Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial

Gane, Edward; Roberts, Stuart K.; Stedman, Catherine; Angus, Peter W; Ritchie, Brett; Elston, Rob; Ipe, David; Morcos, Peter N.; Baher, Linda; Nájera, Isabel; Chu, Tom; Lopatin, Uri; Berrey, M. Michelle; Bradford, William; Laughlin, Mark; Shulman, Nancy S.; Smith, Patrick F.

doi:10.1016/s0140-6736(10)61384-0

Cited by 304 publications

(239 citation statements)

References 27 publications

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“…13 Although the reasons for poor response with short LI are unknown, rapid and profound inhibition of HCV replication might restore IFN responsiveness, as suggested by the decrease of plasma levels of IFNinducible protein 10, a lymphocyte chemokine indicative of endogeneous activation of host IFN pathways, in HCV patients treated with IFN-free regimens. 14 However, further research is required to test this hypothesis. Although the reasons for lower response rates with 3-day LI are not fully understood, this strategy was not selected for further investigation.…”

Section: Discussionmentioning

confidence: 99%

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

et al. 2013

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Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once-daily (QD) dosing. Four hundred and twenty-nine HCV genotype (GT)-1 treatment-naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead-in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8-20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety-two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty-two percent of GT-1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. Conclusion: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. (HEPATOLOGY 2013;57:2143-2154

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Section: Discussionmentioning

confidence: 99%

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

et al. 2013

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“…Ils sont indispensables, notamment chez les patients ayant une fibrose extensive, une fibrose intermédiaire ou une cirrhose, mais des comorbidités hépatiques (surconsommation d'alcool, surpoids) favorisent une progression rapide de la fibrose [4,22]. De nombreux autres antiviraux ont été développés, tels que les inhibiteurs de la polymérase NS5B de type nucléotidiques [23,24] ou non [24], les inhibiteurs du complexe de réplication NS5A [25] et les inhibiteurs de protéases de deuxième génération [26,27]. Ces nouveaux antiviraux ont été, dans un premier temps, associés à l'interféron pégylé et la ribavirine, permettant d'obtenir une guérison des patients dans 75 à 95 % des cas (Figure 4).…”

Section: Revuesunclassified

Virus de l’hépatite C

Pol

2013

Med Sci (Paris)

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> Le traitement de l'infection chronique par le virus de l'hépatite C (VHC) a singulièrement progressé ces deux dernières décennies. Depuis 15 ans environ, la combinaison de l'interféron  pégylé et de la ribavirine permet d'obtenir un taux de réponse virologique prolongée, assimilable à une guérison, chez 45 % des patients infectés par un génotype 1, 65 % de ceux infectés par un génotype 4, 70 % de ceux infectés par un génotype 3 et environ 85 % de ceux infectés par un génotype 2. Une meilleure compréhension du cycle réplicatif du VHC a permis le développement d'antiviraux directs spécifiques du virus ciblant les protéines virales (la protéase NS [non structural] 3/4A, la polymérase NS5B avec des inhibiteurs nucléosidiques et non nucléosidiques, la protéine multifonctionnelle NS5A du complexe de replication). De nombreux résultats ont montré que des combinaisons d'inhibiteurs de première génération, notamment les inhibiteurs de protéases, en association avec l'interféron pégylé et la ribavirine, avaient une efficacité antivirale élevée (75 % de guérison des patients infectés par un VHC de génotype 1) avec une tolérance difficile. Cette première étape majeure a été rapidement suivie de l'utilisation d'une combinaison des antiviraux directs de deuxième génération avec l'interféron pégylé et la ribavirine, permettant d'augmenter sensiblement les taux de guérison (de 75 à 90 %) avec une réduction des durées de traitement et du nombre de comprimés administrés. La prochaine étape sera la combinaison des antiviraux directs, qui deviendra le standard de traitement en 2015. La plupart des études ont inclus des patients « faciles à traiter », en petit nombre, avec des résultats d'efficacité et de tolérance remarquables. Cependant, les résultats obtenus avec les « populations difficiles à traiter » (sujets en échec de traitements antérieurs, notamment par les inhibiteurs de protéases, sujets cirrhotiques, sujets transplantés hépatiques ou rénaux, et sujets infectés par le VIH [virus de l'immunodéficience humaine]) restent à confirmer et sont impatiemment attendus. < . La véritable révolution thérapeutique à laquelle on assiste aujourd'hui est probablement unique, à plus d'un titre. L'infection par le VHC est la seule infection chronique dont on guérit. La rapidité de développement de nouveaux traitements, constamment plus efficaces et mieux tolérés, est sans doute sans comparaison dans l'histoire pharmaceutique. Les capacités de remodelage et de régé-nération hépatiques, permettent potentiellement, avec la guérison virale, la réparation des lésions, notamment de fibrose, générées lors de l'infection. S'ouvrent ainsi de nouveaux défis pour un dépistage plus large, un accès facilité aux traitements les plus efficaces, et une réflexion sociétale sur le rapport coût/efficacité des stratégies diagnostiques et thérapeutiques. Sur cette thématique clinique et de recherche, la France a été et reste dans le trio de tête depuis ces deux dernières décennies. Cette revue résume cette courte histoire exemplaire et récente. Épidémiolog...

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“…Fourteen-day danoprevir monotherapy resulted in robust antiviral responses in treatment-naïve patients and patients who failed prior pegylated interferon therapy (4). This compound is currently in development as a twice-daily, ritonavirboosted agent, where it has demonstrated a favorable side effect profile when administered with SOC for 12 weeks (7,9,43).The high replication rate of HCV and the poor fidelity of the HCV RNA-dependent RNA polymerase result in the selection of drug-resistant HCV variants during treatment (20). In vitro and in vivo studies indicate that overlapping but distinct sets of NS3/4A variants are associated with reduced susceptibility to PIs (18,23,30,38,44,49).…”

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confidence: 99%

“…Many of these compounds are being developed as components of multiple DAA regimens without SOC as well as in SOC-containing regimens (3,6,8,13,25,27,40,47). Danoprevir (ITMN-191/RG7227), a noncovalent macrocyclic PI, is one such compound (37).…”

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confidence: 99%

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Virologic Escape during Danoprevir (ITMN-191/RG7227) Monotherapy Is Hepatitis C Virus Subtype Dependent and Associated with R155K Substitution

Lim¹,

Qin²,

Susser

et al. 2012

Antimicrob Agents Chemother

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Danoprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor that promotes multi-log 10 reductions in HCV RNA when administered as a 14-day monotherapy to patients with genotype 1 chronic HCV. Of these patients, 14/37 experienced a continuous decline in HCV RNA, 13/37 a plateau, and 10/37 a rebound. The rebound and continuous-decline groups experienced similar median declines in HCV RNA through day 7, but their results diverged notably at day 14. Plateau group patients experienced a lesser, but sustained, median HCV RNA decline. Baseline danoprevir susceptibility was similar across response groups but was reduced significantly at day 14 in the rebound group. Viral rebound in genotype 1b was uncommon (found in 2/23 patients). Population-based sequence analysis of NS3 and NS4A identified treatment-emergent substitutions at four amino acid positions in the protease domain of NS3 (positions 71, 155, 168, and 170), but only two (155 and 168) were in close proximity to the danoprevir binding site and carried substitutions that impacted danoprevir potency. R155K was the predominant route to reduced danoprevir susceptibility and was observed in virus isolated from all 10 rebound, 2/13 plateau, and 1/14 continuous-decline patients. Virus in one rebound patient additionally carried partial R155Q and D168E substitutions. Treatment-emergent substitutions in plateau patients were less frequently observed and more variable. Single-rebound patients carried virus with R155Q, D168V, or D168T. Clonal sequence analysis and drug susceptibility testing indicated that only a single patient displayed multiple resistance pathways. These data indicate the ascendant importance of R155K for viral escape during danoprevir treatment and may have implications for the clinical use of this agent.H epatitis C virus (HCV) is a positive-strand RNA virus that infects approximately 170 million people worldwide (39). It is a major cause of chronic liver disease, cirrhosis, and primary hepatocellular carcinoma. Therapy for chronic HCV infection is based on weekly injections of pegylated alpha interferon (PEG-IFN-␣) and twice-daily orally administered ribavirin (RBV). This standard of care (SOC) is associated with significant side effects and achieves a sustained virologic response (SVR) in approximately half of treated patients (5, 28). Thus, novel therapeutic modalities are clearly needed.The addition of one or more direct-acting antiviral agents (DAA) to the SOC has become a favored strategy to improve the treatment outcome of chronic HCV therapy. The two most clinically advanced DAAs, telaprevir (Incivek) and boceprevir (Victrelis), are linear peptidomimetic inhibitors of NS3/4A protease. These two NS3/4A protease inhibitors (PIs) have demonstrated significant improvements in SVR rates in genotype 1 patients when added to SOC (1,14,32,46) and have recently been licensed for use in the treatment of chronic HCV infection in the United States and in Europe. While clearly a dramatic advance in the treatment of chronic HCV, both of these compounds...

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Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial

Cited by 304 publications

References 27 publications

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

Virus de l’hépatite C

Virologic Escape during Danoprevir (ITMN-191/RG7227) Monotherapy Is Hepatitis C Virus Subtype Dependent and Associated with R155K Substitution

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