Drug Profile
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
Daclatasvir for the treatment of hepatitis C virus infection Expert Rev. Gastroenterol. Hepatol. 8(7), 725–738 (2014)
Hugh Adler1 and John S Lambert*1–3 1 Department of Infectious Diseases, Mater Misericordiae University Hospital, Dublin, Ireland 2 Rotunda Hospital, Dublin, Ireland 3 UCD School of Medicine and Medical Science, Dublin, Ireland *Author for correspondence: Tel.: +353 1716 4535 [email protected]
Daclatasvir was pivotal to the trial that established proof-of-concept that an interferon-free regimen could induce a sustained virologic response in patients with chronic HCV infection. This NS5A inhibitor is not currently licensed for the treatment of HCV, but has shown promising efficacy and minimal side-effects in clinical trials to date, where it has been tested in combination with a variety of different HCV therapies. An all-oral, interferon-free curative combination therapy for HCV is now tantalizingly close to becoming part of routine clinical practice, with multiple highly-efficacious direct-acting antiviral agents emerging virtually simultaneously. In this article we will discuss daclatasvir’s background and review the clinical trials published to date, concluding with our predictions regarding its future place in the treatment armamentarium against HCV. KEYWORDS: BMS-790052 • cirrhosis • daclatasvir • hepatitis C virus • hepatocellular carcinoma • interferon • NS5A inhibitor • ribavirin • sofosbuvir
Introduction & unmet needs of current therapies
Until recently, curative treatment of chronic HCV infection, defined as inducing a sustained virologic response, or an undetectable viral load at 24 weeks after the completion of treatment (SVR24) [1], has consisted of a combination of the immunomodulator pegylated interferon (pegIFN) and the nucleoside analog ribavirin (RBV). For example, one trial found that 48 weeks of pegIFN-a-2a plus RBV achieved SVR24 in 56% of patients [2]. Patients who achieve sustained virologic response (SVR) are less likely to develop complications of HCV, including cirrhosis and hepatocellular carcinoma (HCC). However, IFN and RBV are notorious for causing a range of side effects, including severe influenza-like symptoms, mood alteration and cytopenias. In addition, IFN must be administered by subcutaneous injection, placing a further burden on patients and service providers alike. Finally, the six major genotypes of HCV respond at different rates to IFN/RBV-based regimens, in the pivotal trial mentioned above, only 46% of patients with genotype 1 (GT1) achieved SVR24, versus 76% of patients with GT2 or 3 [2]. Genotypes 1–3 are found worldwide, with GT1a commonest in North America, GT1b commonest in Europe and Asia, informahealthcare.com
10.1586/17474124.2014.925798
GT3 commonest in Europe, Southeast Asia and Australia and GT4 commonest in the Middle East, especially in Egypt [3,4]. HCV is a significant public health problem. Worldwide, it is estimated to affect 184 million people and to be responsible for 27% of all cases of cirrhosis and 25% of all cases of HCC [5,6]. In 2002, it was estimated to have caused 366,000 deaths worldwide [6]. At this same point in time, 1.6%, or 225 million Americans were estimated to be seropositive for HCV, with twice the rate of seroprevalence seen in black individuals compared with whites [7]. Recent European data suggest HCV seroprevalence rates of anywhere between 0.4 and 5.2%, depending on country, with lower rates seen in northwestern countries and rates increasing as one travels south and east [8]. Hence, the search for a cure – and the quest to potentially eradicate this chronic disease – grows more with each passing year. Response rates to pegIFN/RBV have been improved by the addition of newer compounds, such as the protease inhibitors telaprevir and boceprevir, which improve the efficacy of pegIFN/RBV [9–15]. However, these improved response rates were accompanied by a substantial pill burden plus the same limitations of all IFN-based therapies, meaning that many patients still did not have an opportunity to benefit from treatment [16], and these agents
2014 Informa UK Ltd
ISSN 1747-4124
725
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
Drug Profile
Adler & Lambert
are no longer recommended by the American Association for the Study of Liver Diseases (AASLD), although they are still recommended by the European Association for the Study of the Liver for patients infected with GT1 [17,18]. The nucleotide analog sofosbuvir (SOF) has recently been licensed by the US FDA and the combination of SOF and RBV has been endorsed by the AASLD for the treatment of GT2 and 3 HCV, although pegIFN/RBV is still recommended (in conjunction with SOF) for GT1 [18,19]. For all these reasons, a well-tolerated, all-oral, IFN-free, RBV-free regimen with pangenotypic activity has been the holy grail of HCV research for many years. Such a regimen will likely feature a combination of direct-acting antivirals (DAAs) with different mechanisms of action [20]. One potential such agent is daclatasvir (DCV). Competitor compounds
It seems inevitable that combinations of antiviral agents – dual, triple or even quadruple therapy – will be the order of the day when guidelines for curative treatments for HCV are laid down. To date, DCV has been trialed in conjunction with the established combination of the pegIFN plus RBV, as well as combinations with newer DAAs such as asunaprevir (ASV) and SOF. DCV established NS5A as a therapeutic target, and many pharmaceutical companies have subsequently developed their own NS5A inhibitors, two of which have come to the fore at the time of writing with the simultaneous release of numerous impressive Phase III trial results: ledipasvir (Gilead Sciences, California) and ombitasvir (AbbVie, Illinois) [21–27]. These will be discussed in a later section. While it seems likely that the majority of future HCV treatment regimens will include an NS5A inhibitor, it is by no means clear which NS5A inhibitor will emerge as the preferred agent, or if different NS5A inhibitors will find favor among select population groups. Currently, it appears that the characteristics of DCV – as discussed in subsequent sections of this review – are similar to those of other NS5A inhibitors. However, certain attributes of these agents may only become apparent during post-licensing surveillance studies in large populations. As rival corporations’ NS5A inhibitors all appear to show similar clinical efficacy and tolerability, other factors – such as pill burden, availability of a single-pill polydrug co-formulation and cost – may well come into play. Introduction to daclatasvir
DCV (Bristol-Meyers Squibb; previously BMS-790052) is a small-molecule, orally-administered, pan-genotypic inhibitor of hepatitis C viral non-structural protein 5A (NS5A). During the course of HCV replication, the HCV polyprotein is cleaved into three structural proteins (one ‘core’ and two ‘envelope’) in addition to at least seven non-structural proteins [28]. Five of these non-structural proteins form a replication complex, and have been widely investigated as therapeutic targets – for example, NS3 protease is a target of boceprevir and ASV (the latter remaining experimental at present), while 726
telaprevir targets the NS3/4A complex and SOF targets the NS5B RNA polymerase. DCV was the first drug to target NS5A, although the exact mechanism of the drug and importance of the protein remain unclear; NS5A has no known enzymatic activity. NS5A dimerization is believed to be a crucial step in HCV replication, but this dimerization is not inhibited by DCV [29]. Modeling data based on results from trials suggest that DCV blocks both viral RNA synthesis and the assembly/ secretion of the completed virion from the host cell [30]. One hypothesis is that NS5A possesses both cis- and trans-acting roles in HCV replication, of which DCV almost certainly inhibits the cis-acting function and may well also act on the trans-acting function [31]. DCV was discovered during a high-throughput screening of over 1 million proprietary compounds. This screening led to the identification of a compound with activity against NS5A, the efficacy and pharmacokinetics of which were manipulated at a molecular level, leading to the creation of DCV [32,33]. DCV demonstrated pangenotypic picomolar efficacy (EC50 9–146 pM against genotypes 1a, 1b, 2a, 3a, 4a and 5a) and appeared safe in vitro, with a therapeutic index (CC50/EC50) of ‡100,000. Initial studies on healthy volunteers and subjects infected with HCV who were given escalating doses of DCV revealed high plasma concentrations 24 h after a single dose (suggesting that once-daily [od] dosing would prove adequate), mild adverse events (of which headache was the most common) and significant declines in plasma HCV RNA (mean 3.3log10 decline 24 h after a single 100 mg dose). DCV has excellent oral bioavailability, with plasma concentrations correlating with dose up to approximately 60 mg. Steady state occurs after 3–4 days of od dosing. It is approximately 99% protein-bound in plasma, which appears to be independent of dose [34]. Mathematical modeling based on results observed in trial subjects suggests that the tissue concentration of DCV, presumed to equate to its ‘active’ concentration, is on the order of 10-fold lower than its plasma concentration [35]. DCV’s drug interaction profile has generally appeared to be favorable; in particular, it appears to have no effect on the pharmacokinetics of drugs commonly used in the combined oral contraceptive pill [36]. Studies in healthy volunteers have suggested a DCV dose reduction of 50% when co-administered with atazanavir/ritonavir and dose increase by 50% when coadministered with efavirenz, with no meaningful interaction between DCV and tenofovir [37]. Clinical efficacy
In designing a trial of treatment for HCV, one must define one’s population carefully. Different genotypes respond to treatments at different rates, as do different patient groups. Some common demographic denominators, such as black race and increasing age, are associated with a poorer response to treatment. Previous treatment exposure, – for example, treatmentnaı¨ve versus IFN failure – is equally relevant. Another important variable is IL-28B genotype, with different polymorphisms of Expert Rev. Gastroenterol. Hepatol. 8(7), (2014)
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
DCV for the treatment of HCV infection
rs12979860 associated with either success or failure of IFN therapy. IL-28B genotype CC is associated with the best response to IFN, with CT and TT associated with poorer responses [38]. All of the Phase II trials of DCV that have been published to date share a number of common features. They were all sponsored, designed, analyzed and co-written by the manufacturers of the experimental drug(s) in question, which likely contributed to their methodological homogeneity. All trials studied patients with chronic HCV with HCV RNA >105 IU/ml, without evidence of cirrhosis, hepatic decompensation, HCC, other causes of chronic liver disease or co-infection with HIV or hepatitis B. A variety of doses of experimental drugs were trialed, but all patients receiving pegIFN-a-2a and RBV were administered standard doses. Although ‘cure’ has been defined as sustained virologic response at 24 weeks post-treatment [1], the primary end point of all but one of these Phase II trials was SVR12, although SVR24 was additionally assessed as a secondary outcome in many of these trials. Some authors have posited that SVR12 is as relevant a measure as SVR24 [39]. All of the Phase II trials in this section are summarized in TABLE 1, with as-of-yet unpublished trials summarized in TABLE 2. Definitions
• Null response to IFN:
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
Daclatasvir for the treatment of hepatitis C virus infection Expert Rev. Gastroenterol. Hepatol. 8(7), 725–738 (2014)
Hugh Adler1 and John S Lambert*1–3 1 Department of Infectious Diseases, Mater Misericordiae University Hospital, Dublin, Ireland 2 Rotunda Hospital, Dublin, Ireland 3 UCD School of Medicine and Medical Science, Dublin, Ireland *Author for correspondence: Tel.: +353 1716 4535 [email protected]
Daclatasvir was pivotal to the trial that established proof-of-concept that an interferon-free regimen could induce a sustained virologic response in patients with chronic HCV infection. This NS5A inhibitor is not currently licensed for the treatment of HCV, but has shown promising efficacy and minimal side-effects in clinical trials to date, where it has been tested in combination with a variety of different HCV therapies. An all-oral, interferon-free curative combination therapy for HCV is now tantalizingly close to becoming part of routine clinical practice, with multiple highly-efficacious direct-acting antiviral agents emerging virtually simultaneously. In this article we will discuss daclatasvir’s background and review the clinical trials published to date, concluding with our predictions regarding its future place in the treatment armamentarium against HCV. KEYWORDS: BMS-790052 • cirrhosis • daclatasvir • hepatitis C virus • hepatocellular carcinoma • interferon • NS5A inhibitor • ribavirin • sofosbuvir
Introduction & unmet needs of current therapies
Until recently, curative treatment of chronic HCV infection, defined as inducing a sustained virologic response, or an undetectable viral load at 24 weeks after the completion of treatment (SVR24) [1], has consisted of a combination of the immunomodulator pegylated interferon (pegIFN) and the nucleoside analog ribavirin (RBV). For example, one trial found that 48 weeks of pegIFN-a-2a plus RBV achieved SVR24 in 56% of patients [2]. Patients who achieve sustained virologic response (SVR) are less likely to develop complications of HCV, including cirrhosis and hepatocellular carcinoma (HCC). However, IFN and RBV are notorious for causing a range of side effects, including severe influenza-like symptoms, mood alteration and cytopenias. In addition, IFN must be administered by subcutaneous injection, placing a further burden on patients and service providers alike. Finally, the six major genotypes of HCV respond at different rates to IFN/RBV-based regimens, in the pivotal trial mentioned above, only 46% of patients with genotype 1 (GT1) achieved SVR24, versus 76% of patients with GT2 or 3 [2]. Genotypes 1–3 are found worldwide, with GT1a commonest in North America, GT1b commonest in Europe and Asia, informahealthcare.com
10.1586/17474124.2014.925798
GT3 commonest in Europe, Southeast Asia and Australia and GT4 commonest in the Middle East, especially in Egypt [3,4]. HCV is a significant public health problem. Worldwide, it is estimated to affect 184 million people and to be responsible for 27% of all cases of cirrhosis and 25% of all cases of HCC [5,6]. In 2002, it was estimated to have caused 366,000 deaths worldwide [6]. At this same point in time, 1.6%, or 225 million Americans were estimated to be seropositive for HCV, with twice the rate of seroprevalence seen in black individuals compared with whites [7]. Recent European data suggest HCV seroprevalence rates of anywhere between 0.4 and 5.2%, depending on country, with lower rates seen in northwestern countries and rates increasing as one travels south and east [8]. Hence, the search for a cure – and the quest to potentially eradicate this chronic disease – grows more with each passing year. Response rates to pegIFN/RBV have been improved by the addition of newer compounds, such as the protease inhibitors telaprevir and boceprevir, which improve the efficacy of pegIFN/RBV [9–15]. However, these improved response rates were accompanied by a substantial pill burden plus the same limitations of all IFN-based therapies, meaning that many patients still did not have an opportunity to benefit from treatment [16], and these agents
2014 Informa UK Ltd
ISSN 1747-4124
725
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
Drug Profile
Adler & Lambert
are no longer recommended by the American Association for the Study of Liver Diseases (AASLD), although they are still recommended by the European Association for the Study of the Liver for patients infected with GT1 [17,18]. The nucleotide analog sofosbuvir (SOF) has recently been licensed by the US FDA and the combination of SOF and RBV has been endorsed by the AASLD for the treatment of GT2 and 3 HCV, although pegIFN/RBV is still recommended (in conjunction with SOF) for GT1 [18,19]. For all these reasons, a well-tolerated, all-oral, IFN-free, RBV-free regimen with pangenotypic activity has been the holy grail of HCV research for many years. Such a regimen will likely feature a combination of direct-acting antivirals (DAAs) with different mechanisms of action [20]. One potential such agent is daclatasvir (DCV). Competitor compounds
It seems inevitable that combinations of antiviral agents – dual, triple or even quadruple therapy – will be the order of the day when guidelines for curative treatments for HCV are laid down. To date, DCV has been trialed in conjunction with the established combination of the pegIFN plus RBV, as well as combinations with newer DAAs such as asunaprevir (ASV) and SOF. DCV established NS5A as a therapeutic target, and many pharmaceutical companies have subsequently developed their own NS5A inhibitors, two of which have come to the fore at the time of writing with the simultaneous release of numerous impressive Phase III trial results: ledipasvir (Gilead Sciences, California) and ombitasvir (AbbVie, Illinois) [21–27]. These will be discussed in a later section. While it seems likely that the majority of future HCV treatment regimens will include an NS5A inhibitor, it is by no means clear which NS5A inhibitor will emerge as the preferred agent, or if different NS5A inhibitors will find favor among select population groups. Currently, it appears that the characteristics of DCV – as discussed in subsequent sections of this review – are similar to those of other NS5A inhibitors. However, certain attributes of these agents may only become apparent during post-licensing surveillance studies in large populations. As rival corporations’ NS5A inhibitors all appear to show similar clinical efficacy and tolerability, other factors – such as pill burden, availability of a single-pill polydrug co-formulation and cost – may well come into play. Introduction to daclatasvir
DCV (Bristol-Meyers Squibb; previously BMS-790052) is a small-molecule, orally-administered, pan-genotypic inhibitor of hepatitis C viral non-structural protein 5A (NS5A). During the course of HCV replication, the HCV polyprotein is cleaved into three structural proteins (one ‘core’ and two ‘envelope’) in addition to at least seven non-structural proteins [28]. Five of these non-structural proteins form a replication complex, and have been widely investigated as therapeutic targets – for example, NS3 protease is a target of boceprevir and ASV (the latter remaining experimental at present), while 726
telaprevir targets the NS3/4A complex and SOF targets the NS5B RNA polymerase. DCV was the first drug to target NS5A, although the exact mechanism of the drug and importance of the protein remain unclear; NS5A has no known enzymatic activity. NS5A dimerization is believed to be a crucial step in HCV replication, but this dimerization is not inhibited by DCV [29]. Modeling data based on results from trials suggest that DCV blocks both viral RNA synthesis and the assembly/ secretion of the completed virion from the host cell [30]. One hypothesis is that NS5A possesses both cis- and trans-acting roles in HCV replication, of which DCV almost certainly inhibits the cis-acting function and may well also act on the trans-acting function [31]. DCV was discovered during a high-throughput screening of over 1 million proprietary compounds. This screening led to the identification of a compound with activity against NS5A, the efficacy and pharmacokinetics of which were manipulated at a molecular level, leading to the creation of DCV [32,33]. DCV demonstrated pangenotypic picomolar efficacy (EC50 9–146 pM against genotypes 1a, 1b, 2a, 3a, 4a and 5a) and appeared safe in vitro, with a therapeutic index (CC50/EC50) of ‡100,000. Initial studies on healthy volunteers and subjects infected with HCV who were given escalating doses of DCV revealed high plasma concentrations 24 h after a single dose (suggesting that once-daily [od] dosing would prove adequate), mild adverse events (of which headache was the most common) and significant declines in plasma HCV RNA (mean 3.3log10 decline 24 h after a single 100 mg dose). DCV has excellent oral bioavailability, with plasma concentrations correlating with dose up to approximately 60 mg. Steady state occurs after 3–4 days of od dosing. It is approximately 99% protein-bound in plasma, which appears to be independent of dose [34]. Mathematical modeling based on results observed in trial subjects suggests that the tissue concentration of DCV, presumed to equate to its ‘active’ concentration, is on the order of 10-fold lower than its plasma concentration [35]. DCV’s drug interaction profile has generally appeared to be favorable; in particular, it appears to have no effect on the pharmacokinetics of drugs commonly used in the combined oral contraceptive pill [36]. Studies in healthy volunteers have suggested a DCV dose reduction of 50% when co-administered with atazanavir/ritonavir and dose increase by 50% when coadministered with efavirenz, with no meaningful interaction between DCV and tenofovir [37]. Clinical efficacy
In designing a trial of treatment for HCV, one must define one’s population carefully. Different genotypes respond to treatments at different rates, as do different patient groups. Some common demographic denominators, such as black race and increasing age, are associated with a poorer response to treatment. Previous treatment exposure, – for example, treatmentnaı¨ve versus IFN failure – is equally relevant. Another important variable is IL-28B genotype, with different polymorphisms of Expert Rev. Gastroenterol. Hepatol. 8(7), (2014)
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/26/14 For personal use only.
DCV for the treatment of HCV infection
rs12979860 associated with either success or failure of IFN therapy. IL-28B genotype CC is associated with the best response to IFN, with CT and TT associated with poorer responses [38]. All of the Phase II trials of DCV that have been published to date share a number of common features. They were all sponsored, designed, analyzed and co-written by the manufacturers of the experimental drug(s) in question, which likely contributed to their methodological homogeneity. All trials studied patients with chronic HCV with HCV RNA >105 IU/ml, without evidence of cirrhosis, hepatic decompensation, HCC, other causes of chronic liver disease or co-infection with HIV or hepatitis B. A variety of doses of experimental drugs were trialed, but all patients receiving pegIFN-a-2a and RBV were administered standard doses. Although ‘cure’ has been defined as sustained virologic response at 24 weeks post-treatment [1], the primary end point of all but one of these Phase II trials was SVR12, although SVR24 was additionally assessed as a secondary outcome in many of these trials. Some authors have posited that SVR12 is as relevant a measure as SVR24 [39]. All of the Phase II trials in this section are summarized in TABLE 1, with as-of-yet unpublished trials summarized in TABLE 2. Definitions
• Null response to IFN:
