Boceprevir: an oral protease inhibitor for the treatment of chronic HCV infection
Expert Rev. Anti Infect. Ther. 10(3), 269–279 (2012)
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Paul M Trembling, Sudeep Tanwar and Geoffrey M Dusheiko*
Centre for Hepatology, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK *Author for correspondence:
Tel.: +44 207 794 0500 ext. 36166
Fax: +44 207 472 6226
Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to affect sustained elimination of the virus (a sustained virological response [SVR]). The success and duration of therapy with interferon is dependent on HCV genotype. The current standard of care comprises combined treatment with pegylated interferon and ribavirin. Rates of SVR in patients with genotype 1 infection, the least responsive group, are less than 50%. Boceprevir is a ketoamide protease inhibitor that binds reversibly to the HCV nonstructural NS3 protease active site inhibiting intracellular viral replication. Phase III clinical studies have demonstrated that, in combination with the current standard of care, boceprevir significantly increases the SVR rate in both treatment-naive and previously treated patients with genotype 1 CHC. Both the US FDA and EMA have approved boceprevir for the treatment of genotype 1 CHC: the first directly-acting antiviral drug to be licensed for this indication. This article will review the pharmacology and pharmacodynamics of boceprevir, the efficacy and safety of the drug, and explore possible future developments in the management of CHC.
Keywords: boceprevir • hepatitis C • pegylated interferon • protease inhibitors • ribavirin
Expert Review of Anti-infective Therapy Downloaded
Chronic hepatitis C (CHC) virus infection
affects more than 170 million people globally
[1] and is a major cause of chronic liver disease. HCV is a positive strand RNA virus with a single open reading frame of approximately 9600 nucleotides. The HCV genome serves as a template for viral production. The RNA genome is translated into a polyprotein of approximately 3000 amino acids that is post-translationally modified to assemble mature HCV virions. The single polypeptide contains the structural and nonstructural proteins: C–E1–E2–P7–NS2– NS3–NS4A–NS4B–NS5A–NS5B. NS3, a tryp-sin-like serine protease, catalyzes cis-cleavage of the NS3–NS4A junction, followed by trans-cleavage of the NS4A–NS4B, NS4B–NS5A and NS5A–NS5B junctions to produce functional proteins. The active site of the protease is sited in an accessible shallow groove and it therefore presents a potential target for inhibition of viral replication [2,3]. The pivotal role played by HCV NS3/4A protease makes it a key drug target [4,5].
The aim of therapy for those infected with HCV is sustained elimination of the virus and prevention of progression of chronic liver dis-ease to cirrhosis and its complications, including
hepatocellular carcinoma. A sustained virological response (SVR) – that is, the failure to detect cir-culating HCV RNA by sensitive PCR 6 months after completing treatment – is considered tan-tamount to a cure. The current standard of care (SOC) comprises combination therapy with once-weekly pegylated interferon (PEG IFN) and daily ribavirin (RBV). SVR rates are dependent on the genotype of the HCV. Patients infected with genotypes 2 or 3 have SVR rates of 70–90% following the treatment. The SVR rate in geno type-1-infected individuals is less than 50%. There is therefore an urgent need to develop more effective regimens for improving treatment of naive patients and patients who failed to achieve SVR with PEG IFN and RBV. Two NS3/4A pro-tease inhibitors, boceprevir (Victrelis™, Merck, NJ, USA) and telaprevir (Incivek™, Vertex Pharmaceuticals, MA, USA; Incivo®, Janssen, High Wycombe, UK), are the first approved for the treatment of HCV infection. Boceprevir is
a peptidomimetic a-ketoamide NS3/4A serine-protease inhibitor that binds to the HCV NS3 serine (Ser139) active site (Figure 1) [6–9]. The bound complex is characterized by formation of a reversible covalent bond between the HCV
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-infective Therapy
protease and boceprevir. The binding to the HCV NS3/4A serine protease is biphasic: a weakly binding transient-collision complex is slowly rearranged to a more tightly bound, long-lived complex. The covalent complex subsequently dissociates. The potency of these compounds is genotype dependent and is also dependent on the ‘on rate’ and ‘off rate’ of the bound complex.
Boceprevir is indicated for the treatment of CHC gentotype 1 infection, in combination with PEG IFN and RBV in adults with compensated liver disease, in both treatment-naive patients and patients who have previously failed PEG IFN and RBV treatment
[101] . In large clinical trials, SVR rates in both these cohorts were significantly higher in those treated with boceprevir. This article will examine the data on the efficacy, safety and tolerability of boceprevir and speculate on the future developments of treatment for CHC.
Pharmacology
The efficacy of PEG IFN and RBV is restricted. In patients with genotype 1 infection, overall rates of SVR with PEG IFN and RBV after 48 weeks of therapy are in the order of 40–50% [10] and are in part dependent on endogenous mechanisms for viral clearance. The mechanism of action of PEG IFN and RBV is complex and not fully understood. Various host factors affect the response. SVR rates are diminished in patients with advanced fibrosis, insulin resistance and an IL-28B TT haplotype [11,12]. Furthermore, numerous adverse events (AEs) occur with PEG IFN and RBV that may preclude or contraindicate therapy, require dose reductions, or result in the early discontinuation of therapy [10].
The development of directly acting antiviral (DAA) therapy, including boceprevir, was initially hampered by the lack of an in vitro HCV replication model. The development of the sub-genomic HCV replicon model in 1999 [13] was a major break-through, enabling DAA agents to be screened for their ability to inhibit viral replication [14]. In addition, the replicon systems have been used to select and characterize resistant mutations against specific DAAs and also to assess replication fitness [15].
Pharmacokinetics & metabolism
Absorption
Boceprevir is absorbed following oral administration with a median time to peak concentration (Tmax) of 2 h with the mean maximum systemic concentrations occurring within 3 h postdose. When given three times daily (t.i.d.), steady-state concentrations are reached within 1 day of dosing. Boceprevir steady-state expo-sures increase in a linear fashion from 200 to 800 mg t.i.d. but less than dose proportionally thereafter, at doses greater than 800 mg t.i.d.. Boceprevir exposure is similar in both healthy subjects and those with HCV infection.
Food increases the mean exposures (area under the curve [AUC]) of boceprevir by up to 65%, at the 800 mg dose t.i.d. relative to the fasting state. This increase in AUC is similar regard-less of the fat content of the meal type or whether boceprevir was ingested immediately before, during or immediately after a meal.
Distribution
The mean apparent volume of distribution (Vd/F) of bocepre-vir is approximately 772 l at steady state in healthy subjects. Human plasma protein binding is approximately 75% following a single dose of boceprevir 800 mg. Human liver concentrations of boceprevir are unknown: in animal liver, concentrations of boceprevir were 11–49-times higher than concentrations seen in blood.
Metabolism
Boceprevir is metabolized primarily via the aldo-ketoreduc-tase-mediated pathway to ketone-reduced metabolites that are inactive against HCV. Boceprevir is also partially metabolized by CYP3A4/5 to form minor reduced metabolites, which appear to account for up to 8% of the initial boceprevir dos-age. Coadministration of boceprevir with drugs that induce or inhibit CYP3A4/5 can therefore increase or decrease exposure to boceprevir.
Elimination
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Pharmacodynamics
In preclinical studies, boceprevir inhibited the replication of a HCV genotype 1b subgenomic replicon in Huh-7 cells with 50% and 90% effective concentration values (EC50 and EC 90) of approximately 200 and 400 nM, respectively. Differences in inhibition of the subtype 1a replicon relative to the 1b replicon were noted [16]. Boceprevir also displayed HCV replicon antiviral activity when administered with IFN-a [17].
In vitro studies have demonstrated the emergence of replicon-infected cells with reduced susceptibility following exposure to boceprevir. The emergence of resistance was not seen in replicon models with the combined use of IFN-a and RBV [18]. The spe-cific substitutions in the NS3 protease coding region of the HCV genome that were detected in the boceprevir-selected replicons included; T54A, A156S, A156T and V170A. These and other com-monly observed boceprevir mutations such as; V36M, R155K and A156V, were shown by site-directed mutagenesis to confer reduced susceptibility to boceprevir.
The mean apparent total clearance (CL/F) of boceprevir is 157 l/h (2.2 l/h/kg). The main route of elimination of boceprevir is hepatic (~80%), although some renal elimination also occurs (~10%).
Drug–drug interactions
As previously discussed, boceprevir is metabolized principally by aldo-ketoreductase enzymes and partially by CYP3A4. Boceprevir is a potent inhibitor of CYP3A4 based on the results of in vitro assessments and the results of drug–drug interaction (DDI) studies. For example, oral midazolam exposure increased over fivefold with boceprevir coadministration. Thus, drugs metabolized primarily by CYP3A may have increased exposure when administered with boceprevir that could increase or prolong their therapeutic and adverse effects. A commonly prescribed class of drugs that is primarily metabolized by CYP3A is the statins, which include lovastatin and simvastatin. The concomi-tant use of boceprevir with statins may result in an increase in their serum levels.
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Drug Profile
Boceprevir: an oral protease inhibitor for the treatment of chronic HCV infection
Of note, pharmacokinetic studies are 9.6 kb RNA
not complete. For example, methadone is
an important medication for the intended
patient population. Whilst methadone is
only metabolized partially by CYP3A4, Core E1 E2 p7 NS2 NS3 NS4a NS4b NS5a NS5b
DDI studies with other potent inhibitors of
CYP3A4 have demonstrated unanticipated
decreases in methadone exposure. Thus,
the effect of boceprevir on methadone Viral particle assembly Viral replication
exposure cannot be accurately predicted
based on in vitro experiments.
Furthermore, the safety and efficacy of
combined oral contraceptive (COC) use Boceprevir – NS3/NS4a protease inhibitor
during boceprevir coadministration have
not been sufficiently characterized. The
Figure 1. HCV genome structure and boceprevir target.
completed DDI study conducted with
ethinyl estradiol/drospirenone (Yaz®) showed a 24% decrease in resulted in more cases of anemia with macrolide antibiotics and
ethinyl estradiol exposure and a 100% increase in drospirenone boceprevir with oral contraceptives was also associated with more
exposure during boceprevir administration. At present women of cases of anemia, but numbers were small in these groups [20].
child bearing age are advised to rely on two barrier methods of
contraception while on concomitant treatment with boceprevir. Clinical efficacy
HMG-CoA reductase inhibitors are metabolized by CYP3A4. Phase I studies
The coadministration of boceprevir with HMG-CoA reductase Twenty Phase I studies were conducted to investigate the phar-
inhibitors can result in a significant increase in their plasma con- macokinetics of boceprevir. These trials included nonresponders
centration. The administration of boceprevir alongside atorvas- with genotype 1 infection, and also subjects with genotype 2 and
tatin and pravastatin, which are primarily and partly metabolized 3 infection [21].
by CYP3A4, respectively, were assessed in fixed open-label studies A Phase I double-blind study investigated the antiviral activity
in healthy volunteers [19]. The coadministration of boceprevir with of escalating doses of boceprevir in patients who had previously
atorvastatin resulted in a 130% increase in the plasma exposure of failed treatment with PEG IFN-a [22]. Subjects received bocepre-
atorvastatin. The coadministration of boceprevir with pravastatin vir 100, 200 or 400 mg twice daily, 400 mg t.i.d. or placebo, for
resulted in a 60% increase in the plasma exposure of pravastatin. 14 days. Dose-dependent antiviral activity was observed, with a
As a result, the use of both drugs alongside boceprevir should be mean maximum reduction in viral load in the highest exposure
subject to close clinical monitoring and may necessitate the use group of 2.06 log10 from baseline. In a sub-group of patients tak-
of a lower maintenance dosage; the manufacturer of boceprevir ing boceprevir 400 mg twice daily or t.i.d., clonal sequencing of
recommends a maximum daily dose of atorvastatin of 20 mg the NS3-protease gene detected resistance mutations at six posi-
alongside boceprevir. Other HMG-CoA reductase inhibitors tions, either alone or in combination [23]. All mutations showed
such as simvastatin and lovastatin have not been formally stud- cross-resistance to telaprevir. These mutations were associated
ied alongside boceprevir and their coadministration alongside with reduced fitness to replicate; by 2 weeks after the end of
boceprevir is not recommended due to the high risk of toxicity. treatment, the wild-type sequence had increased from 85.9% at
Also of note, unanticipated decreases in the exposure of selective the end of treatment to 95.5%.
serotonin reuptake inhibitors, including paroxetine, sertraline and In a second Phase Ib study [7], 26 patients from three European
escitalopram, have been observed in DDI studies conducted with centers received boceprevir for 1 week, weekly PEG IFN-a2b
other HCV and HIV protease inhibitors. A short list of potential for 2 weeks and combination boceprevir and PEG IFN-a2b
drug–drug interactions is presented in Table 1. for 2 weeks, with 2-week washout periods between each dosing
Experience with the use of concomitant medications in bocepre- period. Two doses of boceprevir were studied: 200 mg t.i.d. and
vir Phase II and III trials is now being reported. AEs in patients in 400 mg t.i.d.. All doses were well tolerated, with anemia occur-
SPRINT-1, SPRINT-2 and RESPOND-2 who received concomi- ring in one patient. Twenty two patients completed all treatment
tant CYP3A4/5 substrates, inhibitors and/or inducers, compared arms. Combination therapy with boceprevir at either dose with
with AEs in patients who did not receive these drugs, have been PEG IFN resulted in greater decreases in HCV RNA than with
examined [20]. The most common agents were antidepressants. PEG IFN alone or with boceprevir monotherapy. The response
Other common CYP3A4/5 substrates included statins, phos- was related to dose of boceprevir.
phodiesterase-5 inhibitors, benzodiazepines, calcium-channel
blockers, methadone, oral contraceptives, pioglitazone and ste- Phase II studies
roids. There was no significant increase in AEs associated with Two complex Phase IIb studies evaluated dose response.
boceprevir. Boceprevir in combination with CYP3A4/5 inhibitors RESPOND-1 was a randomized, placebo-controlled,
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Drug Profile Trembling, Tanwar & Dusheiko
Table 1. Summary of the effect of boceprevir on coadministered all patients achieving negative RNA with
addition of boceprevir, while a less than
drugs.
1 log10 drop resulted in 20% success rates.
Coadministered drugs (class) Interactions/guidelines
Although the numbers were small (and the
Midazolam (oral benzodiazepine) Coadministration contraindicated due to significant data quality compromised by multiple
changes in exposure protocol amendments in this study), these
Drospirenone/ethinyl estradiol (oral Drospirenone-containing medications should be data supported the use of a lead-in phase of
PEG IFN and RBV prior to commencing
contraceptive) avoided in patients at risk of hyperkalemia
Efavirenz (antiretroviral) Plasma trough levels of boceprevir were decreased boceprevir. Antiviral activity was shown to
be dose related, with 800 mg t.i.d. result-
when administered with efavirenz
ing in the most rapid reduction in RNA
Amiodarone, flecanide, Likely to result in significant interactions, hence
concentration.
propafenone, quinidine coadministration with boceprevir contraindicated
A Phase II, open-label, randomized
(antiarrhythmics)
controlled trial in the USA, Canada and
Pimozide (antipsychotic) Likely to result in significant interactions, hence
Europe (SPRINT-1) evaluated the safety
coadministration with boceprevir contraindicated
and efficacy of boceprevir in combina-
Alprazolam, midazolam, triazolam Close clinical monitoring for both respiratory
tion with PEG IFN and RBV in previ-
(intravenous benzodiazepines) depression and prolonged sedation required, ously untreated adults with genotype 1
dosage adjustment should be considered
infection [25]. The first part of the study
Dihydroergotamine, ergonovine, Likely to result in significant interactions, hence
assessed treatment durations of 28 weeks
ergotamine, methylergonovine coadministration with boceprevir contraindicated and 48 weeks, with and without a 4-week
(ergot derivatives)
introduction (lead-in period) of PEG
Methadone (opiate) Likely to result in a decrease of the coadministered
IFN and RBV. The second part of the
drug and, thus, caution is advised study assessed the effect of a lower dose
Paroxetine, sertraline, escitalopram Likely to result in a decrease of the coadministered of RBV on efficacy and anemia. Part one
(selective serotonin reuptake drug and, thus, caution is advised consisted of five treatment groups. All
inhibitors) patients received PEG IFN and RBV for
HMG-CoA reductase inhibitors Avoid simvastatin and lovastatin. Approximately 48 weeks. Two groups received PEG IFN
130 and 60% increase in the exposure of and RBV for 4 weeks followed by PEG
atorvastatin and pravastatin, respectively. Close IFN, RBV and boceprevir 800 mg t.i.d. for
clinical monitoring recommended. Maximum daily
24 or 44 weeks (n = 103 and 103, respec-
dose of atorvastatin of 20 mg recommended
tively). Two groups received PEG IFN,
Data from [101].
RBV and boceprevir 800 mg t.i.d. for 28
dose-finding study in 357 CHC genotype-1-infected patients or 48 weeks, without a lead-in (n = 107 and 103, respectively).
who were nonresponders to previous PEG IFN and RBV treat- The control group received PEG IFN and RBV for 48 weeks
ment. Ascending doses of boceprevir (100–800 mg t.i.d.) were (n = 104).
tested in combination with PEG IFN with or without RBV [24]. Part two consisted of two groups, one receiving PEG IFN
A control group, given PEG IFN, RBV and placebo crossed and RBV (800–1400 mg daily) for 48 weeks (the control group,
over to active boceprevir at week 17 if viral RNA was detect- n = 16), and the other receiving PEG IFN, boceprevir and low-dose
able at week 12. A review by the Data Review Advisory Board RBV (400–1000 mg daily; n = 59).
identified poor efficacy in recipients of the lower boceprevir The primary end point was SVR. Patients in all four bocepre-
doses and development of resistance in the groups without vir groups achieved higher rates of SVR than the control group.
RBV. All patients who demonstrated a response (HCV RNA SVR in the part one control group was 38%. SVR was achieved
<1000 IU/ml) were switched to PEG IFN, RBV and bocepre- in 56% of the lead-in 28-week group (p = 0.005 vs control) and
vir at a dose of 800 mg t.i.d. for 24 weeks. SVR rates ranged 54% in the non-lead-in group (p < 0.013 vs control). SVR rates
between 6 and 32%, and were higher in the PEG IFN/RBV/ of 75% in the 48-week lead-in, and 67% in the non-lead-in group
boceprevir 400 mg t.i.d. and PEG IFN/boceprevir 800 mg t.i.d. were observed (p < 0.0001 vs control and p < 0.0001 vs control,
groups, and highest in the control group where boceprevir was respectively). SVR rates were only 36% in the low-dose RBV
added. This study suggested that in previous nonresponders, (48-week) group. Low-dose RBV was also associated with high
boceprevir exerted antiviral activity and was safe, and con- relapse and viral breakthrough rates.
firmed that RBV was required to optimize efficacy and prevent In this study SVR rates were higher in subjects achieving an
resistance. Retrospective analysis of the control group where undetectable HCV RNA at week 4, regardless of total treat-
boceprevir was added found that the response to its addition was ment duration. Lower viral breakthrough and relapse rates were
predicted by the PEG IFN/RBV-induced response at week 12. observed in the lead-in arms. These data provided the rationale
A greater than 2 log10 drop in HCV RNA at week 12 resulted in for a lead-in phase in subsequent Phase III trials.
272 Expert Rev. Anti Infect. Ther. 10(3), (2012)
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Table 2. Summary of efficacy studies of boceprevir.
Study/trial Patients (n) Study design Patients Boceprevir Comparator Duration of Results Ref.
name (year) regimen treatment
Zeuzem et al. 61 Randomized, HCVg1-infected Previously 100, 200 or 400 mg Placebo 14 days Dose-dependent reduction in [22]
(2005) placebo-controlled, failed to achieve <2 log10 twice daily, or viral load
multicenter, reduction in RNA at 400 mg t.i.d.
double-blind 12 weeks with PEG IFN-a
Sarrazin et al. 26 Randomized, HCVg1-infected 200 or 400 mg t.i.d. PEG IFN Boceprevir Dose-related reduction in viral [7]
(2007) placebo-controlled Nonresponders - for 1 week, and with monotherapy load, well tolerated in previous
multicenter, previously achieved PEG IFN for 2 weeks 1 week, PEG IFN nonresponders
open-label, <2log10 reduction in RNA monotherapy
cross-over after at least 12 weeks 2 weeks,
with PEG IFN-a2b ± RBV combination
therapy 2 weeks
Schiff et al. 357 Randomized, HCVg1-infected null- 100, 200, 400 or PEG IFN and Up to 49 weeks Dose-related antiviral activity, [24]
(2008) placebo-controlled, responders, <2 log10 800 mg t.i.d. (or RBV confirmed need for RBV and
multicenter, reduction in RNA after placebo) with PEG demonstrated efficacy of lead-in
cross-over (to 12 weeks or failure to IFN and RBV phase
boceprevir at achieve undetectable (800–1400 mg daily)
week 17 for RNA if treated for more (or placebo)
detectable RNA at than 12 weeks with PEG
week 12) IFN and RBV
Kwo et al./ 595 Part 1 Randomized HCVg1-infected, treatment 800 mg t.i.d., with or PEG IFN and 24 or 44 weeks Higher SVR rates in lead-in arms [25]
SPRINT-1 520 open-label, naive without lead-in, for RBV (28 or 48 weeks 75 and 56% SVR rates in 28-
(2010) multicenter 24 or 44 weeks with for lead-in and 48-week groups,
PEG IFN and RBV groups) respectively, compared with
38% in control group
Undetectable HCV RNA at
week 4 of boceprevir (rapid
virological response) predicted
SVR
Part 2 800 mg t.i.d. with 48 weeks Lower dose RBV associated with
75 PEG IFN and RBV lower SVR rate, increased viral
(600–1000 mg daily) breakthrough and higher relapse
rates
HCVg1: HVC genotype 1; PEG IFN: Pegylated interferon; RBV: Ribavirin; RGT: Response-guided therapy; SVR: Sustained virological response; t.i.d.: Three times daily.
Boceprevir: an oral protease inhibitor for the treatment of chronic HCV infection Drug Profile
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Table 2. Summary of efficacy studies of boceprevir (cont.).
Study/trial Patients (n) Study design Patients Boceprevir Comparator Duration of
name (year) regimen treatment
Poordad 1097 Randomized, HCVg1-infected, treatment 800 mg t.i.d. with PEG IFN-a2b Up to 48 weeks
et al./ Cohort 1: double-blind, naive PEG IFN-a2b and and RBV,
SPRINT-2 938 non-black placebo-controlled, RBV, following following
(2011) subjects multicenter 4-week lead-in with 4-week
Cohort 2: PEG IFN-a2a and lead-in with
159 black RBV PEG IFN-a2a
subjects and RBV
Results Ref.
Overall, SVR rates were 66% in [26]
boceprevir 48-week group, 63% in RGT group and 38% in control group
In the non-black patient groups, SVR rates were 69% in the boceprevir 48-week group, 67% in the RGT group and 40% in the control group. SVR rates in the corresponding black patient groups were 53, 42 and 23%, respectively
Expert Rev. Anti Infect. Ther. 10(3), (2012)
Bacon et al./ 403 Randomized, HCVg1-infected 800 mg t.i.d. with PEG IFN-a2b Up to 48 weeks SVR rates were 66% in the [27]
RESPOND-2 double-blind, Nonresponders: PEG IFN-a2b and and RBV, boceprevir 48-week group, 59%
(2011) placebo-controlled, previously achieved RBV, following following in the RGT group and 21% in
multicenter ≥2 log10 decrease in RNA 4-week lead-in with 4-week the control group, in previously
at 12 weeks, but PEG IFN-a2a and lead-in with treated patients
detectable during RBV PEG IFN-a2a
treatment and RBV
Relapsers: undetectable
at end of treatment, but
detectable at follow-up;
both with PEG IFN/RBV
Flamm et al. 201 Randomized, HCVg1-infected 800 mg t.i.d. with PEG IFN-a2a Up to 48 weeks SVR rates similar to identical [28]
(2011) double-blind, Nonresponders and PEG IFN-a2a and and RBV, regimen with PEG IFN-a2b, in
placebo-controlled, relapsers (as defined in RBV, following following previously treated patients
multicenter RESPOND-2) 4-week lead-in with 4-week
PEG IFN-a2a and lead-in with
RBV PEG IFN-a2a
and RBV
HCVg1: HVC genotype 1; PEG IFN: Pegylated interferon; RBV: Ribavirin; RGT: Response-guided therapy; SVR: Sustained virological response; t.i.d.: Three times daily.
DrugProfileTrembling, Tanwar & Dusheiko
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Review of Anti-infective Therapy and telaprevir .†
Expert boceprevir
Table 3. Safety data for
ADVANCE [33]
REALIZE [32]
RESPOND-2 [27]
SPRINT-2 [26]
Data
Control 361
Telaprevir 8 weeks 364
Telaprevir 12 weeks 363
Control 132
Telaprevirfixedduration with lead- in 264
Telaprevir fixed duration 266
Boceprevir fixed duration 161
Boceprevir RGT 162
Control 80
Boceprevir fixed duration 366
Boceprevir RGT 368
Control 363
Patientscommencingtreatment(n)
7
9
9
5
12
12
14
5 10
12
9 11
events (%) Serious adverse
10 10 7
3
4
6
12
3 8
16
16 12
events (%) due to adverse Discontinuation
F (57) P (36) H (39)
F (58) P (45) H (43)
F (57) P (50) N (43)
F (40) H (37) As (29)
F (50) P (50) H (41)
F (55) P (52) H (42)
F (57) A (46) D (45)
F (54) N (44) A andD(both 43)
F (50) H (48) N (38)
F (57) A (49) H (46)
F (53) A (49) N (48)
F (60) H (42) N (42)
Three most common adverse events(%)
37 35 24
19
36
37
14
5 17
24
Rash (%) 23 25
37 39 19
15
36
30
46
20 43
49
Anemia (%) 29 49
trials as they were not head-to -head studies. P: Pruritus; RGT: Response -guided therapy.
compared across these Headache; N: Nausea;
Neither the efficacy nor adverse event profile can be† A: Anemia; As: Asthenia; D: Dysgeusia; F: Fatigue; H:
Phase III studies
These superiority studies were designed to detect differences in SVR rates between two boceprevir strategies (response-guided and fixed duration) versus PEG IFN/RBV (SOC).
SPRINT-2 was a randomized, placebo-controlled study designed to establish whether addition of boceprevir to PEG IFN and RBV could improve rates of SVR in previously untreated patients infected with HCV genotype 1 [26]. Due to the differences observed in SVR with PEG IFN, black subjects and non-black subjects were enrolled separately in two cohorts. Subjects were randomized to three groups. All groups received a lead-in phase of PEG IFN-a2b and RBV for 4 weeks. Group one, the control group, received placebo from week 5 for 44 weeks. Group two, the response-guided therapy (RGT) group, added boceprevir 800 mg t.i.d. to the regimen at week 5 and treatment continued for a further 24 weeks. Patients with detectable HCV RNA, at any time between weeks 8 and 24, received placebo, PEG IFN and RBV from week 28 to week 48. If HCV RNA was undetect-able between weeks 8 and 24, all treatment was discontinued at week 28. In group three, patients received boceprevir at week 5, and continued treatment for a further 44 weeks. Treatment was discontinued for futility if HCV RNA was detectable at week 24.
Overall, combining black and non-black cohorts, SVR rates were significantly higher than SOC in the boceprevir groups (38, 63 and 66% in groups one, two and three, respectively). Relapse rates were lower in the boceprevir groups (22.2, 9.3 and 9.1% in groups one, two and three, respectively). SVR rates were lower in black patients compared with non-black patients in all groups. In addition to non-black race, geno-type 1b, baseline HCV RNA ≤400,000 IU/ml and absence of advanced fibrosis were all significantly associated with SVR. PEG IFN responsiveness at the end of the lead-in phase (≥1 log10 drop in HCV RNA) was a strong predictor of SVR, and resulted in lower rates of boceprevir resistance-associated mutations. However, regardless of the 4-week PEG IFN response, SVR rates were higher in the boceprevir groups compared with controls.
The two boceprevir treatment strategies were compared. The percentage of patients with undetectable HCV RNA levels at week 8 who had SVR, was high in both treatment groups (88 and 90% in groups two and three, respectively), suggesting that 24 weeks of boceprevir – RGT strategy – is as effective as 44 weeks of boceprevir for early responders. For late responders (HCV RNA detectable at week 8), a longer duration of triple therapy is beneficial.
RESPOND-2 assessed the effect of the combination of boceprevir, PEG IFN-a2b and RBV of the re-treatment of patients with HCV genotype 1 infection [27]. Patients were eligible if they had previously experienced a ≥2 log10 drop in HCV RNA after 12 weeks of standard care but failed to achieve SVR. Both nonresponders (decline in HCV RNA by ≥2 log10 by week 12 but with detectable HCV RNA during the treatment period) and relapsers (undetectable HCV RNA at
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the end of treatment, but subsequent detection during follow-up) were included. Null responders (<2 log10 drop in HCV RNA at week 12) were excluded.
All groups commenced with a 4-week lead-in period. Group one (control) continued PEG IFN-a2b and RBV with placebo boceprevir for 44 weeks. Group two (RGT) received boceprevir 800 mg t.i.d. with PEG IFN and RBV for 32 weeks. Those with undetectable HCV RNA at weeks 8 and 12 stopped all treatment at week 36; however, those with detectable HCV RNA at week 8 (undetectable at week 12) continued to treat-ment week 48. Group three received boceprevir with PEG IFN and RBV for 44 weeks. Treatment was stopped in any patient with detectable HCV RNA at week 12. This study found that addition of boceprevir resulted in high rates of SVR (59% in group two, 66% in group three) compared with controls (21%). SVR rates in previous relapsers were 69 and 75% in groups one and two, respectively and 40 and 52%, in previous non responders. Again, PEG IFN response at 4 weeks predicted SVR, with rates in boceprevir groups higher than controls, in poor and good PEG IFN responders. Early response, at week 8, was associated with higher rates of SVR, and was more com-mon – and similar – in the boceprevir groups. Overall, there was no significant difference in SVR rates in groups two and three.
Using identical inclusion criteria to RESPOND-2, the SVR rate in a substudy of PEG IFN-a2a was assessed in 201 relaps-ers and nonresponders [28]. The two groups received a 4-week lead-in of PEG IFN-a2a and RBV, followed by either the addi-tion of boceprevir or placebo for 44 weeks. Treatment was dis continued if HCV RNA was detectable at week 12. SVR rates were 64% in the active group and 21% in the control group. Again, PEG IFN responsiveness predicted outcome; for those with less than a 1 log10 decrease in HCV RNA after lead-in, 0% (zero out of nine patients) and 39% (seven out of 18 patients) achieved SVR in the control and active groups, respectively. For those with a 1 log10 decrease or more, the SVR rates were 25% (14 out of 57) and 71% (79 out of 112), respectively. Table 2 presents efficacy data for Phase II and III trials.
PROVIDE is a single-arm, multicenter study recruiting patients who did not achieve a SVR whilst in a control arm of a boceprevir study (including discontinuation due to a futility rule, virologi-cal breakthrough or relapse). The study has assessed the effect of boceprevir in patients classified as null responders to PEG IFN and RBV. SVR responses have been reported [29]. In PROVIDE boceprevir was given with PEG IFN and RBV for up to 44 weeks following a 4-week lead-in of PEG IFN and RBV. Forty-eight null responders were enrolled. The primary end point was SVR. Overall SVR in this small study was 38%. SVR was associated with HCV RNA decline at the end of the lead-in period; 50% SVR was seen in those with ≥1 log10 decline in HCV RNA and 34% SVR in those with <1 log10 decline in HCV RNA. More information is needed in patients with prior null response and cirrhosis.
Impact of IL-28B genotype
Retrospective pooled analyses of the Phase III studies are now underway. These include the effect of a single nucleotide
polymorphism near the IL-28B gene on SVR rates. A favorable genotype at this site (CC gene allele compared with CT or TT) is associated with a significantly higher rate of SVR [11]. An ana lysis of SPRINT-2 and RESPOND-2 found that in SPRINT-2, the CC haplotype was associated with higher SVR rates than the other genotypes in both the boceprevir and the control groups
[30] . In RESPOND-2 there were higher SVR rates with all geno-types in the boceprevir groups compared with controls. Pooled data confirmed IL-28B genotype is a strong predictor of viral response at week 4 and week 8, and of SVR even in the presence of boceprevir.
Safety & tolerability
Most patients in the Phase III studies experienced AEs, with fatigue, headache and nausea being most commonly reported. Frequencies of these AEs were comparable in SOC and bocepre-vir-treated groups [26,27]. A recent study analyzed safety data in 1548 patients who had received boceprevir with PEG IFN and RBV and 547 patients who had received PEG IFN and RBV alone in SPRINT-1, SPRINT-2 and RESPOND-2
[31] . The safety profiles were similar for treatment-naive and previously treated patients. Boceprevir was associated with significantly increased anemia, neutropenia and dysgeusia. Thrombocytopenia was seen in 4% of boceprevir-treated patients compared with 1% in the SOC groups. Toxicity did not limit treatment duration in either group, although dose modifications were more common in the boceprevir groups (mainly PEG IFN adjustments).
Table 3 summarizes the AE characteristics in the Phase III studies, and also presents AE data from Phase III studies of telaprevir (REALIZE and ADVANCE) [32,33]. Anemia was a notable AE in the boceprevir studies, and rash was notable in the telaprevir studies. Neither the efficacy nor AE profile can be compared across these trials, however, as they were not head-to-head studies.
Regulatory affairs
Boceprevir was granted US FDA approval in May 2011 and received approval from the EMA in July 2011. This market-ing authorization is valid in all European states in addition to the Free Trade Association states; Iceland, Liechtenstein and Norway. To date, boceprevir has been launched in the UK, France, Germany, Italy and Spain. Health Canada also approved boceprevir in July 2011.
Dosage & administration
The EMA has approved the use of boceprevir for the treatment of CHC genotype 1 infection, in combination with PEG IFN-a and RBV, in adult patients with compensated liver disease who are treatment naive or who have failed previous therapy.
In treatment-naive patients, treatment is initiated with PEG IFN-a2b or PEG IFN-a2a and RBV for 4 weeks (treatment weeks 1–4). Boceprevir 800 mg orally t.i.d. is added to the regimen at treatment week 5. For patients without cirrhosis who are previously untreated, HCV RNA is measured at treatment
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weeks 8 and 24; if HCV RNA is undetectable from week 8 to 24, all treatment can be discontinued at week 28. If RNA is detectable at week 8 and undetectable at week 24, triple therapy is continued to the end of treatment week 36; PEG IFN and RBV are continued to treatment week 48.
For patients who have failed previous therapy, if HCV RNA is undetectable at treatment week 24, triple therapy is continued until the end of treatment week 36, and PEG IFN and RBV is continued until the end of treatment week 48.
For patients with cirrhosis and prior null responders (i.e., those who had less than a 2 log10 reduction in HCV RNA at treat-ment week 12), following a 4 week lead-in phase, boceprevir 800 mg t.i.d. should be added and continued together with PEG IFN and RBV for a further 44 weeks. Although null responders were excluded from the Phase III trial, in view of the high cor-relation of lead-in phase poor PEG IFN responders and treat-ment week 8 HCV RNA detection, poor PEG IFN responders were considered representative of null responders [21,101]. More recently, a secondary study has provided information on prior null responders [29].
All treatment should be stopped if any patient has a HCV RNA concentration of 100 IU/ml or higher at treatment week 12 to avoid complex resistance. If HCV RNA is detected at treatment week 24, treatment should be stopped for futility because of the low likelihood of a SVR.
Conclusion
Adding boceprevir to PEG IFN-a2b (or PEG IFN-a2a) and RBV treatment significantly increases SVR rates in both treat-ment-naive and treatment-experienced patients with CHC geno-type 1 infection. The lead-in period can indicate the likelihood of SVR in both treatment-naive and previously treated patients, and in those with a poor PEG IFN response, addition of boceprevir significantly increases SVR rate.
Expert commentary
Boceprevir increases the SVR rate in combination with PEG IFN and RBV in both treatment-naive and prior nonresponders. The drug regimen has an acceptable toxicity, against a background of PEG IFN and RBV toxicity. The backbone of PEG IFN and RBV is still required. Response rates are impaired in patients with cirrhosis and/or prior null responses, and these patients require a longer duration of treatment. Response rates differ between subtype 1a and 1b. Higher rates of anemia may be problem-atic in some patients and will require careful monitoring and management.
Further guidance, derived from cohort studies, is required to aid clinicians in the appropriate use of this new therapy. The cost of treatment is increased with the addition of boceprevir. The optimal use of boceprevir versus SOC in patients with a rapid virological response requires further evaluation, in order to maximize the utilization of resources to treat CHC; in par-ticular to highlight which patients do not require a DAA. The relevance and implications of resistance are as yet uncertain, but there are concerns that some patients, particularly those
with advanced fibrosis may be disadvantaged by the develop-ment of resistance to the DAA class. Stopping rules may limit complex resistance. Adherence will require close monitoring. Clinicians will be required to carefully weigh up the risks versus the benefits of treatment in prior null responders with a poor response to PEG IFN after the lead-in.
Five-year view
The protease inhibitors boceprevir and telaprevir are the first DAAs to be licensed by the US FDA and EMA for the treatment of CHC genotype 1 infection. Shorter duration treatment with boceprevir may be possible for patients with innate sensitivity to PEG IFN. Further drug–drug interaction data will be required to utilize boceprevir for liver-transplant recipients. Regimens active against first generation protease inhibitor resistance-associated variants will soon be required. Drug development for the treat-ment of HCV infection will continue to focus on difficult-to-treat populations.
Improved treatments for patients with cirrhosis are required. Boceprevir is likely to be replaced in the next few years by second generation protease inhibitors. Advances in the understanding of the structure and life cycle of HCV have accelerated the devel-opment of potential novel therapeutic strategies. In addition to protease inhibitors, nucleoside and non-nucleoside polymerase inhibitors, NS5a inhibitors, cyclophilin inhibitors and immuno-modulatory therapies including Toll-like-receptor agonists and entry inhibitors are being developed [34]. Although RBV may remain an integral part of next generation therapeutic regimens, there is a realistic possibility of developing PEG IFN-free oral combinations.
There is about to be a paradigm shift in the treatment of CHC. The expectations are high; very high SVR rates, achieved with drugs that have pan-genotypic activity, high potency, a high barrier to resistance and once-daily dosing are all anticipated.
PEG IFN-free regimens will also facilitate the treatment of patients in special groups such as those with decompensated cirrhosis, liver-transplant recipients, patients with renal failure, HIV–HCV co-infected patients and patients on methadone substitution programs.
Financial & competing interests disclosure
GM Dusheiko is on the advisory board, is involved in protocol development and acts as investigator in studies for Vertex, Abbott, Boehringer Ingelheim, Bristol Myers, Gilead Sciences, GlaxoSmithKline, Novartis, Pharmasett, Merck and Tibotec. He has also received consulting fees from Abbott, Boehringer Ingelheim, Bristol Myers, Gilead Sciences, GlaxoSmithKline, Human Genome Sciences, Novartis, Pharmasett, Pfizer, Roche/Genentech, Schering Plough/Merck and Tibotec. His institution has received funding for research studies from the above groups. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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Key issues
• Boceprevir, an oral protease inhibitor, is approved by the US FDA and the EMA for the treatment of chronic hepatitis C genotype 1 infection, in combination with pegylated IFN and ribarvirin, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.
• In both treatment-naive and treatment-experienced patients, rates of sustained virological response were higher when boceprevir was added to standard therapy of pegylated IFN and ribavirin.
• The most significant adverse events associated with boceprevir treatment were anemia, neutropenia and dysgeusia.
• IFN response at week 4 of the lead-in phase predicts response, and week 8 HCV RNA levels can guide treatment duration.
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References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
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•• Demonstrated higher sustained virological response (SVR) rates with addition of boceprevir, and demonstrated benefit of lead-in period of peginterferon and ribavirin prior to adding boceprevir. Demonstrated the lower SVR rates and higher rates of relapse and viral breakthrough with lower doses of ribavirin.
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•• Phase III study in treatment-naive patients demonstrating significant improvement in SVR rates with addition of boceprevir.
27 Bacon BR, Gordon SC, Lawitz E et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N. Engl. J. Med. 364(13), 1207–1217 (2011).
•• Phase III study in patients who previously failed treatment, showing improvement in SVR rates with addition of boceprevir compared to retreatment with standard of care.
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