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Direct-Acting Antivirals Now Ready For Prime Time With Promising Alternatives On The Way


Studies show encouraging data in a wide range of HCV patient populations

New data from a number of clinical trials presented for the first time at the International Liver Congress™ 2013 demonstrate encouraging results in the use of new direct-acting antiviral agents (DAAs) for the treatment of hepatitis C.

The following covers key results from the much anticipated Phase III trials conducted among with a range of genotypes (GT 1 to 6) on DAA treatment.

POSITRON

A study of interferon (IFN)-ineligible, IFN-intolerant, or IFN-unwilling cirrhotic and non-cirrhotic GT 2 and 3 HCV-infected patients treated with a combination of sofosbuvir and for 12 weeks achieved a high SVR12 rate without evidence of resistance.1 In the POSITRON Phase III trial, the SVR12 rate of 78% for sofosbuvir and (161/207) was superior to placebo (0%, p< 0.001) and all 278 patients became HCV RNA negative on treatment. In terms of adverse events only 2% of patients discontinued treatment in the sofosbuvir + group due to adverse events vs. 4% in the placebo group.

Treatment with a combination of sofosbuvir, and ribavirin for 12 weeks achieved 90% SVR12 in treatment naïve genotype 1, 4, 5, or 6 HCV-infected patients with no viral resistance detected in failures, according to the results of the Phase III NEUTRINO study.2 The regimen was well tolerated and is a short, simple and effective treatment option for patients with these genotypes. A total of 327 patients (292 genotype 1, 28 genotype 4, 7 genotype 5/6) were enrolled and received the study drug.

EASL Secretary General Prof. Mark Thursz commented on the studies: “Unlike the US, in Europe and Asia genotype 3 is quite common. As such for European audiences the interferon-free results in genotype 3 are not as impressive as expected; however the side effect profile and lack of viral resistance means that longer treatment durations will be evaluated in the near future. In the meantime, we feel it’s not time to bury pegylated interferon just yet.”

“Many patients can tolerate 12 weeks of an interferon based regime particularly when it produces SVR rates of more than 90%; so clearly the results of the NEUTRINO study will be welcomed by clinicians and patients” added Prof. Thursz.

STARTVerso™1

Faldaprevir, an oral once-daily protease inhibitor, in combination with peginterferon alfa-2a and ribavirin (PegIFN/RBV) significantly increased SVR12 rates in treatment-naïve HCV GT-1 patients in Europe and Japan compared with PegIFN/RBV alone and was well tolerated.3 In total 652 patients were treated and 88% of patients treated with faldaprevir were eligible to stop all treatment at week 24.

QUEST-1 and -2

QUEST-1: Simeprevir, an oral once-daily protease inhibitor, in combination with peginterferon alfa-2a and ribavirin (PegIFN/RBV) achieved SVR12 rates of 80% compared to placebo, 50% (p<0.001).4 Of the 394 patients, 85% in the simeprevir treatment group were eligible to complete treatments at week 24. On-treatment failure rate was also much lower with simeprevir treatment, compared to placebo.

QUEST-2: Simeprevir versus placebo as part of regimen including PegIFN or PegIFN/RBV was well tolerated.5 SVR12 rates significantly increased in the simeprevir group compared to placebo (81 vs. 50% respectively (p<0.001) and of the 391 patients treated, 91% were eligible to stop all treatment at week 24.

Prof. Mark Thursz commented on the exciting protease inhibitor data showcased at the congress: “With genotype-1 the most common and most challenging type of HCV to cure, both studies have demonstrated extremely encouraging results with cleaner profiles than existing protease inhibitors. It is unlikely telaprevir and boceprevir will remain in the hepatic armoury for much longer.”

“We truly are in a prime time for HCV therapy; these effective new treatment options have the potential to pave the way for future interferon-sparing regimens and we look forward to using them in the clinic” added Prof Thursz.

Other promising Phase II data presented at the congress may provide further options:

ELECTRON

Results of the ELECTRON study6 show that all-oral regimens containing sofosbuvir in combination with a second DAA and ribavirin show promising efficacy, with rapid and consistent antiviral suppression in both treatment-naïve patients and prior null responders. High response rates in those treatment arms employing a second agent supports the hypothesis that the addition of another DAA with a different mechanism of action and non-overlapping resistance profile would improve rates of SVR.

IFN and RBV Free Regimen

Interim analysis of a Phase II study7 show that an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (NS5A inhibitor), asunaprevir (protease inhibitor) and BMS-791325 (non-nucleoside NS5B inhibitor) achieved, overall, an SVR4 of 92% (46/50), SVR12 of 94% (30/32), and SVR24 of 94% (15/16) in treatment-naive genotype (GT) 1 patients, mainly GT1a and IL28B non-CC. Patients were initially randomised (1:1) to daclatasvir 60mg QD, asunaprevir 200mg BID, and BMS-791325 75mg BID for a period of 24 or 12 weeks. Following one month of safety observation, a second cohort was randomized (1:1) to the same regimen but including BMS-791325 150mg BID (24 or 12 weeks). The primary end point was HCV RNA < 25 IU/mL at 12 weeks post-treatment (SVR12). Sixty four of the 66 patients had a HCV RNA < 25 IU/mL by week 4, with no difference in virological responses between 12 and 24 weeks of treatment.

AVIATOR

Latest results from the AVIATOR study8, using a combination of ABT-450/r (HCV protease inhibitor dosed with ritonavir 100 mg) with ABT-267 (NS5A inhibitor) and/or ABT-333 (non-nucleoside NS5B inhibitor) +/- ribavirin, demonstrate impressive SVR12 in patients with chronic HCV GT1 infection. The overall intention-to-treat SVR12 rate for 12-week treatment with three DAAs in combination with ribavirin was 98.7% (78/79) in treatment-naïve patients, and 93% (42/45) in null responders.

EASL Secretary General Prof. Mark Thursz commented further: “With such high success rates and increased safety and tolerability with novel DAAs, patients can be optimistic about oral treatment regimens in the not-too-distant future.”

Disclaimer: The data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.

Source

1 Jacobson, I et al, TREATMENT WITH SOFOSBUVIR+RIBAVIRIN FOR 12 WEEKS ACHIEVES SVR12 OF 78% IN GT2/3 INTERFERON- INELIGIBLE, -INTOLERANT, OR -UNWILLING PATIENTS: RESULTS OF THE PHASE 3 POSITRON TRIAL. Presented at the International Liver Congress™ 2013

2 Lawitz, E et al, SOFOSBUVIR + PEGINTERFERON + RIBAVIRIN FOR 12 WEEKS ACHIEVES 90% SVR12 IN GENOTYPE 1, 4, 5, OR 6 HCV INFECTED PATIENTS: THE NEUTRINO STUDY. Presented at the International Liver Congress™ 2013

3 Ferenci, P et al, FALDAPREVIR PLUS PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN CHRONIC HCV GENOTYPE-1 TREATMENT-NAÏVE PATIENTS: FINAL RESULTS FROM STARTVERSO1, A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE III TRIAL. Presented at the International Liver Congress™ 2013

4 Jacobson, I et al, SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NAÏVE PATIENTS; RESULTS FROM QUEST-1, A PHASE III TRIAL. Presented at the International Liver Congress™ 2013

5 Manns M, et al, SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NAÏVE PATIENTS; RESULTS FROM QUEST-2, A PHASE III TRIAL. Presented at the International Liver Congress™ 2013

6 Gane EJ, et al, ALL-ORAL SOFOSBUVIR-BASED 12-WEEK REGIMENS FOR THE TREATMENT OF CHRONIC HCV INFECTION: THE ELECTRON STUDY Presented at the International Liver Congress™ 2013

7 Everson, GT et al, INTERIM ANALYSIS OF AN INTERFERON (IFN)- AND RIBAVIRIN (RBV)-FREE REGIMEN OF DACLATASVIR (DCV), ASUNAPREVIR (ASV), AND BMS-791325 IN TREATMENT-NAIVE, HEPATITIS C VIRUS GENOTYPE 1-INFECTED PATIENTS. Presented at the International Liver Congress™ 2013

8 Kowdley, KV et al, SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/R, ABT-267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY. Presented at the International Liver Congress™ 2013

9 EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. European Association for the Study of the Liver. Journal of Hepatology 2011;55:245–264

10 Hepatitis C Fact Sheet. World Health Organisation factsheet. Available here. Last accessed 28.03.13