Pharmacology Xagena

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Xagena Newsletter

Hepatitis C: new regimens with direct acting antivirals

The approval of two hepatitis C virus ( HCV ) protease inhibitors by the FDA ( Food and Drug Administration ) in 2011, Boceprevir ( Victrelis ) and Telaprevir ( Incivo, Incivek ), marked the start of a new chapter in hepatitis C treatment.
These were the first new drugs approved in 10 years for hepatitis C treatment.

With Boceprevir and Telaprevir, triple combination therapy for patients with genotype 1 HCV infection became available, combining Peginterferon and Ribavirin with either of these two agents. This represented a huge advance in hepatitis C treatment, with improved sustained viral response ( SVR ) rates among patients who had never been treated before as well as among patients who had relapsed after treatment or did not fully respond to standard treatment.

But the story of hepatitis C treatment did not end here. Multiple other drugs were also developed for all strains of HCV, not just genotype 1.

In 2013, the FDA approved two more drugs, Sofosbuvir ( Sovaldi ) and Simeprevir ( Olysio ). Sofosbuvir represented the first approved drug for use as an all oral regimen, in combination with Ribavirin, and marked a very significant new era for hepatitis C patients who had not been eligible for treatment previously due to interferon contraindications. It is anticipated that several other new agents and combinations of agents may be approved in 2014-2015, making several new treatment regimens available for patients.

All of these new drugs are called DAAs ( direct acting antivirals ). There are four major different HCV DAA classes: HCV NS3/4 protease inhibitors, nucleos(t)ide HCV NS5B polymerase inhibitors, non-nucleos(t)ide HCV NS5B polymerase inhibitors, HCV NS5A inhibitors.

Many DAAs have been showing phase 2 and phase 3 trials with increased SVR rates, shortened durations of treatment, and acceptable adverse event profiles, creating intriguing possibilities for patients who have not been candidates for hepatitis C treatment because of the toxicities caused by Interferon. But, it is also important to know that these results have been obtained in carefully selected clinical trial populations and that effectiveness in the real-world is unlikely to be as high. In addition, the relatively small numbers of patients treated in these trials mean that these new drugs may show unexpected side effects.

Clinical trials

The following are summaries of some of the key reported clinical trials of newly-approved and investigational HCV agents.

New DAAs: selected clinical trials in HCV-monoinfected patients

Sofosbuvir trials ( nucleoside polymerase inhibitor )

NEUTRINO trial: phase 3 trial of Sofosbuvir / Peglyated Interferon / Ribavirin in treatment-naive for 12 weeks in genotype 1, 4, 5, 6; 90% achieved SVR12;

FISSION: phase 3 trial of Sofosbuvir / Ribavirin compared to Sofosbuvir / Pegylated Interferon / Ribavirin in treatment naive for 12 weeks in genotype 2/3 patients; 97% SVR12 in genotype 2 and 56% SVR12 in genotype 3;

POSITRON: phase 3 trial of Sofosbuvir / Ribavirin compared to placebo in treatment naive, Interferon-ineligible for 12 weeks in genotype 2/3 patients; 93% SVR12 in genotype 2, 61% SVR12 in genotype 3;

FUSION: phase 3 trial of Sofosbuvir / Ribavirin in treatment experienced for 12 weeks in genotype 2/3 patients with an 86% SVR12 in genotype 2 and a 30% SVR12 in genotype 3 patients. For 16 weeks, there was a 94% SVR12 in genotype 2 and a 62% SVR12 in genotype 3;

VALENCE trial: phase 3 trial of Sofosbuvir plus Ribavirin for genotype 2 or 3; SVR in 93% genotype 2 and 85% genotype 3;

ELECTRON: phase 2 trial of 12 weeks of Sofosbuvir and Ledipasvir plus Ribavirin for varying durations in genotype 1; SVR12 in 100% of treatment-naive patients, and SVR 12 of 100% in prior null-responders from past treatment-experience;

LONESTAR: phase 2 trial of a fixed-dose combination of Sofosbuvir / Ledipasvir, with or without Ribavirin for varying durations in genotype 1; SVR12 of 100% in treatment-naive patients for 8 weeks of treatment including Ribavirin, and SVR4 of 95% in patients failing prior treatment with protease inhibitors treated for 12 weeks;

PHOTON-1: phase 3 trial of Sofosbuvir / Ribavirin in genotype 1, 2, 3 patients with HIV/HCV coinfection; 76% SVR 12 in genotype 1, 81% SVR-12 in genotype 2, 76% SVR12 in genotype 3;

Simeprevir trials ( NS3/4a protease inhibitor ):

QUEST: phase 3 trial of Simeprevir / Pegylated Interferon / Ribavirin for 12 weeks followed by 12 weeks of Pegylated Interferon / Ribavirin alone in genotype 1 treatment naive patients; 86-91% SVR 12;

Simeprevir / Sofosbuvir trial:

COSMOS trial: phase 2 trial of Sofosbuvir plus Simeprevir with or without Ribavirin for 12 weeks or 24 weeks. In previous null responders with low fibrosis scores, 24 weeks of treatment without Ribavirin resulted in 100% SVR12. In patients either treatment naive or prior null responders with high fibrosis scores, 12 weeks of treatment without Ribavirin resulted in 100% SVR4;

ABT-450 / ritonavir / ABT-333 /ABT-267 trials:

AVIATOR: ABT-450 / Ritonavir plus ABT-333 plus ABT-267 with Ribavirin in genotype 1 in treatment naive and prior null responders, 24 weeks of treatment resulted in 93% SVR12 in treatment naive patients, and 24 weeks of treatment resulted in 98% SVR12 in prior null responders. ( Xagena )

Rena K. Fox, U.S. Department of Veterans Affairs, 2013