Danoprevir, a small-molecule NS3/4A protease inhibitor for the potential oral treatment of HCV infection.

Abstract	Danoprevir (ITMN-191; RG-7227), under development by InterMune Inc and Roche Holding AG, is a promising, potent NS3/4A protease inhibitor for the oral treatment of HCV infection. Preclinical data demonstrated that danoprevir binds with high affinity and dissociates slowly from the HCV NS3 protease, allowing high liver drug exposure with only modest plasma drug exposure. A phase Ib, 'IFN-free' clinical trial demonstrated that danoprevir, combined with the HCV polymerase inhibitor RG-7128 (Pharmasset Inc/Roche Holding AG), was effective in reducing HCV-RNA levels in a large proportion of treatment-naïve patients with HCV infection and in approximately half of previously non-responsive patients with HCV-1 infection, without resistance or safety concerns. In a phase IIb trial in treatment-naïve patients with HCV-1 infection, danoprevir plus pegylated IFNalpha2a and ribavirin resulted in undetectable levels of HCV-RNA in the majority of patients, without any evidence of viral resistance; however, the high-dose danoprevir arm was prematurely terminated because of grade 4 ALT elevations. Phase I trials have also demonstrated that ritonavir boosting improved the pharmacokinetic profile of danoprevir; therefore, at the time of publication, a phase IIb trial to evaluate ritonavir-boosted, low-dose danoprevir in combination with RG-7128 was planned.
Authors	Melanie Deutsch, George V Papatheodoridis
Journal	Current opinion in investigational drugs (London, England : 2000) (Curr Opin Investig Drugs) Vol. 11 Issue 8 Pg. 951-63 (Aug 2010) ISSN: 2040-3429 [Electronic] England
PMID	20721837 (Publication Type: Journal Article)
Chemical References	Antiviral Agents Cyclopropanes Interferon alpha-2 Interferon-alpha Isoindoles Lactams Lactams, Macrocyclic NS3 protein, hepatitis C virus Protease Inhibitors Recombinant Proteins Sulfonamides Viral Nonstructural Proteins Polyethylene Glycols Ribavirin danoprevir Proline Ritonavir peginterferon alfa-2a
Topics	Animals Antiviral Agents (adverse effects, pharmacokinetics, pharmacology, therapeutic use) Clinical Trials as Topic Cyclopropanes Dogs Drug Evaluation, Preclinical Drug Therapy, Combination Haplorhini Hepacivirus (drug effects, genetics, metabolism) Hepatitis C (drug therapy, virology) Humans Interferon alpha-2 Interferon-alpha (therapeutic use) Isoindoles Lactams (adverse effects, pharmacokinetics, pharmacology, therapeutic use) Lactams, Macrocyclic Polyethylene Glycols (therapeutic use) Proline (analogs & derivatives) Protease Inhibitors (adverse effects, pharmacokinetics, pharmacology, therapeutic use) Rats Rats, Sprague-Dawley Recombinant Proteins Ribavirin (therapeutic use) Ritonavir (therapeutic use) Sulfonamides (adverse effects, pharmacokinetics, pharmacology, therapeutic use) Viral Nonstructural Proteins (antagonists & inhibitors, metabolism)

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