Drugs DOI 10.1007/s40265-015-0362-5

ADIS DRUG EVALUATION

Daclatasvir: A Review of Its Use in Adult Patients with Chronic Hepatitis C Virus Infection Paul L. McCormack

Ó Springer International Publishing Switzerland 2015

Abstract Daclatasvir (DaklinzaÒ) is an inhibitor of hepatitis C virus (HCV) NS5A protein. It is a new, oral, direct-acting antiviral with potent pangenotypic activity. This article provides a narrative review of the efficacy and tolerability of daclatasvir in combination with other agents in the treatment of patients with chronic HCV infection and summarizes its pharmacological properties. Since daclatasvir has a different mechanism of action to other current direct-acting antivirals, it provides additive or synergistic antiviral activity when used in combination. It produces high sustained virological response rates when used in combination with peginterferon-a plus ribavirin in patients chronically infected with HCV genotypes 1–4, and provides even higher response rates when used in an interferon-free, all-oral combination with sofosbuvir, with or without ribavirin. Daclatasvir has a moderately high genetic barrier to resistance, is effective during short-term treatment over 12 weeks and has a tolerability profile similar to that of placebo. In conclusion, daclatasvir is a highly effective and well tolerated, oral, once-daily, directacting antiviral for use in combination therapy in adult patients chronically infected with HCV.

The manuscript was reviewed by: E. Brochot, Department of Virology, Amiens University Hospital, Amiens, France; E. Druyts, Faculty of Medicine, University of British Columbia, and Redwood Outcomes, Vancouver, BC, Canada; A. Mangia, Liver Unit, Hospital IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy; P. J. Pockros, Division of Gastroenterology/ Hepatology, Scripps Clinic, La Jolla, CA, USA; M. Puoti, Division of Infectious Diseases, AO Ospedale Niguarda Ca’ Granda, Milan, Italy. P. L. McCormack (&) Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand e-mail: [email protected]

Daclatasvir in chronic hepatitis C virus infection: a summary Potent inhibitor of hepatitis C virus (HCV) NS5A protein with pangenotypic antiviral activity Daclatasvir plus sofosbuvir (with or without ribavirin) achieves high sustained virological response rates at 12 weeks post-treatment (SVR12) in chronic HCV genotype 1–3 infection Daclatasvir plus peginterferon-a/ribavirin achieves high SVR12 rates in HCV genotype 1–4 infection Optimal responses are achievable with a treatment duration of 12 weeks Daclatasvir is generally well tolerated

1 Introduction Hepatitis C virus (HCV) is a blood-borne, single-stranded (positive-sense), RNA virus for which the common transmission vectors are unscreened blood transfusions, poorly sterilized medical equipment and unsafe injection practices [1, 2]. A majority of people (55–85 % [2]) infected with HCV develop chronic HCV infection, which may lead to cirrhosis of the liver, liver failure and hepatocellular carcinoma [1, 2]. It is estimated that 130–150 million people worldwide are chronically infected with HCV and that 15–30 % of these are likely to develop cirrhosis of the liver within 20 years [2]. There are at least seven distinct HCV genotypes, and many subtypes, based on genomic sequence heterogeneity,

P. L. McCormack

which differ in their geographical prevalence [1, 3]. Genotype 1 is the most prevalent genotype worldwide (&70 % of HCV in the USA [4] and 59 % in Western Europe [3]), for which subtype 1b has a higher prevalence in Europe and subtype 1a has a higher prevalence in the US [3]. Genotypes 3 (25 %), 2 (11 %) and 4 (5 %), respectively, are the next most prevalent in Western Europe, while genotypes 5 and 6 are relatively rare [3]. Intravenous drug users in Europe have a high prevalence of genotypes 3a and 4 [1]. The HCV genotype influences the response to antiviral drug therapy and the development of resistance [1]. In addition, a single nucleotide polymorphism in the patient’s gene coding for interleukin-28B (IL28B) influences the natural clearance of HCV and its response to peginterferon-based therapy [5, 6]. IL28B is involved in the immune response and individuals with the IL28B CC genotype, are more likely to spontaneously clear HCV and are 2–3 times more likely to respond to peginterferon-a plus ribavirin than those with the CT or TT (i.e. non-CC) genotypes [5, 6]. Prior to 2011, the standard treatment for chronic HCV infection consisted of combination therapy for 24 or 48 weeks with peginterferon-a/ribavirin [2, 7]. While this therapy is active to varying degrees against all HCV genotypes, it produces sustained virological response [SVR; defined as undetectable HCV RNA in the serum or HCV RNA levels below the lower limit of quantification (LLOQ)] rates at 12 (SVR12) or 24 weeks (SVR24) after treatment completion of only 40–50 % in patients infected with HCV genotype 1, although rates are higher for other HCV genotypes [1]. In addition, peginterferon-a is poorly tolerated in some patients, leading to poor adherence to medication [2]. The first direct-acting antivirals to be licensed for use in combination with peginterferon-a/ribavirin in chronic HCV genotype 1 infection were telaprevir and boceprevir, both inhibitors of the HCV nonstructural protein 3 (NS3) and its cofactor nonstructural protein 4A (NS4A) [7]. NS3/4A has serine protease and helicase enzymatic activity essential for viral replication [8]. In 2014, the NS5B (RNA-dependent RNA polymerase) inhibitor sofosbuvir [9] and the NS3/4A inhibitor simeprevir [10] were each licensed in the EU for use in combination with other medicinal products for the treatment of chronic HCV infection (both were approved in the US in 2013 [11, 12]). When administered in combination with peginterferon-a/ribavirin, these four direct-acting antivirals are each more effective than peginterferon-a/ribavirin alone and don’t appear to differ greatly with respect to SVR rates in treatment-naive patients with HCV genotype 1 infection [13]. Most recently, daclatasvir (DaklinzaÒ; BMS790052), an inhibitor of the HCV phosphoprotein NS5A involved in HCV replication, has been approved in the EU for use in combination with other medicinal products to treat chronic HCV infection in adults [14]. Depending upon the

HCV genotype and the patient characteristics, the new direct-acting antivirals (simeprevir, sofosbuvir and daclatasvir) are being used in various combinations, with or without peginterferon-a and/or ribavirin, to treat chronic HCV infection, with a future emphasis on interferon-free, all-oral regimens [7]. This article provides a narrative review of the efficacy and tolerability of oral daclatasvir in combination with other antiviral agents in the treatment of chronic HCV infection in adults, and overviews its pharmacology.

2 Pharmacodynamic Properties Daclatasvir was identified as a nonenzymatic inhibitor of HCV RNA replication in vitro in subgenomic replicons for a broad range of HCV genotypes [15]. 2.1 Mechanism of Action Daclatasvir is an inhibitor of the HCV-encoded NS5A phosphoprotein and appears to bind within the first 100 amino acids of the amino terminus (i.e. domain 1) of the protein [15]. The exact function of NS5A is not known; it appears to have multiple functions in the virus lifecycle and has a key role in the replication complex. The initial rapidity with which daclatasvir reduces HCV RNA in the serum (&2 log10 reduction within 6 h of administration, with a slower decline thereafter) suggests that it blocks virion assembly and release as well as viral RNA synthesis [16]. 2.2 Antiviral Activity Daclatasvir displayed potent inhibitory activity against all HCV genotypes tested (genotypes 1–6) [14]. In replicon assays, the half-maximal effective concentration (EC50) values of daclatasvir against HCV genotypes 1a, 1b, 2a, 3a, 4a and 5a were 50, 9, 71–103, 146, 12 and 33 pmol/L, respectively [15]. Daclatasvir displayed additive or synergistic inhibitory activity in replicon assays when used in combination with peginterferon-a/ribavirin, NS3/4A inhibitors (danoprevir or asunaprevir) or NS5B inhibitors [BMS-791325 (beclabuvir) or NM-107] [15, 17]. Daclatasvir inhibited JFH-1 genotype 2a replication in cell culture with an EC50 of 28 pmol/L [15]. Daclatasvir was specific for HCV as evidenced by the lower potency (EC50 of 9–12 lmol/L) against the related flavivirus bovine viral diarrhoea virus [15]. 2.3 Resistance Amino acid substitutions that confer resistance to daclatasvir in replicon assays have been localized to the

Daclatasvir: A Review

N-terminus region of NS5A [15, 18, 19]. The primary drug-induced resistance substitutions for genotype 1b were at amino acid residues 31 (L31F/V) and 93 (Y93H/N). The combination of the L31V and Y93H substitutions together conferred 8,336-fold resistance to daclatasvir compared with 23- and 19-fold resistance, respectively, for each variant alone [18]. The primary drug-induced resistance substitutions for genotype 1a were M28T, Q30E/H/R, L31M/V and Y93C/H/N [18]. The Y93N (47,017-fold) and Q30E (24,933-fold) substitutions conferred the greatest level of resistance in the genotype 1a replicon. Replicon assays have indicated that HCV genotype 1b has the highest relative barrier to NS5A-daclatasvir resistance and genotype 2a has the least, with the rank order being: 1b [ 4a C 5a [ 6a & 1a [ 2a JFH [ 3a [ 2a M31 [20]. HCV replicons with amino acid substitutions conferring resistance to daclatasvir remained fully susceptible to interferon-a and other direct-acting anti-HCV drugs with differing mechanisms of action, such as NS3/4A or NS5B inhibitors [14]. Breakthrough infections were more common in daclatasvir-treated patients infected with HCV genotype 1a than genotype 1b, and the substitutions conferring the greatest resistance to daclatasvir were consistent with those found in vitro [19]. Of 16 patients with HCV genotype 3 infection who experienced post-treatment relapse in the ALLY-3 trial (Sect. 4.1), nine had treatment-emergent Y93H substitutions (another six had Y93H at baseline) and one had a treatment-emergent L31I substitution [21]. In clinical trials of daclatasvir in combination with peginterferon-a/ribavirin or sofosbuvir (with or without ribavirin) (Sect. 4), breakthrough infections were uncommon or absent, but did occur at rates of 10, 4 and 7 % in the COMMAND-1 [22], COMMAND-3 [23] and COMMAND-4 [24] studies, assessing daclatasvir plus interferon-a/ribavirin in treatment-naive patients with HCV genotype 1 or 4, genotype 1 or genotype 4 infection, respectively. Virological failures (breakthrough or relapse), most commonly in patients with non-CC IL28B genotypes, frequently had treatment-emergent daclatasvir-resistant NS5A polymorphisms, particularly L31 and Y93 for genotype 1, at the time of failure [21–27].

mean Cmax was 1,726 ng/mL, the mean Cmin was 255 ng/ mL and the area under the plasma concentration–time curve over the dosing interval (AUCs) was 15,121 ng
h/mL [28]. The mean Cmin value was substantially greater than the replicon protein binding-adjusted 90 % median effective concentration (EC90) values for genotype 1a (0.283 ng/mL) or genotype 1b (0.036 ng/mL); the mean Cmin exceeded these EC90 values after the first dose. In this multiple ascending dose study, the plasma concentrations of daclatasvir increased in a near dose-proportional manner for doses between 1 and 60 mg, but overlapped for the 60 and 100 mg doses [28]. Steady state was achieved after 3–4 days of once-daily administration. Administering oral daclatasvir 60 mg after a light meal did not reduce daclatasvir exposure, although administration after a high-fat meal reduced the Cmax of daclatasvir by 28 % and the AUCs by 23 % [14]. It is recommended that daclatasvir be taken orally with or without meals [14]. Approximately 99 % of plasma daclatasvir was bound to plasma proteins, independent of dose [28]. The estimated volume of distribution at steady state is 47 L [14]. Daclatasvir is a substrate of the P-glycoprotein (P-gp) efflux pump and the absolute oral bioavailability is 67 % [14]. Daclatasvir is an inhibitor of P-glycoprotein, organic anion-transporting polypeptide (OATP) 1B1 and breast cancer resistance protein (BCRP) transporters [14, 29]. In vitro, daclatasvir also inhibits renal uptake transporters, OAT 1 and 3, and organic cation transporter (OCT)2, but is unlikely to have a clinically significant effect on the transporter substrates [14]. 3.2 Metabolism and Elimination

3 Pharmacokinetic Properties

Daclatasvir is metabolized by cytochrome P450 (CYP) 3A isoenzymes, predominantly CYP3A4 [14]. There are no metabolites present in the circulation at concentrations [5 % of the parent drug concentration [14]. Studies with radiolabelled daclatasvir found that 88 % of the dose was excreted in the faeces (53 % as unchanged drug) and 6.6 % was excreted in urine (largely as unchanged drug) [14]. The mean terminal elimination half-life of daclatasvir in patients with chronic HCV infection receiving multiple-dose oral daclatasvir 60 mg once daily was 12–15 h [28]. In patients administered 100 lg of radiolabelled daclatasvir intravenously after receiving a 60 mg oral tablet, the total clearance of daclatasvir was 4.24 L/h [28].

3.1 Absorption and Distribution

3.3 Special Patient Populations

Oral daclatasvir is readily absorbed, attaining peak plasma concentrations (Cmax) at a median time (tmax) of 1–2 h after administration. In patients with chronic HCV infection receiving oral daclatasvir 60 mg once daily for 14 days, the

In subjects with creatinine clearance values of 60, 30 and 15 mL/min receiving a single 60 mg oral dose of daclatasvir, it was estimated that the AUC of unbound daclatasvir would be increased by 18, 39 and 51 %,

P. L. McCormack

respectively, compared with that in subjects with normal renal function [14]. The AUC of total daclatasvir (bound and unbound) was increased by 27 % and the AUC of unbound daclatasvir was increased by 20 % in subjects with end-stage renal disease requiring haemodialysis, compared with subjects with normal renal function. However, adjustment of daclatasvir dosage is not considered necessary in patients with any level of renal impairment [14]. The Cmax and AUC of total daclatasvir were reduced in subjects with mild, moderate or severe hepatic impairment, but hepatic impairment had no clinically significant effect on unbound daclatasvir concentrations [14]. Therefore, dosage adjustment is not necessary in patients with hepatic impairment, although it has not been assessed in patients with decompensated cirrhosis [14]. The pharmacokinetics of daclatasvir are not altered in the elderly and have not been assessed in children [14]. Female sex, and black or ‘other’ (non-white, non-black and non-Asian) race affect the clearance and/or distribution of daclatasvir, but not to a clinically significant extent [14]. 3.4 Potential Drug Interactions When daclatasvir is given concomitantly with strong inhibitors of CYP3A4, the dosage of daclatasvir should be reduced (e.g. with atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, ketoconazole, telaprevir and telithromycin) [Sect. 6] or caution exercised (e.g. with calcium channel blockers and erythromycin) [14, 30]. Concomitant administration with strong inducers of CYP3A4 or P-gp, such as phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, dexamethasone and St John’s wort, is contraindicated since the AUC of daclatasvir may be reduced sufficiently to cause loss of efficacy [14]. The dosage of daclatasvir should be increased when given concomitantly with moderate inducers of CYP3A4 or P-gp, such as efavirenz (Sect. 6) [14, 30]. Since daclatasvir inhibits P-gp, OATP 1B1, OCT1 and BCRP, caution is required when daclatasvir is used together with drugs that are substrates of these transporters, such as dabigatran etexilate, digoxin and HMG-CoA reductase inhibitors (statins); this is particularly relevant when they have a narrow therapeutic range [14].

4 Therapeutic Efficacy Daclatasvir is approved in the EU in combination with other drugs for the treatment of adults with chronic HCV infection. It is currently recommended in combination with sofosbuvir (with or without ribavirin) or peginterferon-a/ ribavirin (see Sect. 6). In published phase 3 [21, 23, 24] and

phase 2 [22, 26, 27, 31–34] clinical trials, the efficacy of daclatasvir in the treatment of chronic HCV infection has been assessed in combination with sofosbuvir (with or without ribavirin) [21, 26] or peginterferon-a/ribavirin [22–24, 27, 31–34]. 4.1 In Combination with Sofosbuvir The phase 3, ALLY-3 trial (AI444-218) assessed the efficacy of oral daclatasvir 60 mg once daily combined with oral sofosbuvir 400 mg once daily for 12 weeks in treatment-naive (n = 101) or treatment-experienced (n = 51) patients with chronic HCV genotype 3 infection [21]. Treatment-experienced patients had experienced prior treatment failure, including previous treatment with sofosbuvir or alisporivir, but patients who had received prior treatment with NS5A inhibitors were excluded. Overall, 61 % of patients had non-CC IL28B genotypes, 21 % had cirrhosis and 71 % had plasma HCV RNA C8 9 105 IU/ mL [21]. High SVR12 (primary endpoint) rates were achieved by both treatment-naive and treatment-experienced patients (Table 1). Responses were numerically lower in patients with cirrhosis irrespective of prior treatment; the SVR12 was 96 % in patients without cirrhosis compared with 63 % in those with cirrhosis [21]. SVR12 rates were also descriptively lower in patients with a fibrosis stage of F4 (based on FibroTest scores) compared with F0–F3 (70 vs. 93 %) [21]. Sixteen patients, 11 of whom were cirrhotic, relapsed post-treatment before achieving SVR12 and one patient experienced rebound at the end of treatment, but no patient experienced virological breakthrough during therapy [21]. The phase 2, randomized, open-label AI444-040 trial initially assessed the efficacy of once-daily daclatasvir 60 mg plus sofosbuvir 400 mg, with or without ribavirin, for 24 weeks in 44 treatment-naive patients with HCV genotype 1 infection and 44 treatment-naive patients with HCV genotype 2 or 3 infection [26]. Patients with cirrhosis were excluded. Following a protocol amendment, a further 82 treatment-naive patients were treated for 12 weeks and 41 patients who had experienced virological failure (noneradication, breakthrough or relapse) on previous treatment with telaprevir or boceprevir in combination with interferon-a/ribavirin were treated for 24 weeks. Overall, 91 % of treatment-naive patients with genotype 2 or 3 infection achieved SVR12 (primary endpoint) and 93 % achieved SVR24 following 24 weeks of treatment with daclatasvir plus sofosbuvir, with or without ribavirin, with only minor differences between treatment arms (Table 1) [26]. The SVR12 rate for patients with genotype 2 infection was 92 % and that for patients with genotype 3 infection was 89 %. Similarly, 98 % of all patients with HCV genotype 1 infection achieved SVR12 after either 12 or 24 weeks of

Daclatasvir: A Review Table 1 Efficacy of oral daclatasvir 60 mg once daily in combination with sofosbuvir, with or without ribavirin, in the treatment of patients with chronic HCV genotype 1, 2 or 3 infection: results of the randomized, open-label, phase 3 ALLY-3 and phase 2 AI444-040 trials Study (identifier) [name]

Patient type

Treatmenta

Duration (weeks)

No. of pts

Responders (% of pts) SVR4

Nelson et al. [21] (AI444-218) [ALLY-3] Sulkowski et al. [26] (AI444-040)

SVR12b

SVR24

TN GT 3

DCV ? SOF

12

101

90

TE GT 3

DCV ? SOF

12

51

86

TN GT 2/3 TN GT 2/3

SOF, then DCV ? SOF DCV ? SOF

1, then 23 24

16 14

88 100

88 100

88 100

TN GT 2/3

DCV ? SOF ? RBV

24

14

86

86

93

TN GT 1

SOF, then DCV ? SOF

1, then 23

15

100

100

93

TN GT 1

DCV ? SOF

24

14

100

100

100 100

TN GT 1

DCV ? SOF ? RBV

24

15

100

100

TN GT 1

DCV ? SOF

12

41

98

100

95

TN GT 1

DCV ? SOF ? RBV

12

41

95

95

93

TEc GT 1

DCV ? SOF

24

21

100

100

DCV ? SOF ? RBV

24

20

100

95

c

TE GT 1

DCV daclatasvir, GT genotype, HCV hepatitis C virus, pt(s) patient(s), RBV ribavirin, SOF sofosbuvir, SVR sustained virological response [HCV RNA \lower limit of quantification (25 IU/mL)], SVR4 SVR at 4 weeks post-treatment, SVR12 SVR at 12 weeks post-treatment, SVR24 SVR at 24 weeks post-treatment, TE treatment experienced, TN treatment naive a

Oral DCV 60 mg once daily and oral SOF 400 mg once daily; oral RBV 500–600 mg twice daily for HCV GT 1 (500 mg twice daily for bodyweight \75 kg and 600 mg twice daily for bodyweight [75 kg) and 400 mg twice daily for HCV GT 2/3

b

Primary efficacy endpoint

c

Patients with confirmed virological failure (eradication failure, virological breakthrough or post-treatment relapse) after treatment with telaprevir 750 mg three times daily or boceprevir 800 mg three times daily together with peginterferon-a/ribavirin

treatment, regardless of whether they were treatment naive or had failed previous therapy with telaprevir or boceprevir plus peginterferon-a/ribavirin [26]. The SVR12 rates were similar for genotypes 1a (98 %) and 1b (100 %), as well as for IL28B genotypes CC (93 %) and non-CC (98 %) [26]. Only one patient, a patient with HCV genotype 3 infection, experienced relapse and one patient with genotype 3 infection experienced virological breakthrough, but achieved SVR12 after rescue therapy; both of these patients were allocated to the sofosbuvir lead-in treatment arm (sofosbuvir for 1 week, followed by daclatasvir plus sofosbuvir for 23 weeks (see Table 1) [26]. 4.2 In Combination with Peginterferon-a Plus Ribavirin Two phase 3 trials assessing the efficacy of daclatasvir in combination with peginterferon-a/ribavirin have been published in abstract form [23, 24]. The COMMAND-3 noninferiority trial [23] compared daclatasvir with telaprevir, each in combination with peginterferon-a/ribavirin, in patients with chronic HCV genotype 1 infection (subsequently restricted to genotype 1b patients) and the placebo-controlled COMMAND-4 trial [24] compared daclatasvir plus peginterferon-a/ribavirin with peginterferon-a/ribavirin alone in patients with chronic HCV genotype 4 infection.

Patients in these studies were treatment-naive adults with plasma HCV RNA C105 IU/mL [23, 24]. In each trial, 75–76 % of patients were IL28B non-CC genotype and 10–11 % had cirrhosis. Daclatasvir-treated patients in each study who achieved an extended rapid virological response (eRVR; that is, undetectable HCV RNA at both weeks 4 and 12 of treatment) received 24 weeks of treatment with daclatasvir plus peginterferon-a/ribavirin, while those who did not achieve eRVR received an additional 24 weeks of treatment with peginterferon-a/ribavirin [23, 24]. Placebo recipients in COMMAND-4 received 48 weeks of therapy with peginterferon-a/ribavirin [24]. The primary endpoint in each trial was the SVR12. In COMMAND-3, daclatasvir plus peginterferon-a/ribavirin was noninferior to telaprevir plus peginterferon-a/ ribavirin in patients with HCV genotype 1b infection (Table 2); the treatment difference in SVR12 being 4.3 % (95 % CI -3.3 to 11.9) [23]. Noninferiority was not formally tested in patients with HCV genotype 1a infection. In patients with HCV genotype 1b infection, eRVR was achieved by 75 % of daclatasvir recipients and 73 % of telaprevir recipients; post-treatment relapse occurred in 5 % of daclatasvir recipients compared with 15 % of telaprevir recipients; and breakthrough infections occurred in 4 % of daclatasvir recipients [23]. In COMMAND-4, daclatasvir plus peginterferon-a/ribavirin achieved significantly higher SVR12 rates than

P. L. McCormack Table 2 Efficacy of oral daclatasvir 60 mg once daily in combination with peginterferon-a/ribavirin in adult patients with chronic HCV infection in phase 3, randomized, double-blind [24] or open-label [23], controlled trials Study name (identifier)

Pt type

Treatmenta (treatment duration; weeks)

No. of ptsb

SVR12c (% of pts)

COMMAND-3 (AI444-052) [23]

TN GT 1b

DCV ? PEGIFN-a/RBV (24-48)

268

85

TVR ? PEGIFN-a/RBV (24-48)

134

81

DCV ? PEGIFN-a/RBV (24-48)

134

65

TVR ? PEGIFN-a/RBV (24-48)

66

70

TN GT 1a COMMAND-4 (AI444-042) [24]

TN GT 4

DCV ? PEGIFN-a/RBV (24-48)

82

73*

PL ? PEGIFN-a/RBV (48)

42

38

DCV daclatasvir, GT genotype, PEGIFN-a peginterferon-a, PL placebo, pt(s) patient(s), RBV ribavirin, SVR12 sustained virological response at post-treatment week 12, TN treatment naive, TVR telaprevir * p \ 0.0001 vs. PL ? PEGIFN-a/RBV a

Oral DCV 60 mg once daily, oral TVR 750 mg three times daily or matching PL, each in combination with subcutaneous PEGIFN-a 180 lg once weekly plus oral ribavirin 500–600 mg twice daily (according to bodyweight)

b c

Modified intent-to-treat populations Primary efficacy endpoint

peginterferon-a/ribavirin alone (Table 2) [24]. The SVR rate at post-treatment week 12 or later (including patients with missing 12-week data) was 82 % for daclatasvir compared with 43 % for peginterferon-a/ribavirin alone (p \ 0.0001) [24]. In the daclatasvir and placebo groups, eRVR was achieved by 79 and 12 % of patients, respectively. Post-treatment relapse occurred in 3 % of patients receiving daclatasvir plus peginterferon-a/ribavirin compared with 30 % of those receiving peginterferon-a/ribavirin alone. Breakthrough HCV infection occurred in 7 % of daclatasvir recipients [24]. A number of phase 2, randomized, double-blind, placebo-controlled trials of 12–48 weeks duration (all but one of which were dose ranging studies) had previously demonstrated the efficacy of daclatasvir 60 mg in combination with peginterferon-a/ribavirin in treatment-naive patients with chronic HCV genotype 1 [22, 27, 31, 33], 2 [34], 3 [34] or 4 [22] infections, as well as in treatmentexperienced HCV genotype 1 patients with prior null or partial responses to peginterferon-a/ribavirin [31–33]. The combination therapy produced SVR24 rates of 60–100 % against HCV genotype 1, 83 % against genotype 2, 67–69 % against genotype 3 and 100 % against genotype 4, as well as demonstrating efficacy (20–78 % eRVR) in prior null or partial responders to peginterferon-a/ribavirin.

5 Tolerability In published placebo-controlled clinical trials, the incidences of adverse events and laboratory abnormalities with daclatasvir 60 mg administered together with peginterferon-a/ribavirin were descriptively similar to those observed with peginterferon-a/ribavirin alone [22,

24, 27, 31–34]. None of these studies identified any unique daclatasvir-related adverse events. Common adverse events with this drug combination included fatigue, headache, pruritus, insomnia, decreased appetite and alopecia [22, 27, 31–33]. In the larger, dose-ranging, COMMAND-1 (n = 395) [22] and COMMAND-2 (n = 419) [32] studies, the incidences of adverse events were descriptively similar between the daclatasvir 20 and 60 mg dose groups and placebo, and did not differ between different durations of treatment with daclatasvir (12 or 24 weeks) in COMMAND-1 [22]. The incidences of the most common adverse events and grade 3–4 laboratory abnormalities with daclatasvir 60 mg plus peginterferon-a/ribavirin compared with peginterferon-a/ribavirin alone in COMMAND-1 are shown in Fig. 1. The incidences of serious adverse events with daclatasvir 60 mg plus peginterferon-a/ribavirin were generally similar across the COMMAND-1, -2 and -4 trials (5.0–9.8 %); the corresponding incidences with peginterferon-a/ribavirin alone ranged from 4.8 to 17.6 % [22, 24, 32]. Likewise, the incidences of discontinuations as a result of adverse events were 3.7–5.0 % with daclatasvir 60 mg plus peginterferon-a/ribavirin compared with 7.1–17.6 % for peginterferon-a/ribavirin alone [22, 24, 32]. The incidences of grade 3 or 4 adverse events in the respective treatment groups were 14.6 vs. 23.1 % in COMMAND-1 and 12.1 vs. 41.2 % in COMMAND-2 [22, 32]. For the comparison between daclatasvir and telaprevir, each in combination with peginterferon-a/ribavirin, in the COMMAND-3 trial, the respective incidences of serious adverse events were 6 vs. 10 %, while the respective rates for discontinuation as result of adverse events were 7 vs. 19 % [23]. Daclatasvir was associated with a significantly lower frequency of anaemia (haemoglobin \10 g/dL)

Daclatasvir: A Review Fig. 1 Treatment-emergent adverse events occurring in [20 % of daclatasvir recipients and grade 3–4 laboratory abnormalities occurring during treatment with oral daclatasvir 60 mg once daily or placebo in combination with peginterferona/ribavirin in the COMMAND1 study [22]. DCV Daclatasvir, PEGIFN-a peginterferon-a, PL placebo, RBV ribavirin

DCV 60 mg + PEGIFN -α + RBV (n = 158) PL + PEGIFN -α + RBV (n = 78) Neutropenia Lymphopenia Anaemia Elevated ALT Thrombocytopenia

Fatigue Headache Pruritus Insomnia Nausea Flu-like illness Myalgia Dry skin Alopecia Rash Decreased appetite Irritability Diarrhoea 0

10

20

30

40

50

60

70

Incidence (% of patients)

through to week 12 than telaprevir (treatment difference -29.1 %; 95 % CI -38.8 to -19.4) [23]. In the studies combining daclatasvir with sofosbuvir, with or without ribavirin, there were no placebo groups to provide a comparison between daclatasvir and the concomitant agents [21, 26]. For daclatasvir 60 mg in combination with sofosbuvir in the phase 3 ALLY-3 trial (n = 152), there were no deaths, discontinuations as a result of adverse events or treatment-related serious adverse events [21]. The most common adverse events were headache (20 %), fatigue (19 %), nausea (12 %), diarrhoea (9 %), insomnia (6 %), abdominal pain (5 %) and arthralgia (5 %) [21]. In combination with sofosbuvir in the phase 2 AI444040 study (n = 211), the most common adverse events were fatigue (29–50 % per treatment group; 37 % overall), headache (16–38 %; 29 % overall), nausea (0–32 %; 19 % overall), arthralgia (6–14 %; 10 % overall), diarrhoea (5–20 %; 10 % overall) and cough (0–21 %; 9 % overall) [26]. Two patients discontinued treatment as a result of adverse events (both considered unrelated to therapy), 10

experienced serious adverse events and seven experienced grade 3 or 4 adverse events [26].

6 Dosage and Administration Oral daclatasvir is indicated in the EU in combination with other drugs for the treatment of chronic HCV infection in adults [14]. The recommended dosage is 60 mg once daily without regard to food. Since daclatasvir may induce resistance, it must not be given as monotherapy. Daclatasvir is recommended in the EU in combination with sofosbuvir in patients with HCV genotypes 1 or 4 without cirrhosis (12 weeks treatment duration) or with compensated cirrhosis (24 weeks treatment duration) [7, 14]. It is recommended in combination with sofosbuvir plus ribavirin in patients with HCV genotype 3 and compensated cirrhosis (24 weeks treatment duration), and in treatment-experienced patients with HCV genotype 3, with or without compensated cirrhosis (24 weeks treatment duration). Daclatasvir is also recommended in combination with

P. L. McCormack

peginterferon-a/ribavirin in patients with HCV genotype 4 (24 weeks daclatasvir and 24–48 weeks peginterferon-a/ ribavirin) [7, 14]. The daclatasvir dosage should be reduced to 30 mg once daily when given concomitantly with strong inhibitors of CYP3A4 and increased to 90 mg once daily when given concomitantly with moderate inducers of CYP3A4 (see Sect. 3.4) [14]. Concomitant use of daclatasvir and strong inducers of CYP3A4 and P-gp is contraindicated. Dosage modification is not required in the elderly or in patients with renal or hepatic impairment [14]. The efficacy and safety of daclatasvir in children and adolescents have not been established. Local prescribing information should be consulted for detailed information, including contraindications, precautions, drug interactions and use in special patient populations.

7 Place of Daclatasvir in the Management of Chronic Hepatitis C Virus Infection HCV infection is a major cause of chronic liver disease worldwide, but early diagnosis and treatment of chronic infection can markedly reduce the virus’ impact [2]. Approximately 99 % of patients who achieve SVR24 after treatment are permanently cured of the infection [1]. While the combination of subcutaneous peginterferon-a with oral ribavirin is active against all HCV genotypes, it achieves SVR24 rates of only 40–50 % against infections with HCV genotype 1, the most prevalent genotype [1]. Triple therapy regimens with the earlier, oral, direct-acting antivirals (telaprevir and boceprevir) in combination with peginterferon-a/ribavirin have proven effective, but tolerability issues (mostly related to peginterferon-a) mean that many patients do not complete their treatment [2]. Recent European guidelines recognize that interferon-sparing and interferon-free combination regimens using newer, oral, direct-acting antivirals (simeprevir, sofosbuvir and daclatasvir) offer highly effective and well tolerated treatment options [7]. In addition, optimal responses may be achieved with shorter treatment durations using these newer agents (e.g. 12 weeks compared with 24 or 48 weeks for peginterferon-a/ribavirin-based regimens) [21]. Daclatasvir, an NS5A inhibitor and the newest directacting antiviral to be approved in the EU, as well as being assessed initially in combination with peginterferon-a/ribavirin, has been evaluated in interferon-free, all oral, dual or triple regimens in combination with the NS5B inhibitor sofosbuvir (with or without ribavirin). Daclatasvir plus sofosbuvir (with or without ribavirin) produced SVR12 rates of 95–100 % in both treatment-naive

and treatment-experienced patients with HCV genotype 1 infection and 86–100 % in both treatment-naive and treatment-experienced patients with HCV genotype 2 or 3 infection (Sect. 4.1). High SVR12 rates were achieved after treatment with daclatasvir plus sofosbuvir (with or without ribavirin) for either 12 or 24 weeks. These high SVR rates were observed despite most patients having non-CC IL28B genotypes and most patients with HCV genotype 1 having genotype 1a, rather than 1b; the non-CC IL28B and HCV 1a genotypes have previously been associated with poor responses to treatment [26]. SVR12 rates with daclatasvir plus sofosbuvir were notably lower in patients with cirrhosis, particularly those with more severe fibrosis, suggesting that the addition of ribavirin to the regimen in these patients may be beneficial [21]. In phase 3 trials, daclatasvir 60 mg once daily in combination with peginterferon-a/ribavirin for 24–48 weeks in treatment-naive patients produced SVR12 rates of 65–85 % against HCV genotype 1 and 73 % against genotype 4 (Sect. 4.2). In supportive phase 2 studies, daclatasvir in combination with peginterferon-a/ribavirin for 12–48 weeks demonstrated high efficacy against HCV genotypes 1, 2, 3 and 4, as well as against treatment-experienced genotype 1 patients (Sect. 4.2). However, interferon-free, all-oral regimens are likely to be increasingly favoured as new direct-acting antiviral drug combinations are developed. An ongoing phase 2 trial (NCT02262728) is currently assessing the efficacy of daclatasvir 60 mg/day in combination with simeprevir 150 mg/day and sofosbuvir 400 mg/day for 12 weeks in patients with HCV genotype 1 or 4 infection and decompensated liver disease, with the 5-year follow-up expected to be completed in early 2020 [35]. The potential of daclatasvir 60 mg/day in combination with sofosbuvir 400 mg/day plus ribavirin for 12 weeks in patients with chronic HCV infection and cirrhosis, or in patients with chronic HCV infection who had already undergone liver transplantation is being assessed in the phase 3 ALLY-1 trial (NCT02032875), while the combination of daclatasvir 30, 60 or 90 mg/day plus sofosbuvir 400 mg/day for 8–12 weeks in chronic HCV patients coinfected with HIV-1 is being assessed in the phase 3 ALLY-2 trial (NCT02032888); both trials were estimated to be completed during 2015 [35]. Daclatasvir appears to have a moderately high genetic barrier to resistance. Where detailed in clinical trials, virological breakthrough, presumably reflecting the development of resistant mutations, was generally uncommon, although it did occur in up to 10 % of patients treated with daclatasvir in combination with peginterferon-a/ribavirin (Sect. 2.3). Although virological breakthrough was rare to non-existent with daclatasvir in combination with

Daclatasvir: A Review

sofosbuvir, resistance mutations did emerge in some patients with HCV genotype 3 infection who relapsed after therapy in the ALLY-3 trial—many of these patients were cirrhotic. Oral daclatasvir was well tolerated, generally displaying placebo-level tolerability in placebo-controlled clinical trials (Sect. 5). Serious adverse events and treatment discontinuations due to adverse events were uncommon. In conclusion, daclatasvir is a highly effective and well tolerated, oral, once-daily, direct-acting antiviral for use in combination therapy in adult patients chronically infected with HCV. Daclatasvir has a different mechanism of action to other current direct-acting antivirals and provides another alternative in combination regimens. It produces high SVR rates when used in combination with peginterferon-a/ ribavirin in patients chronically infected with HCV genotypes 1–4, but provides even higher response rates when used in an interferon-free, all-oral combination with sofosbuvir, with or without ribavirin. It has a moderately high genetic barrier to resistance, is effective during short-term treatment over 12 weeks and has a tolerability profile virtually indistinguishable from that of placebo. Thus, the pangenotypic NS5A inhibitor daclatasvir is an important new agent for the treatment of chronic HCV infection in adults. Data selection sources: Relevant medical literature (including published and unpublished data) on daclatasvir was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 10 February 2015], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Daclatasvir, Daklinza, BMS-790052. Study selection: Studies in patients with chronic hepatitis C infection who received daclatasvir. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Paul McCormack is a salaried employee of Adis/Springer.

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