tests negative, but the person still has reason to believe he or she has been exposed to HIV, repeat testing is encouraged.

For information on the at-home HIV test market, visit www.HIVhometestfacts.com today.

About Home Access Health Corporation

Home Access Health Corporation (HAHC) was founded in 1993 to provide anonymous, direct-to-consumer laboratory test services using self-collected fingerstick blood. Individuals collect, package and send a small fingerstick blood specimen to the Company's CAP-accredited laboratory, using components provided in the Home Access test kits. HAHC received FDA approval for its HIV-1 Test System in 1996 and immediately launched a national consumer awareness campaign.

In 1998, responding to the U.S. Surgeon General's order for public health departments (and other healthcare entities) to combat Hepatitis C (HCV), the company adapted its HIV platform and fast-tracked clinical trials and regulatory filings, resulting in an FDA approval for Home Access® Hepatitis C Check test service in 1999. HAHC markets its HCV test primarily through public health departments.

In 2007, the Company received FDA clearance for its complete Cholesterol Panel, a comprehensive laboratory test system that uses self-collected fingerstick blood to measure total cholesterol, HDL-cholesterol, Triglycerides and LDL-cholesterol. The accuracy levels of the Cholesterol Panel achieve the standards established by the National Cholesterol Education Program and the test method has been certified by the CDC-sponsored National Cholesterol Reference Method Laboratory Network. The Cholesterol Panel has been approved by the American Diabetes Association as part of their CheckUp America program.

The Home Access FDA-approved test system for HIV-1 and Hepatitis C are sold directly to consumers without the need for physician intervention. (http://www.fda.gov/consumer/updates/hivtestkit012908.html). These tests are anonymous, include confirmatory testing, and access to the HAHC counseling center for results delivery, counseling, and referrals.

SOURCE Home Access Health Corporation


PR Newswire (http://s.tt/1oRgj)


Medivir announces that Simeprevir (TMC435) data will be presented at the upcoming AASLD Meeting


01-Oct-12 Stockholm, Sweden—Medivir AB (OMX: MVIR), announced today that four abstracts related to simeprevir (TMC435), have been accepted for presentation at the 63nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), taking place from November 9-13 in Boston, USA.

Simeprevir is a once daily potent HCV NS3/4A protease inhibitor in phase III clinical development for the treatment of chronic hepatitis C jointly developed by Medivir and Janssen Research & Development Ireland (Janssen).


Two of the abstracts will be presented as oral presentations and two as posters at the Hynes Convention Center in Boston.


Parallel Session 12, HCV New Agents: Hard to Treat Patients, Hynes Ballroom B & C, November 11, 16:45-18:15

· Efficacy and tolerability of TMC435 150 mg once daily with peginterferon α-2a and ribavirin for treatment of HCV genotype 1 infection in patients with Metavir score F3 and F4 (PILLAR and ASPIRE trials)

Fred Poordad, Michael W. Fried, Stefan Zeuzem, Peter Ferenci, Oliver Lenz, Rekha Sinha, Katleen Callewaert, Monika Peeters, Maria Beumont-Mauviel

· No clinically significant interaction between the investigational HCV protease inhibitor TMC435 and the immunosuppressives cyclosporine and tacrolimus
Sivi Ouwerkerk-Mahadevan, Alexandru Simion, Steven Mortier, Monika Peeters, Maria Beumont Mauviel


Clinical HCV 1, Poster Hall, November 11, 08:00-17:30

· Safety and tolerability of TMC435 in combination with peginterferon α-2a and ribavirin for treatment of HCV genotype 1 infection in treatment-naïve and -experienced patients (Phase IIb PILLAR and ASPIRE trials)
Michael W. Fried, Fred Poordad, Stefan Zeuzem, Peter Ferenci, Oliver Lenz, Sivi Ouwerkerk-Mahadevan, Monika Peeters, Rekha Sinha, Maria Beumont-Mauviel

· No pharmacokinetic interaction between the investigational HCV protease inhibitor TMC435 and an oral contraceptive containing ethinylestradiol and norethindrone
Sivi Ouwerkerk-Mahadevan, Maria Beumont-Mauviel, Kurt Spittaels, Alexandru Simion, Monika Peeters

The abstracts have been published today and can be accessed on the AASLD website: http://www.aasld.org.

For more information about Medivir, please contact:

Medivir Direct: +46 8 440 6550 or:
Rein Piir, EVP Corporate Mobile: +46 708 537 292
Affairs & IR
M:Communications medivir@mcomgroup.com
Europe: Mary-Jane Elliott, +44(0)20 7920 2330
Amber Bielecka, Hollie Vile

About Simeprevir (TMC435)

Simeprevir is is a once daily potent HCV NS3/4A protease inhibitor jointly developed by Medivir and Janssen Research & Development Ireland (Janssen) to treat chronic hepatitis C virus infections.

Simeprevir is being developed both in combination with PegIFN/RBV and in combination with other Direct-acting Antiviral (DAA) agents in an all oral Interferon (IFN) free regimen, with or without Ribavirin (RBV).

Simeprevir is currently being evaluated in three global phase III studies, QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior PegIFN/RBV-treatment. In parallel to these trials, phase III studies for simeprevir in Japan, in both treatment naive and treatment experienced hepatitis C genotype-1 infected patients, are ongoing.

In parallel with the ongoing global phase III-studies, simeprevir is currently in three phase II Interferon free trials with or without Ribavirin.

· In the first trial simeprevir is evaluated in combination with GS7977 (Gilead) in null responder hepatitis C genotype-1 infected patients.
· In the second trial simeprevir is evaluated in combination wtih daclatasvir (BMS) in treatment-naïve or previous null responder hepatitis C genotype-1 infected patients.
· In the third trial simeprevir is evaluated in combination with TMC647055 (Janssen R&D) and ritonavir in low doses in treatment-naïve, relapser or null responder hepatitis C genotype-1 infected patients.

For additional information about simeprevir (TMC435) please see www.clinicaltrials.gov

About Hepatitis C

Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The World Health Organization estimates that nearly 170 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC (Centers for Disease Control and Prevention) has reported that more than three million people in the United States are chronically infected with HCV.

About Medivir

Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir (TMC435), a novel protease inhibitor in phase III clinical development for hepatitis C that is being developed in collaboration with Janssen Research & Development Ireland.

In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia and today Medivir has a broad product portfolio with prescription pharmaceuticals in the Nordics.

Medivir’s first product, the unique cold sore product Xerese®/Xerclear®, is launched in collaboration with GlaxoSmithKline to be sold OTC under the brand name ZoviDuo in Europe, Japan and Russia.

Medivir’s IPO was in 1996 and currently the company has around 180 employees.
For more information about Medivir, please visit the Company’s website: www.medivir.com

Medivir is a collaborative and agile pharmaceutical company with an R&D focus on infectious diseases and a leading position in hepatitis C. We are passionate and uncompromising in our mission to develop and commercialize innovative pharmaceuticals that improve people’s lives.


New Hepatitis C Data from Boehringer Ingelheim to be Presented at AASLD Annual Meeting


October 1, 2012

Ridgefield, CT, October 1, 2012 – New data from Boehringer Ingelheim’s hepatitis C virus (HCV) clinical development program, HCVersoTM, have been accepted for presentation at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), taking place November 9 – 13 in Boston, MA.

Results from all arms of SOUND-C2, a Phase 2b trial evaluating an investigational interferon-free HCV treatment, along with other analyses of the trial program will be presented at the meeting. The data will include results of a comparison of SVR4, 12 and 24 from the SOUND-C2 study, and virologic and pharmacokinetic evaluations. SVR is defined as sustained viral response after treatment ends, and is considered viral cure after 24 weeks. Collectively, these data underscore the company’s focus on finding answers to the challenges faced by HCV patients and treaters.

“We are looking forward to sharing the full results of our Phase 2 interferon-free trial, and other HCVersoTM clinical trial data, at the upcoming AASLD meeting in November,” said Peter Piliero, M.D., Vice President, Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “Through a robust HCV development program, BI is striving to deliver new solutions with real-life patient needs at the core.”

Boehringer Ingelheim’s abstracts can be accessed through the AASLD website today, www.aasld.org.


Oral Presentations

Title Lead Author Presentation Details

Efficacy and safety of the interferon (IFN)-free combination of BI 201335 + BI 207127 ± ribavirin (RBV) in

treatment-naïve patients with HCV genotype (GT) 1 infection and compensated liver cirrhosis: Results from the SOUND-C2 study
V. Soriano

ID# 84

Parallel Session 12: HCV New Agents: Hard to Treat Patients

Date: Sun, Nov. 11

Time: 6:00 – 6:15 PM ET
Location: Hynes: Ballroom B & C

Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the nonnucleoside NS5B inhibitor
BI 207127 ± ribavirin (R): Final results of SOUND-C2 and predictors of response
S. Zeuzem

ID# 232

Parallel Session 34: HCV Clinical Trials: New Agents and Interferon-free

Date: Tues, Nov. 13

Time: 11:30 – 11:45 AM ET
Location: Auditorium

Poster Presentations

Title Lead Author Presentation Details
SOUND-C2: SVR4, 12, and 24 concordance in genotype (GT) 1 HCV patients receiving interferon (IFN)-free treatment with the HCV NS3/4A protease inhibitor BI 201335 and the NS5B polymerase inhibitor BI 207127 S. Zeuzem

ID# 778

Session: Clinical HCV 1

Date: Sun, Nov. 11
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall

HCV NS3 and NS5B variants that emerged in patients with virologic breakthrough and relapse from the Phase II SOUND-C2 trial investigating interferon-free BI 201335 and
BI 207127 therapy ± ribavirin
A. Côté-Martin ID# 788

Session: Clinical HCV 1

Date: Sun, Nov. 11
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall
Pharmacokinetics of the interferon-free combination of BI 207127 and
BI 201335 plus ribavirin in treatment naïve patients with genotype (GT) 1 HCV: Results from the SOUND-C1 study
J. Sabo ID# 777

Session: Clinical HCV 1

Date: Sun, Nov. 11
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall

Analysis of baseline polymorphisms and persistence of emergent variants from Phase Ib and II trials evaluating the HCV NS3 protease inhibitor
BI 201335
K. Berger ID# 785

Session: Clinical HCV 1

Date: Sun, Nov. 11
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall
Addition of the NS5B polymerase inhibitor BI 207127 to pegylated interferon and ribavirin (PegIFN/RBV) for 4 weeks followed by PegIFN/RBV for 44 weeks improves SVR24 rates in treatment-naïve patients with HCV genotype (GT) 1 and is well tolerated A. Lohse ID# 767

Session: Clinical HCV 1

Date: Sun, Nov. 11
Time: 8:00 AM – 5:30 PM ET
Location: Poster Hall

About Boehringer Ingelheim in Hepatitis C Virus (HCV)
In partnership with the scientific community, our clinical trial program, HCVersoTM, is rigorously designed to find answers to the challenges that HCV patients face, including those who are the most difficult to treat.

Faldaprevir, also known as BI 201335, is an investigational oral HCV NS3/4A protease inhibitor that may improve cure rates as compared to PegIFN/RBV therapy alone, and has completed clinical trials through Phase 2b (SILEN-C studies). The ongoing multi-study Phase 3 STARTVersoTM trial program, evaluating faldaprevir combined with PegIFN/RBV in treatment-naïve, treatment-experienced and HIV co-infected patients with chronic genotype-1 HCV, is near clinical completion. BI 207127 is an NS5B non-nucleoside polymerase inhibitor that has shown the potential to eliminate interferon from HCV treatment when combined with faldaprevir and RBV. Phase 2 trials of this interferon-free regimen have been completed and Phase 3 HCVersoTM trials investigating this regimen will commence later this year.

HCV is an infectious disease of the liver and is a leading cause of chronic liver disease, transplant and failure that affects as many as 150 million people globally. In the United States, an estimated 4.1 million Americans have been infected with HCV, of which approximately 3.2 million have chronic HCV infection. Chronic HCV leads to an estimated 8,000 to 10,000 deaths annually in the United States.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 42,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

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Merck to Present New Data for VICTRELIS® (boceprevir) and MK-5172 at The American Association for the Study of Liver Diseases 2012 Annual Meeting


WHITEHOUSE STATION, N.J., Oct. 1, 2012 – Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced today that new data from Phase III studies of VICTRELIS® (boceprevir) 200 mg Capsules, the company’s oral hepatitis C virus (HCV) NS3/4A protease inhibitor will be presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). The meeting will take place November 9-13 in Boston.

More than 20 abstracts highlighting Merck medicines and investigational therapies for chronic HCV will be presented at AASLD, including two oral presentations and six posters on VICTRELIS. New data will also be presented on the efficacy and safety of MK-5172, Merck’s investigational, once-daily, second generation oral HCV NS3/4A protease inhibitor, in patients chronically infected with HCV genotype 1.

“We are pleased to present new data on VICTRELIS that provides healthcare professionals with information that may better inform them as they consider VICTRELIS combination therapy for appropriate patients,” said Eliav Barr, M.D., vice president, Infectious Diseases, Project Leadership and Management, Merck Research Laboratories. "We also look forward to continued discussions with the global scientific and patient communities about Merck's investigational medicines for chronic hepatitis C, as we remain committed to reducing the burden of this serious disease worldwide."

The abstracts were published today and can be accessed on the AASLD website. For program information, please visit https://www.aasld.org.

Key presentations for VICTRELIS (boceprevir)
Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/RBV) in Treatment-Naïve Chronic HCV Genotype 1 Patients with Compensated Cirrhosis: Sustained Virologic Response (SVR) and Safety Subanalyses From the Anemia Management Study. Lawitz, F. et al. Oral Presentation: Sunday, Nov. 11, 3:15 p.m.-3:30 p.m., Hynes Convention Center, Ballroom B/C.
Timing and Magnitude of Ribavirin Dose Reduction (RBV DR) Do Not Impact Sustained Virologic Response Rates with Boceprevir (BOC) + Peginterferon alfa-2b / Ribavirin (P/RBV) in the Anemia Management Study in Chronic HCV Genotype 1 Patients. Poordad, F. et al. Oral Presentation: Monday, Nov. 12, 3:45 p.m.-4:00 p.m., Hynes Convention Center, Ballroom B/C.

Other key Merck presentations
Safety and Sustained Viral Response of MK-5172 for 12 Weeks in Combination with Pegylated Interferon Alfa-2b and Ribavirin for 24 Weeks in HCV Genotype 1 Treatment-Naïve Noncirrhotic Patients. Marcellin, P. et al. Poster 766. Sunday, Nov. 11, 8:00 a.m.-5:30 p.m., Hynes Convention Center Poster Hall.

MK-5172, A Potent Second-Generation HCV NS3/4a Protease Inhibitor, Retains Potent in vitro Activity Against a Panel of Boceprevir Resistant HCV G1a and G1b Patient Isolates. Ogert, R.A. et al. Poster 1724. Tuesday, Nov. 13, 8:00 a.m.-12:00 p.m., Hynes Convention Center Poster Hall. Selected as a Presidential Poster of Distinction.

Indications and usage for VICTRELIS
VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (PR), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:

  • VICTRELIS must not be used as monotherapy and should only be used in combination with PR.
  • VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
  • VICTRELIS in combination with PR has not been studied in patients documented to be historical null responders (less than a 2 log HCV-RNA decline by treatment week 12) during prior therapy with PR. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log HCV-RNA decline in viral load at treatment week 4 with PR alone are predicted to have a null response (less than a 2 log viral load decline by treatment week 12) to PR therapy.
  • Poorly interferon responsive patients who were treated with VICTRELIS in combination with PR have a lower likelihood of achieving a sustained virologic response (SVR), and higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to PR.

Important safety information about VICTRELIS

All contraindications to PR also apply since VICTRELIS must be administered with PR. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with PR is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS.

VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers, where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

Anemia and/or Neutropenia -- The addition of VICTRELIS to PR is associated with an additional decrease in hemoglobin concentrations compared to PR alone and/or may result in worsening of neutropenia associated with PR therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of PR.

Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate.

The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with PR were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for PR alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent) and dysgeusia (44 vs. 11 percent), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.
Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.

About Merck
Today'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 Statement
This 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 mergerbetween 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 all of 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 in the United States and internationally; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; 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 2011 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).


Please see Prescribing Information for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and Medication Guide for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.

# # #

VICTRELIS® is a trademarks of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Revatio® and Adcirca® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.


Vertex Announces Presentation of New Data from Hepatitis C Development Program at AASLD Annual Meeting


October 1, 2012

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that 11 abstracts from its hepatitis C research and development program will be presented at The Liver Meeting®, the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, November 9 to 13, 2012. Presentations will include data on INCIVEK® (telaprevir) tablets, Vertex's approved medicine for the treatment of genotype 1 chronic hepatitis C, and two of the company's hepatitis C treatments in development: VX-222, a non-nucleoside polymerase inhibitor, and ALS-2200 (VX-135), a uridine nucleotide analogue pro-drug.

These accepted abstracts are now available on the AASLD website at: https://www.aasld.org/lm2012.

ALS-2200 (VX-135) Presentations

1. "ALS-2200, a Novel Once-Daily Nucleotide HCV Polymerase Inhibitor, Demonstrates Potent Antiviral Activity over 7 Days in Treatment-Naïve Genotype 1 (GT1) Patients." November 11, 2012, 5:00 p.m. EST. Oral Presentation #86

2. "Preclinical Characterization of ALS-2200, a Potent Nucleotide Polymerase Inhibitor for the Treatment of Chronic Hepatitis C." November 13, 2012, 8:00 a.m. - 12:00 p.m. EST. Poster Presentation #1882

3. "Analysis of ALS-2200, a Novel Potent Nucleotide Analog, Combination Drug Interactions in the Hepatitis C Virus (HCV) Subgenomic Replicon System." November 13, 2012, 8:00 a.m. - 12:00 p.m. EST. Poster Presentation #1887

INCIVEK (telaprevir) Presentations

1. "Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIV Co-infected Patients: SVR24 Final Study Results." November 11, 2012, 4:15 p.m. EST. Oral Presentation #54

2. "Evaluation of Liver and Plasma HCV RNA Kinetics and Telaprevir Levels in Genotype 1 HCV Patients Treated with Telaprevir using Serial Fine Needle Aspirates." November 13, 2012, 9:00 a.m. EST. Oral Presentation #215

3. "The Safety of Telaprevir in the Absence of Interferon and/or Ribavirin: Analysis of On-Treatment Data from the ZENITH Trial." November 11, 2012, 8:00 a.m. - 5:30 p.m. EST. Poster Presentation #786

4. "Factors Predictive of Anemia Development in Treatment-Experienced Patients Receiving Telaprevir (TVR) Plus Peginterferon/Ribavirin (PR) in the REALIZE Trial." November 11, 2012, 8:00 a.m. - 5:30 p.m. EST. Poster Presentation #771

5. "Rate of Disappearance of Telaprevir Resistant Variants Using Clonal and Population Sequence Data from Phase 3 Studies." November 11, 2012, 8:00 a.m. - 5:30 p.m. EST. Poster Presentation #756

6. "Deep Sequencing of the HCV NS3/4A Region Confirms Low Prevalence of the Telaprevir-Resistant Variants Both at Baseline and End of Study." November 11, 2012, 8:00 a.m. - 5:30 p.m. EST. Poster Presentation #1091

VX-222 Presentations

1. "VX-222, Telaprevir and Ribavirin in Treatment-Naïve Patients with Genotype 1 Chronic Hepatitis C: Results of the ZENITH Study Interferon-Free Regimen." November 13, 2012, 11:15 a.m. EST. Oral Presentation #231

2. "Effect of Hepatic Impairment on the Pharmacokinetics of VX-222: Results From a Multicenter Phase 1 Study." November 13, 2012, 8:00 a.m.- 12:00 p.m. EST. Poster Presentation #1880

About ALS-2200 (VX-135) and VX-222

ALS-2200 (VX-135) is a uridine nucleotide analogue pro-drug that appears to have a high barrier to drug resistance based on in vitro studies. It is designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. In vitro studies of the compound showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the United States.

Vertex gained worldwide rights to ALS-2200 through an exclusive worldwide licensing agreement signed with Alios BioPharma, Inc. in June 2011. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on hepatitis C polymerase. Vertex has the option to select additional compounds for development emerging from the research program.

VX-222 is an oral medicine in development that is a non-nucleoside inhibitor of the HCV NS5B polymerase. Vertex has worldwide commercial rights for VX-222.


INCIVEK® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication.

INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for adults with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).

Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic®.



INCIVEK® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.2 However, approximately 60 percent of people do not achieve SVR,3,4,5 or viral cure,6 after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, up to 5 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9,10 Hepatitis C is four times more prevalent in the United States compared to HIV.10 The majority of people with hepatitis C in the United States were born between 1945 and 1965, accounting 82 percent of people with the disease.11 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 15,000 deaths annually.12,13 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.10

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, Mass., we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and for three years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences

Vertex's press releases are available at www.vrtx.com.



1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf Updated June 2010. Accessed September 21, 2012.

2 Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

3 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

4 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

5 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

9 Chak, E, et. al. Hepatitis C Virus Infection In USA: An Estimate of True Prevalence. Liver Intl. 2011;1096 -1098.

10 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 Updated January 11, 2010. Accessed September 21, 2012.

11 Smith, BD, et al. Hepatitis C Virus Antibody Prevalence, Correlates and Predictors among Persons Born from 1945 through 1965, United States, 1999-2008. AASLD 2011 Annual Meeting.

12 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

13 S.D. Holmberg, K.N. Ly., et.al. The Growing Burden of Mortality Associated with Viral Hepatitis in the United States, 1999-2007. AASLD 2011 Annual Meeting.

Vertex Pharmaceuticals Incorporated
Erin Emlock or Zach Barber, 617-444-6992
Kelly Lewis, 617-444-7530
Michael Partridge, 617-444-6108

Source: Vertex Pharmaceuticals Incorporated

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