Tuesday, April 17, 2012

BMS-650032 (Asunaprevir) BMS-790052 (Daclatasvir)-A revolution in HCV treatment with direct-acting antivirals: from non response to eradication

International hepatology
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Discussion-(In Press Accepted Manuscript)
Accepted Manuscript 28 March 2012
International hepatology

A revolution in HCV treatment with direct-acting antivirals: from non response to eradication
Tarik Asselah
PII: S0168-8278(12)00235-8
DOI: 10.1016/j.jhep.2012.03.005
Reference: JHEPAT 4176
To appear in: Journal of Hepatology
Received Date: 10 March 2012
Revised Date: 16 March 2012
Accepted Date: 18 March 2012

Please cite this article as: Asselah, T., A revolution in HCV treatment with direct-acting antivirals: from non response to eradication, Journal of Hepatology (2012), doi: 10.1016/j.jhep.2012.03.005

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A revolution in HCV treatment with direct-acting antivirals: from non response to eradication

Hepatology Department, AP-HP, University Paris Diderot 7 and INSERM U773, CRB3, Beaujon
Interferon free regimen, NS5A inhibitors, Null response, Protease inhibitors,Immune response, Genotype 1 Address: Hepatology Department, AP-HP, University Paris Diderot 7 and INSERM U773 CRB3, Beaujon Hospital, Clichy, France. Tel.: +33(0)140875579
Abbreviations: HCV, hepatitis C virus;PegIFN, peginterferon alfa, RBV, ribavirin; SVR,
sustained virologic response, DAAs, Direct-acting antivirals.

COMMENTARY ON:
Preliminary study of two antiviral agents for hepatitis C genotype 1. Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F,Wind-Rotolo M, Persson A, Zhu K, Dimitrova DI, Eley T, Guo T, Grasela DM,Pasquinelli C. N Engl J Med. 2012 Jan 19;366(3):216-24. Copyrigth (2012).

Abstract
reprinted with permission from the Massachusetts Medical Society.
http://www.ncbi.nlm.nih.gov/pubmed/22256805

Abstract.
BACKGROUND: Patients with chronic hepatitis C virus (HCV) infection who have
not had a response to therapy with peginterferon and ribavirin may benefit from the addition
of multiple direct-acting antiviral agents to their treatment regimen.

METHODS: This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not had a response to previous therapy (i.e.,had not had 2 log(10) decline in HCV RNA after 12 weeks of treatment with peginterferon and ribavirin). We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage ofpatients with a sustained virologic response 12 weeks after the end of the treatment period

RESULTS: A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment.. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment

Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range.

CONCLUSIONS: This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895

Approximately 170 million people are infected with hepatitis C virus (HCV) worldwide.
Treatment of genotype 1 naïve chronic hepatitis C with peginterferon alfa (PegIFN) and ribavirin (RBV) for 48 weeks results in sustained virologic response (SVR) in approximately 40% of patients. Retreatment of previous non-responders to PegIFN/RBV therapy with triple therapy, a protease inhibitor (telaprevir or boceprevir), PegIFN/RBV, results in a SVR in less than 30% of cases [1-2]. Direct-acting antivirals (DAAs) with different viral targets, including NS3 protease inhibitors,nucleoside/nucleotide analogue and non-nucleoside inhibitors of the RNA-dependent RNA polymerase, and NS5A inhibitors are under development [3]. Gane and colleagues found that a combination of two DDAs can suppress HCV RNA in genotype 1 non-responder patients but the treatment with the DAAs combination was limited to 13 days and was followed immediately by treatment with PegIFN/RBV, thus preventing the assessment of SVR with DAAs alone [4]. Studies of DAAs combinations in the genotype 1 non-responder population are warranted. Recently, Lok et al., in a preliminary study including patients with HCV genotype 1 infection who were non-responders to prior therapy showed that a SVR could be achieved with two DAAs [5].

Daclatasvir (BMS-790052)
Daclatasvir (BMS-790052) is a first-in-class, highly selective HCV NS5A replication complex inhibitor with picomolar potency in vitro [6]. NS5A is a membrane- associated phosphoprotein resent in basally phosphorylated (p56) and hyperphosphorylated (p58) forms. It was previously reported that only p58-defective mutants could be complemented in trans, and NS5A is involved in HCV virion production, suggesting that different forms of NS5A exert multiple functions at various stages of the viral life cycle. The N terminus of NS5A (domain I) has been crystallized in alternative dimeric forms and contains both zincand RNA-binding domains, properties that have been demonstrated in vitro. Daclatasvir is active at picomolar concentrations in vitro towards replicons expressing a broad range of HCV genotypes and acts in an additive to synergistic fashion with interferon and other small molecule antiviral compounds [6-7]. The resistance profile of BMS-790052 reveals that inhibitor sensitivity maps to the N terminus of domain 1 of NS5A [6-8]. In addition, it has
been demonstrated that NS5A inhibitors could block hyperphosphorylation of NS5A, which is believed to play an essential role in the viral life cycle.

Asunaprevir (BMS-650032)
Asunaprevir (BMS-650032) is a highly active HCV NS3 protease inhibitor. NS3 serine protease is located in the N-terminal region of NS3. The NS3 serine protease domain associates with the NS4A cofactor to cleave four specific sites. This enzyme has been extensively characterized at the biochemical level and its structure is known [9]. The serine protease activity of NS3 is an attractive target for new drugs that could effectively block viral replication. Protease inhibitors have high anti-viral efficacy and usually a low genetic barrier. The genetic barrier to resistance is defined as the number of amino acid substitutions required to confer full resistance to a drug. The genetic barrier to protease inhibitors and NS5A inhibitors is usually low.

Both daclatasvir and asunaprevir produce marked declines in HCV RNA levels in patients with HCV genotype 1 infection [9-10] and administration of the two drugs in combination did not produce a clinically meaningful pharmacokinetic interaction [11].

In the study reported by Lok et al., patients with HCV genotype 1 infection with no response to previous treatment with PegIFN/RBV, were randomly assigned to receive daclatasvir (60 mg once daily) and asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with PegIFN -2a and RBV (group B, 10 patients) for 24 weeks [5]. A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a SVR 12 weeks after treatment and also 24 weeks after treatment (Fig. 1). Six patients (all with HCV genotype 1a) had a viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but relapsed after the treatment period.


Viral variants in the NS5A domain included Q30R, L31 M/V, and Y93C/N; variants in the NS3 protease domain included R155K and D168A/E/T/V/Y. The patient with a viral relapse had a pre-existing NS3 protease resistance variant, R155K, at baseline and at the time of viral relapse, whereas the NS5A resistance variant Q30E was only detected at relapse.

Although there were only 2 patients with HCV genotype 1b infection in group A, the observation that both of the patients had a SVR with two direct-acting antiviral agents alone may reflect a higher resistance barrier for this combination of drugs in patients with HCV genotype 1b infection than in those with HCV genotype 1a infection. The high frequency of resistance seen in patients with HCV genotype 1a infection who were treated with DAAs alone suggests that studies of DAAs combinations without PegIFN/RBV in patients with HCV genotype 1a infection should proceed carefully. In group B, the inclusion of Peg IFN/RBV with daclatasvir and asunaprevir provided sufficient antiviral activity to suppress the emergence of resistance. All 10 patients in group B had a SVR 12 weeks after
treatment, and 9 had a SVR 24 weeks after treatment.

It should be noticed that among the 14 patients who had an SVR 12 weeks after treatment,an HCV RNA level of less than 25 IU/ml was detected in 1 patient 24 weeks after treatment and in 2 other patients 48 weeks after treatment. All 3 patients had undetectable HCV RNA on re-testing. These data indicate that late relapse is unlikely to occur in patients who havean SVR with the DAAs combination 12 weeks after treatment as previously established with PegIFN/RBV treatment [13].

The most common adverse events were diarrhea, fatigue, headache, and nausea. Most adverse events were mild to moderate. There were no deaths, serious adverse events, or discontinuations of study treatment due to adverse events. Diarrhea was the most common adverse event in both groups. Six patients had transient elevation of alanine aminotransferase levels to more than 3 times the upper limit of the normal range.

Finally, Lok et al. reported interesting results with daclatasvir and asunaprevir in HCV genotype 1 non-responders to previous treatment with PegIFN plus ribavirin [5]. Similarly, Chayama et al. reported impressive results in a pilot study of combination therapy with asunaprevir and daclatasvir in 10 Japanese patients with HCV genotype 1b infection and who had not responded to previous therapy with PegIFN/RBV : nine patients achieved a SVR [14]. Several studies of DAA combinations are ongoing with different HCV targets:
NS3/4a protease inhibitors combined with an agent targeting the HCV polymerase complex
– either a non-nucleoside NS5B, nucleoside NS5B, or NS5A inhibitor [3, 5, 14-15]. Preliminary results of DAA combinations show increased antiviral efficacy, reduced resistance and a good safety profile. It is important to note that some of these drugs have pan-genotypic activity. This rapid progress strongly suggests that in the near future, IFNfree short duration DAA combinations will make HCV the first chronic viral infection to be eradicated worldwide.

Conflict of interest.
Tarik Asselah is a speaker and investigator for BMS, Boehring-Ingelheim, Tibotec, Janssen,Gilead, Roche and Merck
.
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