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Faldaprevir for the treatment of genotype-1 hepatitis C virus Expert Rev. Gastroenterol. Hepatol. 9(3), 277–288 (2015)
Kosh Agarwal* and Ashley Barnabas Kings College Hospital, Institute for liver studies, London, UK *Author for correspondence: [email protected]
Historically, pegylated interferon in combination with ribavirin was the standard of care in hepatitis C virus; however, this combination is often poorly tolerated, has a significant side-effect profile and is of limited efficacy in hepatitis C virus genotype-1. More recently, pegylated interferon/ribavirin has been combined with direct acting antiviral agents such as the first generation NS3/4A protease inhibitors. Faldaprevir, a first generation, second-wave protease inhibitor, when used with a pegylated interferon/ribavirin regimen, has also been shown to increase treatmentsuccess while shortening treatment duration; however, second generation direct acting antiviral agents offer even betterefficacy and tolerability. Various direct acting antiviral agent combinations in interferon-free regimens have been effective in over 95% of patients and are now in licensed use. While faldaprevir was a pioneering drug, by the time it reached late phase development it was superseded by newer agents. KEYWORDS: boceprevir . faldaprevir . hepatitis C . liver transplantation . pegylated interferon . ribavirin . simeprevir .
telaprevir
Overview
About 2–3% of the world’s population (130–170 million people) is chronically infected with the hepatitis C virus (HCV) [1,2]. There are six major genotypes of HCV. Genotype 1 is the most prevalent in much of the developed world and accounts for 73% of cases in the USA [1]. Acute infection with HCV results in chronic HCV in 70% of patients. Between 5 and 25% of patients infected with chronic infection will progress to cirrhosis within 20 years. Once cirrhosis develops, there is a 3–6% annual risk of hepatic decompensation and a 1–5% annual risk of developing hepatocellular carcinoma [3,4]. If cure from HCV infection could be achieved, liver fibrosis undergoes partial reversal, life expectancy improves and the risk of developing hepatocellular carcinoma is markedly reduced [5,6]. Prior to the advent of directacting antiviral agents (DAAs), the goal of virological cure could be achieved in fewer than half of patients infected with HCV. Most long-term follow-up data in patients treated for HCV has been published in patients treated with pegylated interferon (PEG IFN)/ ribavirin (riba). PEG-IFN targets the host immune system, and it is felt that riba has a similar mode of action. The HCV informahealthcare.com
10.1586/17474124.2015.1001742
virus encodes three structural and seven nonstructural proteins. DAAs, as the name implies, are designed to act specifically against HCV at one of three well-conserved nonstructural proteins: . . .
NS 3/4A protease NS 5A replication complex NS5B polymerase
Should a patient persist with an undetectable HCV RNA viral load 24 weeks after completing HCV treatment (sustained virological response for 24 weeks, SVR24), permanent eradication of HCV with PEG IFN/riba can be assumed [7]. In patients with an undetectable viral load 12 weeks after completing treatment in DAA-containing PEG IFN/riba regimens (sustained virological response at week 12, SVR 12), virological relapse thereafter is rare, and now SVR12 is accepted as a equivalent to virological cure [8]. PEG-IFN/riba treatment is effective in less than half of patients infected with HCV. It is also extremely resource intensive, which has historically limited access to treatment. Since the introduction of DAAs in 2011, however, drug development has been relentless, with successive generations of DAAs rendering recently marketed drugs obsolete within intervals as brief as 2 years. Not only are cure rates
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Drug Profile
Agarwal & Barnabas
higher, but resource utilization has been dramatically reduced by IFN-free DAA regimens. In patients with HCV genotype 1 disease, current treatment regimens offer up to a 68–89% chance of cure, dependent on pre-treatment factors. At present, most treatment regimens with marketing authorization in the USA and Europe consist of a single DAA agent in combination with PEG IFN/riba, unless a patient is IFN ineligible or IFN intolerant. The first wave, first-generation protease inhibitors telaprevir and boceprevir, as well as the second-wave, first-generation protease inhibitor simeprevir are commercially available in North America and Europe. Sofosbuvir, a nucleotide analogue NS 5B polymerase inhibitor, has also received marketing authorization in these regions. A single pill, fixed-dose combination of sofosbuvir and ledipasvir, an NS5A inhibitor, is likely to be licensed in the third quarter of this year in a PEG-IFN-free regimen. Telaprevir and boceprevir were the first commercially available DAAs. They achieve 68–75% cure rates in patients who have not previously been treated. These response rates are better, as high as 88%, in patients who have relapsed following previous treatment with PEG IFN/riba [9]. Response rates are poor in treatment-experienced patients who have had a partial or null virological response to PEG IFN/riba previously. Both tolerability and therapeutic efficacy are reduced in more advanced liver disease [10]. Ironically, the subset of the sickest patients in this group, who potentially stand to gain the most from being cured, will often be too sick to tolerate IFN. Of drugs currently licensed, sofosbuvir appears to be the most potent DAA. A 12-week course of PEG IFN and riba in combination with sofosbuvir has been shown to offer much improved SVR rates of 89% in treatment-naı¨ve patients [11]. Genotype 1b patients, however, had a lower SVR rate than genotype 1a patients (82 vs 98%). Patients with compensated cirrhosis also had a lower SVR rate, at 80%. Whilst efficacy of this regimen in treatment-experienced patients, co-infected patients and liver transplant recipients (LTRs) is not known, sofosbuvir has a very high genetic barrier to resistance and is very well tolerated. Sofosbuvir is highly effective in IFN-free regimens. When combined with various other DAAs, an SVR rate in excess of 95% in IFN-free regimens, even in previously difficult to treat populations, has been shown in genotype 1 disease [12,13]. Areas of need
Currently, the greatest urgency for HCV treatment exists in patients who have failed HCV treatment and have cirrhosis. Several studies have also highlighted the poor tolerability and reduced efficacy of boceprevir and telaprevir in this population. In the French early access cohort of patients with cirrhosis, 511 treatment-experienced patients were retreated with either boceprevir or telaprevir in combination with PEG IFN/riba. 54–76% of patients with previous relapse 38–40% of partial responders and 0–19% of previous null responders were cured. 49% of patients experienced a serious adverse event (SAE), 21% of patients discontinued treatment due to SAEs and 2.2% 278
of patients died whilst receiving treatment [10]. By contrast, a landmark IFN-free study of 380 patients with compensated HCV cirrhosis has demonstrated cure rates in excess of 90% with a three-drug IFN-free regimen, with remarkably good tolerability [14]. This tolerability is substantiated by a reduction in resource utilization whilst on treatment, even in this historically difficult to treat cohort. 15–30% of patients infected with HIV are co-infected with HCV [15,16]. This prevalence is even higher in HIV-positive intravenous drug users. HIV appears to have multiple permissive effects on HCV infection, with lower rates of spontaneous resolution of infection, higher HCV viral loads and low success rates with IFN-based treatment regimens. Meta-analysis suggests that HIV co-infection doubles the likelihood that an individual will progress to cirrhosis and makes it up to six-times more likely that an individual will develop decompensated liver disease. Immune reconstitution with highly active antiretroviral treatment only partially ameliorates these effects [17]. Cure rates with PEG IFN/riba treatment are as low as 21–29% [18,19] in genotype 1 HCV. Even in affluent countries, only a small proportion of co-infected patients are treated for HCV. Data here also suggest that IFN-free treatment will be an effective strategy [20]. HCV infection is now the commonest indication for liver transplantation in the USA and western Europe. HCV recurrence in LTRs is universal. Progression to cirrhosis thereafter is accelerated. Between 20 and 30% of LTRs will have graft cirrhosis at 5 years after liver transplantation. In LTRs with genotype 1 HCV, only 13–30% of patients will be cured with PEG IFN/Riba [21]. Coilly et al. have reported a multicentre cohort study in which a first-generation protease inhibitor (boceprevir or telaprevir) was used in addition to PEG IFN/riba in 47 patients [22]. The observed SVR rate was 50%. However, 43% of patients discontinued treatment and three patients died whilst receiving treatment. Current EASL guidelines do not advocate the use of telaprevir or boceprevir after liver transplantation. It is clear that more tolerable and effective treatments for LTRs is a key area of need, and this is one of the patient groups that should be prioritized for early access to new agents. Furthermore, Curry et al. have demonstrated that the combination of sofosbuvir and riba prevents graft orthotopic liver transplantation (OLT) recurrence when given to patients waitisted for OLT [23]. HCV is a common cause of morbidity in the hemodialysis population. Its prevalence varies between 5 and 80 % in hemodialysis patients in different countries [24,25]. HCV treatment with PEG IFN, with or without riba, is often poorly tolerated and much less effective with overall SVR rates of 38% and treatment discontinuation rates as high as 15% [26]. DAAs that can be used in end-stage renal failure will thus have an important role to play. As 50% of patients treated with PEG IFN/riba will not be cured, a significant pool of patients that have failed treatment has accumulated. These patients can be characterized as: Expert Rev. Gastroenterol. Hepatol. 9(3), (2015)
Faldaprevir for the treatment of genotype-1 HCV
.
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.
Relapsers: Patients who had an undetectable HCV RNA viral load at the end of PEG IFN/riba treatment, but subsequently had a detectable HCV viral load. Partial responders: Patients who demonstrated some response to PEG IFN/riba treatment, but were never HCV RNA negative on treatment. Null responders: Patients who did not demonstrate virological response to PEG IFN/riba treatment, as defined by a less than two log decline in HCV RNA 12 weeks after starting antiviral treatment.
Studies including all three groups will be discussed
The greatest challenge in HCV is in making effective treatment and well-tolerated treatments available to all patients. Screening, referral and treatment rates remain low, despite guidelines. After referral, the upfront costs of DAA treatment are high, but need to be balanced against long-term outcomes. Faldaprevir Faldaprevir
Faldaprevir is a non-covalently binding, linear HCV NS3/4a protease inhibitor. In vitro, it has potent antiviral activity and is highly specific to HCV genotypes 1, 2, 4 and 6 [27]. Faldaprevir has a pharmacokinetic profile that makes oncedaily dosing a feasible option, unlike both boceprevir and telaprevir. In a double-blind multiple-rising dose Phase I study, its half-life was 20–30 h and steady state was reached in 120 h [28]. When faldaprevir is given as monotherapy, its trough concentration correlates well with both dosage and decrement in viral load in the first 6 days of treatment. The relationship between dose exposure and plasma serum concentration is moderately variable. The measured coefficient of variation for AUC (0-t) is as high as 65%. Pharmacokinetic parameters for faldaprevir are similar in patients without cirrhosis and those with compensated cirrhosis. There do not appear to be significant drug–drug interactions between faldaprevir and PEG IFN/riba. A single-dose phase one study has suggested that faldaprevir dose adjustment is not required in severe renal impairment [29]. Faldaprevir is a moderate inhibitor of cytochrome p450 3A4. It also has inhibitory effects on cytochromes CYP2C9 and UGT1A1. It does not have significant interactions with methadone or buprenorphine or naloxone [30]. However, exposure to the combined oral contraceptive, more specifically the combination of ethinyloestradiol and levonorgestrel, is moderately increased by faldaprevir [31]. Faldaprevir is also a substrate of CYP3A4 and may need dose adjustment with highly active antiretroviral treatment in co-infected patients. In patients treated with efavirenz, faldaprevirhas been studied at the higher dose of 240 mg once daily, whereas a 120 mg daily dose has been studied in patients being treated with the HIV protease inhibitors daurunovir/ritonovir, or atazanavir [32]. TABLE 1 summarizes clinical trial data for faldaprevir in PEG IFN/ribaregimens. informahealthcare.com
Drug Profile
Summary of Phase I & II data Phase I BI1220.2
Unpublished work suggested that in doses between 20–240 mg once daily, faldaprevir would be well tolerated for up to 28 days. In a Phase Ib dose finding study (BI1220.2), 34 treatment naı¨ve patients received either placebo or faldaprevir at doses of 20–240 mg once daily for 14 days. Nineteen treatment-experienced patients received faldaprevir at doses of 48–240 mg once daily, with PEG IFN/riba for 28 days [28]. Viral load reduction in the monotherapy group was highest in the 240 mg group with a medium of decline of 4.4 log 10 IU/ml. Most patients experienced viral breakthrough during the 14 days of monotherapy. In the treatment-experienced arm, where a three-drug regimen was used, five of the six patients treatment with faldaprevir 240 mg once daily had an undetectable viral load 28 days after starting treatment. There was no virological breakthrough on treatment in the 240 mg dosage group. However, two of the six patients treated with the 48 mg dose and one of the seven treated with 120 mg of faldaprevir once daily developed virological breakthrough on treatment. Based on these data, further studies have investigated 120 and 240 mg once-daily doses. Phase II Silenc1
The SILEN-C1 study (n = 429) was a Phase IIb double-blind trial of faldaprevir in 120 mg and 240 mg once-daily doses, with PEG IFN/riba, in comparison to a PEG IFN/riba control group [33]. In an attempt to minimize resistance to faldaprevir developing, this study incorporated a 3-day ‘lead-in’ of PEG IFN/riba dual therapy before their first dose of faldaprevir. Patients with cirrhosis were excluded from this study. All patients received 24 weeks of either faldaprevir or placebo. All patients received PEG IFN/riba for 24 to 48 weeks. In both 120 mg and 240 mg faldaprevir groups, 50% of patients were allocated to receive a 3-day lead-in of PEG IFN/rib and placebo before receiving their first dose of faldaprevir. 50% of patients allocated to 240 mg dosage arms were randomized to discontinue all treatment at week 24 if they had a maintained rapid virological response on treatment (mRVR). This was defined as a viral load below the lower limit of quantification at week 4, which remained undetectable thereafter up to week 20. Patient randomization was not stratified by HCV G1 subtype, due to laboratory limitations. At the time of study design, the relevance of IL-28B genotyping was not known, and this was also not included in randomization criteria. 56% of patients who received PEG IFN/riba and placebo achieved an SVR 24. 73% of patients in the 120 mg dose group achieved an SVR 24. 72% of patients who received a 3-day PEG IFN/riba lead-in, followed by 240 mg of faldaprevir daily, achieved an SVR 24. 84% of patients who received 240 mg of faldaprevir without a lead-in had an SVR 24. 279
Drug Profile
Agarwal & Barnabas
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Table 1. Outcomes of interferon-containing regimens with faldaprevir. Study
Comment
Subjects enrolled
Doseage arms
Duration of PEG IFN/riba (weeks)
SVR
SVR in G1a vs G1b
BI1220.2
Phase Ib dose-finding study
Silen-C1
Phase IIb double blind placebo controlled study
429 all treatment naı¨ve and non-cirrhotic
1:1:2:2 placebo 24 weeks + PEG IFN/riba 48 weeks
24–48 weeks (response guided in 240 mg faldaprevir arm)
Silen-C1
Phase IIb double blind placebo controlled study
71
Placebo 24 weeks + PEG IFN/riba 48 weeks
48
56.00%
not assigned at randomization
Silen-C1
69
FDV 120 mg q.d. 24 weeks (after 3 day LI) + PEN IFN/riba 48 weeks
48
73.00%
not assigned at randomization
Silen-C1
143
FDV 240 mg q.d. 24 weeks (after 3 day LI) + PEN IFN/riba 48 weeks
24–48
72.00%
not assigned at randomization
FDV 240 mg q.d. 24 weeks (no LI) + PEN IFN/riba 48 weeks (no RGT)
24–48
84.00%
not assigned at randomization
Silen-C1
Phase IIb double blind placebo controlled study
146
Silen-C2
Phase IIb double blind study
290 non-cirrhotic patients with previous null or partial response to PEG IFN/riba
Silen-C2
142 (40% previous null response)
FDV 240 mg q.d. 24 weeks (after 3 day LI) + PEN IFN/riba 24–48 weeks
24–48
40.00%
Silen-C2
76 (53%previous null response)
FDV 240 mg q.d. 24 weeks (no LI) + PEN IFN/riba 48 weeks (no RGT)
48
31.00%
Silen-C2
70 (54% previous null response)
FDV 240 mg BID 24 weeks (after 3 day LI) + PEN IFN/riba 24–48 weeks
48
22.00%
81
FDV 120 mg q.d. for 12 weeks (after 3 day LI) + PEG IFN/riba for 24–48 weeks
24–48
67.00%
53 vs 82%
79
FDV 120 mg q.d. for 24 weeks 9 after 3 day LI) + PEG IFN/riba for 24–48 weeks
24–48
74.00%
72 vs 75%
Silen-C2 Silen-C3 Silen-C3
Phase IIb open label study
Silen-C3
160
Silen-C3 Silen-C3 StartVERSO 1 and 2 StartVERSO 1 and 2
Phase III reported pooled analysis
1309 264
40 vs 23% Placebo + PEG IFN/riba 48 weeks
48
50%
PEG IFN: Pegylated interferon; riba: Ribavirin.
280
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Faldaprevir for the treatment of genotype-1 HCV
Drug Profile
Percentage of patients with mRVR eligible for 24 weeks total treament
SVR in patients with cirrhosis
SVR in preious relapsers (Telaprevir/ boceprevir)
SVR in partial responders
SVR in null responders
Overall discontinuation rates due to adverse events
SAE rate
Discontinuation rate due to rash
NA
NA
NA
NA
NA
4.00%
3.00%
0.00%
NA
NA
NA
NA
NA
6.00%
4.00%
0.00%
77.00%
NA
NA
NA
NA
13.00%
13.00%
4.00%
85.00%
NA
NA
NA
NA
9.00%
8.00%
3.00%
43.00%
NA
32.00%
21.00%
6.00%
0.00%
NA
NA
50.00%
35.00%
4.00%
0.00%
NA
NA
42.00%
29.00%
23.00%
10.00%
70.00%
3 out of 10
NA
NA
NA
6.00%
12.00%
0.00%
83.00%
4 out of 10
NA
NA
NA
6.00%
9.00%
1.00%
4
6
84%
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Table 1. Outcomes of interferon-containing regimens with faldaprevir (cont.).
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Study
Subjects enrolled
Doseage arms
Duration of PEG IFN/riba (weeks)
SVR
StartVERSO 1 and 2
521
FDV 120 mg q.d. for 12–24 weeks + PEG IFN/riba 24–48 weeks (RGT)
24–48%
73%
StartVERSO 1 and 2
524
FDV 240 mg q.d. for 12 weeks + PEG IFN/riba 48 weeks (RGT)
48%
72%
StartVERSO 3
Comment
Phase III, partially placebo controlled
677
StartVERSO 3
99 previous relapsers
FDV 240 mg q.d. for 12 24 weeks + PEG IFN/riba 48 weeks (RGT)
70%
StartVERSO 3
49 previous relapsers
placebo for 12 weeks + PEG IFN/riba 48 weeks (RGT)
7%
57 previous partial responders
FDV 240 mg q.d. for 12 weeks + PEG IFN/riba 48 weeks (RGT)
53%
29 previous relapsers
placebo for 12 weeks + PEG IFN/riba 48 weeks (RGT)
3%
145 previous null responders
FDV 240 mg q.d. for 12 weeks + PEG IFN/riba 48 weeks (RGT)
33%
StartVERSO 3
SVR in G1a vs G1b
PEG IFN: Pegylated interferon; riba: Ribavirin.
78 and 87% of patients in the 240 mg/LI and 240 mg/no LI groups, respectively, had an mRVR and qualified to consider stopping all treatment after 24 weeks. Shortening treatment duration did not compromise efficacy in the 240 mg/no LI arm as the SVR rate (91%) was identical in both groups. However, in the 240 mg/LI arm, SVR was 96% in patients who received 48 weeks of total treatment, versus 81% in those who shortened treatment to 24 weeks (p = 0.051) Overall, 9% of patients treated with faldaprevir/PEG IFN/ riba had a SAE in association with antiviral treatment. Only 3% of patients in the placebo/PEG IFN/riba group had an SAE. Patients who were allocated faldaprevir were likely to discontinue treatment due to an adverse event (4–11 vs 1%). 3% of patients who received 240 mg of faldaprevir daily developed a rash that led to treatment discontinuation, whereas no patients treated with a 120 mg dose or placebo did so. However, there were no reported cases of severe cutaneous adverse reactions (SCAR) such as Stevens–Johnson syndrome, erythema multiforme or drug rash with erythema and systemic symptoms (DRESS) in any patient in this study. The addition of faldaprevir, in this study, to PEG IFN/riba did not increase the incidence or severity of anemia on treatment. Both telaprevir and boceprevir are often associated with significant treatmentrelated anemia. 282
Virological breakthrough whilst receiving faldaprevir was reported to be associated with the development of NS3 mutants encoded for R155K in genotype 1a and D168V in genotype 1b. However, five of the six patients with these mutations present at baseline achieved SVR. Thus in non-cirrhotic, treatment-naive patients, faldaprevir improved HCV treatment efficacy when added to PEG IFN/ riba. 120 and 240 mg doses of faldaprevir appeared to of equivalent efficacy. Response-guided therapy allowed most patients to shorten treatment without compromising efficacy. A 120 mg dose might lead to fewer dose-related side effects, in particular fewer cutaneous and gastrointestinal side effects than a 240 mg dose. Treatment efficacy may be compromised by a 3-day ‘lead-in’ of pegylated IFN a 2a and riba, although this duration is considerably shorter than that required to approach steady state for either riba or pegylated IFN a-2a. Trials of other protease inhibitors given with a 4 week lead-in do however support the conclusion that HCV treatment efficacy is not improved by a PEG IFN/riba lead-in. SILEN-C2
The SILEN-C2 study included 290 patients who had previous null or partial response to PEG IFN/riba [34]. Patients with cirrhosis were not included in this study. All patients received at Expert Rev. Gastroenterol. Hepatol. 9(3), (2015)
Faldaprevir for the treatment of genotype-1 HCV
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Percentage of patients with mRVR eligible for 24 weeks total treament
SVR in patients with cirrhosis
SVR in preious relapsers (Telaprevir/ boceprevir)
SVR in partial responders
least 24 weeks of PEG IFN/riba in combination with the study medication. Patients received 240 mg once daily of faldaprevir with a 3-day PEG IFN/riba lead-in (240/LI), 240 mg once daily with no lead-in (240/no LI) or 240 mg twice daily of faldaprevir with a 3-day PEG IFN/riba lead-in(480/LI). In order to assess the usefulness of response-guided treatment in treatmentexperienced subjects, in the 240/LI group, 50% of patients with an mRVR were allocated to 24-week total treatment duration. All other patients received 48 weeks of PEG IFN/riba. 35% of previous null responders and 50% of previous partial responders had an SVR with faldaprevir. In similarity with SILEN-C1, a 3-day PEG IFN/riba lead in to a ±10% reduction in SVR rate. A 240 mg bd dose also did not improve SVR rate, but did lead to more treatment discontinuation. 4% of patients in 240 mg groups discontinued treatment due to adverse events, whereas 23 % did so in the 480/LI group. 19% of patients in the 480/LI group experienced a SAE on treatment, against 7% in the 240 mg groups. Response-guided treatment in patients with mRVR in the 240/LI arm leads to a reduction in SVR rates, 42 vs 73% (p = 0.035). 24 % of patients experienced viral breakthrough on faldaprevir. SVR rates tended to be lower in patients with HCV genotype 1a than 1b. informahealthcare.com
SVR in null responders
Overall discontinuation rates due to adverse events
SAE rate
5
7
8
8
5% in cohorts 1 and 2 combined, 6% in cohort 3
9% in FDV treated patients
Drug Profile
Discontinuation rate due to rash
In summary, SILEN-C1 and SILEN-C2 trials demonstrated that faldaprevir was potentially at least as potent as other protease inhibitors in late stage development at the time. A 3-day ‘lead-in’ was not of utility. Dose-related side effects were considerable at 240 mg dosage, although this dose may be more effective in treatment-experienced patients. Response-guided treatment appeared justifiable in treatment-naive patients with an mRVR and 24 weeks of total treatment duration appears feasible. However, patients with previous partial or null response would require 48 weeks of PEG IFN/riba. Discontinuation rates were relatively high in this study. SILEN-C3
The SILEN-C3 study was a Phase IIb open label study which investigated the possibility of further shortening faldaprevir treatment [35]. Patients received 120 mg of faldaprevir once daily for either 12 or 24 weeks, along with PEG IFN/riba for 24 or 48 weeks. 160 treatment-naı¨ve patients were enrolled. Patients with compensated cirrhosis were also eligible and constituted 12% of the study population. Patients with mRVR in this study had 24 weeks of PEG IFN/riba, whilst those without early treatment success (ETS) continued PEG IFN/riba for 48 weeks. The study design specified a 3-day lead-in of PEG IFN/riba prior to receiving faldaprevir. An initial ‘loading dose’ 283
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Agarwal & Barnabas
dose of faldaprevir 240 mg was given as a first dose of faldaprevir after completion of the lead-in phase. 77% of patients had ETS and stopped all treatment at week 24. Overall, 67 and 74% of patients in the 12- and 24-week faldaprevir treatment arms achieved an SVR 24. This was not a statistically significant difference and was felt to be related to imbalances in IL-28B genotypes between the two study groups. IL28 B genotyping was assessed in retrospect as the utility of IL28B genotyping had not been established at the time of study design. The overall early discontinuation rate was 11% (15% in the 24-week group and 7% in the 12-week group). Discontinuations consequent to treatment-related adverse events occurred in 6% of patients overall. 4% of patients reported SAEs on treatment. 11% of patients experienced viral breakthrough on treatment. In the group that received 12 weeks of faldaprevir, 50% of viral breakthroughs occurred after faldaprevir treatment has been completed, whereas in the 24-week group viral breakthrough was always seen whilst on faldaprevir. As in SILEN-C1, virological breakthrough whilst on faldaprevir associated with the development of NS3 mutants encoding for R155K in genotype 1a, in 79% (15/19) patients. In genotype 1b, 59% (10/17) showed a D168V mutation. One patient had a GT-1g R155K mutation. The authors concluded that faldaprevir was effective at a 120 mg once-daily dose when given for either 12 or 24 weeks, with most patients being able to shorten PEG IFN/riba to 24 weeks duration. Phase II- IFN-free
The most recent advance in HCV studies has been the rapid emergence of a series of studies in which an NS5-B inhibitor (most often sofosbuvir) is used with either an NS 5A inhibitor and/or an NS 3/4A protease inhibitor. Riba may also be incorporated into treatment. Multiple studies show that in combination, these drugs exceed the potency of PEG IFN/riba-based regimens, with SVR 12 rates >90% being reported in multiple Phase II and III studies, even in difficult-to-treat populations such as previous null responders. The investigational non-nucleoside 5B polymerase inhibitor deleobuvir was investigated in the SOUND C and HCV Verso study series. In January 2014, Boehringer Ingelheim announced that it was halting further development of deleobuvir following interim analysis from the HCV Verso study series, which showed an unacceptably high rate of virological breakthrough. Faldaprevirpotency may be inadequate for further development in IFN-free regimens.
patients would be allocated to a riba-free arm, but recruitment to this arm was discontinued at FDA request following poor reported outcomes from other clinical trials where neither PEG IFN nor riba was used. Treatment duration was between 16 and 40 weeks. All patients received faldaprevir 120 mg once daily. Deleobuvir was dosed at 600 mg two- or three-times per day. All patients received a loading dose of 1200 mg deleobuvir and 240 mg of faldaprevir at baseline. 9% of patients had cirrhosis. The reported SVR12 in this trial was 52–69%. Published data do not specifically discuss the SVR rate in patients with cirrhosis. 16% of patients experienced virological breakthrough on treatment. Overall, prolongation of treatment to 28 and 40 weeks did not improve its efficacy. Increasing the dose of deleobuvir from 600 mg BID to 600 mg TID did not improve treatment outcomes but did appear to increase the premature discontinuation rate. A post hoc subgroup analysis showed much improved SVR rates in patients treated with patients with genotype 1b infection (57–85%), compared to genotype 1a (11–47%). 9% of patients had severe adverse events on treatment. 13% of patients discontinued study medication prematurely, comparable to trials that include PEG IFN. Overall, the authors concluded in post-hoc analysis that the combination of deleobuvir, faldaprevir and riba appeared to be highly effective HCV genotype 1b when given for 16 weeks. SOUND-C3
SOUND-C3 enrolled 32 previously untreated patients, 12 of whom had genotype 1a infection and an IL28B CC Genotype. The remaining 20 had HCV 1b and varying IL28 B genotypes. All patients received faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily and weight-based riba. 95% of genotype 1b and 17% of genotype 1a patients had an SVR 12. One patient had an SAE. 9% of patients discontinued treatment due to adverse events. This discontinuation rate is comparable to several IFN-containing regimens. PPI668 as third agent
PPI-668 is an investigational NS 5A inhibitor. Lalezari et al. reported preliminary data in an initial cohort of 37 HCV genotype 1a patients treated with the combination of faldaprevir 120 mg daily, deleobuvir 400–600 mg twice daily and PPI-668 200 mg daily and weight-based riba [37]. All patients were treatment naive. One patient discontinued treatment due to adverse events. At the time of their report, 100% of the 27 patients who completed treatment were still HCV RNA negative 4 weeks after stopping treatment. Further follow-up data are awaited.
SOUND-C2
Phase III START Verso 1–4
The first Phase II study to be published which uses faldaprevir in an IFN-free regimen is the SOUND-C2 trial [36]. 362 treatment-naı¨ve patients received a combination of faldaprevir and deleobuvir, along with riba. Patients with cirrhosis were included in this study. It was initially planned that 20% of
START Verso is a series of four Phase III clinical trials of faldaprevir. STARTVerso 1 and 2 assessed the efficacy of a faldaprevir-based regimen in treatment-naive patients with genotype 1 HCV. In START-Verso3, however, the study population had previously received PEG-IFN/riba for HCV.
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START Verso 1 & START Verso 2
START Verso 1 and 2 are multicentre Phase III placebocontrolled studies of identical design. Response-guided therapy was used in one arm. ETS was defined as HCV unquantifiable or undetectable at week 4 and undetectable at week 8. This qualified patients to be considered for treatment abbreviation. Pooled analysis data from this study have been presented [38]. 1314 patients were recruited. 9% had cirrhosis. All patients were treatment naive and received one of: .
.
.
faldaprevir 120 mg once daily for 12 to 24 weeks, with PEG IFN/riba for 24–48 weeks in a response-guided manner (patients with ETS stopped all treatment at 24 weeks); faldaprevir 240 mg once daily for 12 weeks, with PEG IFN/ riba for 24–48 weeks (patients with ETS stopped all treatment at 24 weeks); placebo + PEG IFN/riba for 48 weeks.
The overall SVR rate was 73%, against 53% in the placebo group. A 240 mg faldaprevir dose was not more effective than 120 mg. 84% of patients on either dose of faldaprevir had ETS. Patients with ETS stopped faldaprevir at week 12 and PEG IFN/riba at week 24 and had an 83% SVR rate. Patients without ETS had an 84% overall SVR rate. When a 120 mg dose of faldaprevir was used, adverse events leading to discontinuation of all treatment were similar to the placebo/PEG IFN/riba arm (5 vs 4%), but a 240 mg faldaprevir dose resulted in numerically higher discontinuation rates (8%). Virological failure was more common in genotype 1a than 1b (40 vs 23%).The presence of a Q80 K mutation at baseline did not affects treatment efficacy in this study, unlike the effect seen with simeprevir. Phase III: START Verso 3
START-Verso 3 assessed the efficacy of faldaprevir 240 mg in 678 treatment-experienced patients, when administered with PEG IFN/riba [39]. This was a double-blind, partially placebocontrolled study. Previously treated patients were characterized as previous relapsers, partial responders or null responders. Previous relapsers and partial responders received 48 weeks of PEG IFN and either placebo or 12–24 weeks of faldaprevir 240 mg once daily. In this cohort, patients with ETS could stop all treatment at week 24. Previous null responders received 48 weeks of PEG IFN and either placebo or 12–24 weeks of faldaprevir 240 mg once daily. No response-guided therapy was allowed in this study cohort. Partial responders showed a 53% response rate and previous relapsers had a 70% SVR rate. This was a marked improved on patients treated with placebo and PEG IFN/riba in these cohorts. In comparison to historical data of null retreated with PEG IFN/riba alone, the addition of faldaprevir leads to a significant increase in SVR rate to 33%.Cirrhosis was present in 21% of patients. In previous relapsers, the presence of cirrhosis did not affect treatment efficacy, but in both null and partial informahealthcare.com
Drug Profile
responders, cirrhosis markedly reduced treatment efficacy. Regardless of previous treatment history, faldaprevir appeared to be less effective in genotype 1a infection. Overall, adverse events rates were similar to PEG IFN/riba, but gastrointestinal side effects were more frequent. Phase III: START Verso 4
Following this series, START Verso 4 was initiated to assess the use of faldaprevir in patients with HIV co-infection [32]. This study included either treatment-naive patients, or those who had relapsed on previous PEG IFN/riba treatment. 310 patients were enrolled in this study. 45 patients had cirrhosis. Only interim data up to 4 weeks post cessation of treatment are available. Patients received either 120 mg/day of faldaprevir for 24 weeks, or 240 mg/day of faldaprevir/day for either 12 or 24 weeks, in addition to PEG IFN/riba for up to 48 weeks. At 24 weeks, patients with ETS across all arms were randomized 1:1 to stop all medication at 24 weeks or continue with PEG IFN/riba for a further 2 weeks. Allocation to 120 and 240 mg arms was random unless patients were on efavirenz (allocated 240 mg dosage arm) or daurunovir/atazanavirbased regimens (allocated 120 mg dosage arm). Overall, 74 % of patients achieved SVR 4. There was similar efficacy across all dosage arms. 80% of patients had ETS, and treatment efficacy was similar between 24- and 48-week PEG IFN/riba arms. SVR 4 rates were similar in G1a and G1b (74 and 77%). 89% of Il28b CC genotype patients had an SVR4, whereas SVR was only achieved in 67% of non-CC genotype patients. The 45 patients with cirrhosis had similar SVR4 (76%) to non-cirrhotic patients. In keeping with previous similar studies, patients with previous relapse had an improved SVR compared to treatment-naive patients (87 vs 71%). 80% of patients achieved early treatment success and 88% of these had an SVR4. In the ETS group that stopped all medication at 24 weeks, the SVR4 comparable to the ETS group extended PEG-IFN/riba treatment to 48 weeks. 8–10% of patients experienced viral breakthrough on treatment. 7% of patients discontinued treatment due to adverse events. 10% of patients had an SAE on treatment, and there was one death, in a patient who received 240 mg of faldaprevir. This death was adjudged to secondary to Stevens– Johnson syndrome. Phase III: HCVerso1 & HCVerso2
Based on data from STARTverso 4, HCVerso 1 and 2 studies were designed to assess the safety and efficacy of a faldaprevircontaining, IFN-free regimen in patients infected with HCV genotyping 1b. These studies completed recruitment in August 2013. In January 2014, Boehringer Ingelheim announced that it was halting further development of deleobuvir. Preliminary data from HCVerso 1 and 2 have been reported to have shown a high discontinuation rate due to inadequate virological response. 285
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Safety & tolerability
Unlike the first-generation PIs, telaprevir and boceprevir, faldaprevir does not appear to exacerbate the anaemia caused by PEG IFN/riba. However, newer IFN free regimens have far fewer side effects/faldaprevir does not appear to be more well tolerated than first-generation PIs. GI side effects and rash appear to be particularly important side effects. Regulatory status
In April 2011, the US FDA granted fast track designation for the development of regimens containing faldaprevir and PEG IFN/riba, and faldaprevir and deleobuvir. In March 2014, the FDA accepted a new drug application for filing, for faldaprevir in combination with PEG IFN/riba. This is targeted for the fourth quarter of 2014. In November 2013, the European Medicines agency granted an accelerated assessment for faldaprevir. On 20 June 2014, BI announced that it was halting further development of all investigational agents for HCV, including of course faldaprevir. Conclusions & five-year view
The treatment of HCV is a rapidly changing and highly competitive field. Ciluprevir, the first clinically important DAA against HCV, was developed by BI. Initial published data in 2004 showed that it was a ground-breaking agent in HCV. Although ciluprevir’s development was halted because of concern of its potential cardiotoxicity, faldaprevir appeared to be a promising substitute. In early clinical trials, faldaprevir seemed to offer incremental benefit over other DAAs. Since then, it has become one of the most widely studied DAAs across Phase I, II and III clinical trials. The potential advantages of faldaprevir, in comparison to first-wave DAAs, included: .
Early potency against HCV; Once-daily dosing; Safety in renal failure; Reduced on-treatment anemia, and thus greater tolerability.
. . .
Newer competitors have overtaken it in all these areas however, and it is no surprise that product development was terminated. Discontinuation rates are significantly higher than its competitors, and SVR rates at best are similar. One is forced to speculate that BI does not feel that faldaprevir is potent enough a DAA to be used in an IFN-free regimen. With IFNcontaining regimens, breakthrough on faldaprevir occurs frequently, which is indicative of its relatively low genetic barrier to resistance. Several new DAAs appear to be potent enough to consider an IFN-free regimen for as little as 6 weeks. A pan-genotypic, fixed dose two-drug combination pill, in a riba-sparing regimen appears entirely feasible from clinical trial data. Drug–drug interactions with immunosuppressants in the OLT population, and highly active antiretroviral treatment medication in co-infected patients, may be far less of a problem than at present. Newer regimens also have the potential to be equally effective and well tolerated. As drugs become more potent, response-guided therapy also becomes less relevant. In 5 years therefore, it is entirely possible that patients will only need a qualitative HCV PCR at diagnosis and 12 weeks after stopping treatment to confirm cure. It is foreseeable that for most patients, monitoring of viral load on treatment will be undertaken only to confirm adherence, as efficacy will be near-universal. Faldaprevir, and indeed BI’s HCV entire program was strategically flawed in two ways. First, faldaprevir had a slow development program in relation to its competitors. Second, unlike its competitors, BI did not widely explore the potential for a three-DAA regimen inclusive of an NS 5A inhibitor. In a rapidly changing field, therefore, its first mover advantage was rapidly lost. Financial & competing interests disclosure
K Agarawal and A Barnabas have been principle investigators and subinvestigators in clinical trials of faldaprevir, respectively. 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.
Key issues .
Faldaprevir, a protease inhibitor, showed initial promise as a potent DAA for the treatment of hepatitis C, when used in combination with PEG IFN/riba.
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From phase 2 and 3 trial clinical data, however, it emerged that competing direct acting antiviral agents offer significant advantages in terms of both tolerability and efficacy.
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Further trial data showed that in interferon-free regimens incorporating faldaprevir, efficacy appeared to be inferior to emerging DAAs.
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Further development of faldaprevir was discontinued on 20 June 2014.
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Faldaprevir for the treatment of genotype-1 hepatitis C virus Expert Rev. Gastroenterol. Hepatol. 9(3), 277–288 (2015)
Kosh Agarwal* and Ashley Barnabas Kings College Hospital, Institute for liver studies, London, UK *Author for correspondence: [email protected]
Historically, pegylated interferon in combination with ribavirin was the standard of care in hepatitis C virus; however, this combination is often poorly tolerated, has a significant side-effect profile and is of limited efficacy in hepatitis C virus genotype-1. More recently, pegylated interferon/ribavirin has been combined with direct acting antiviral agents such as the first generation NS3/4A protease inhibitors. Faldaprevir, a first generation, second-wave protease inhibitor, when used with a pegylated interferon/ribavirin regimen, has also been shown to increase treatmentsuccess while shortening treatment duration; however, second generation direct acting antiviral agents offer even betterefficacy and tolerability. Various direct acting antiviral agent combinations in interferon-free regimens have been effective in over 95% of patients and are now in licensed use. While faldaprevir was a pioneering drug, by the time it reached late phase development it was superseded by newer agents. KEYWORDS: boceprevir . faldaprevir . hepatitis C . liver transplantation . pegylated interferon . ribavirin . simeprevir .
telaprevir
Overview
About 2–3% of the world’s population (130–170 million people) is chronically infected with the hepatitis C virus (HCV) [1,2]. There are six major genotypes of HCV. Genotype 1 is the most prevalent in much of the developed world and accounts for 73% of cases in the USA [1]. Acute infection with HCV results in chronic HCV in 70% of patients. Between 5 and 25% of patients infected with chronic infection will progress to cirrhosis within 20 years. Once cirrhosis develops, there is a 3–6% annual risk of hepatic decompensation and a 1–5% annual risk of developing hepatocellular carcinoma [3,4]. If cure from HCV infection could be achieved, liver fibrosis undergoes partial reversal, life expectancy improves and the risk of developing hepatocellular carcinoma is markedly reduced [5,6]. Prior to the advent of directacting antiviral agents (DAAs), the goal of virological cure could be achieved in fewer than half of patients infected with HCV. Most long-term follow-up data in patients treated for HCV has been published in patients treated with pegylated interferon (PEG IFN)/ ribavirin (riba). PEG-IFN targets the host immune system, and it is felt that riba has a similar mode of action. The HCV informahealthcare.com
10.1586/17474124.2015.1001742
virus encodes three structural and seven nonstructural proteins. DAAs, as the name implies, are designed to act specifically against HCV at one of three well-conserved nonstructural proteins: . . .
NS 3/4A protease NS 5A replication complex NS5B polymerase
Should a patient persist with an undetectable HCV RNA viral load 24 weeks after completing HCV treatment (sustained virological response for 24 weeks, SVR24), permanent eradication of HCV with PEG IFN/riba can be assumed [7]. In patients with an undetectable viral load 12 weeks after completing treatment in DAA-containing PEG IFN/riba regimens (sustained virological response at week 12, SVR 12), virological relapse thereafter is rare, and now SVR12 is accepted as a equivalent to virological cure [8]. PEG-IFN/riba treatment is effective in less than half of patients infected with HCV. It is also extremely resource intensive, which has historically limited access to treatment. Since the introduction of DAAs in 2011, however, drug development has been relentless, with successive generations of DAAs rendering recently marketed drugs obsolete within intervals as brief as 2 years. Not only are cure rates
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higher, but resource utilization has been dramatically reduced by IFN-free DAA regimens. In patients with HCV genotype 1 disease, current treatment regimens offer up to a 68–89% chance of cure, dependent on pre-treatment factors. At present, most treatment regimens with marketing authorization in the USA and Europe consist of a single DAA agent in combination with PEG IFN/riba, unless a patient is IFN ineligible or IFN intolerant. The first wave, first-generation protease inhibitors telaprevir and boceprevir, as well as the second-wave, first-generation protease inhibitor simeprevir are commercially available in North America and Europe. Sofosbuvir, a nucleotide analogue NS 5B polymerase inhibitor, has also received marketing authorization in these regions. A single pill, fixed-dose combination of sofosbuvir and ledipasvir, an NS5A inhibitor, is likely to be licensed in the third quarter of this year in a PEG-IFN-free regimen. Telaprevir and boceprevir were the first commercially available DAAs. They achieve 68–75% cure rates in patients who have not previously been treated. These response rates are better, as high as 88%, in patients who have relapsed following previous treatment with PEG IFN/riba [9]. Response rates are poor in treatment-experienced patients who have had a partial or null virological response to PEG IFN/riba previously. Both tolerability and therapeutic efficacy are reduced in more advanced liver disease [10]. Ironically, the subset of the sickest patients in this group, who potentially stand to gain the most from being cured, will often be too sick to tolerate IFN. Of drugs currently licensed, sofosbuvir appears to be the most potent DAA. A 12-week course of PEG IFN and riba in combination with sofosbuvir has been shown to offer much improved SVR rates of 89% in treatment-naı¨ve patients [11]. Genotype 1b patients, however, had a lower SVR rate than genotype 1a patients (82 vs 98%). Patients with compensated cirrhosis also had a lower SVR rate, at 80%. Whilst efficacy of this regimen in treatment-experienced patients, co-infected patients and liver transplant recipients (LTRs) is not known, sofosbuvir has a very high genetic barrier to resistance and is very well tolerated. Sofosbuvir is highly effective in IFN-free regimens. When combined with various other DAAs, an SVR rate in excess of 95% in IFN-free regimens, even in previously difficult to treat populations, has been shown in genotype 1 disease [12,13]. Areas of need
Currently, the greatest urgency for HCV treatment exists in patients who have failed HCV treatment and have cirrhosis. Several studies have also highlighted the poor tolerability and reduced efficacy of boceprevir and telaprevir in this population. In the French early access cohort of patients with cirrhosis, 511 treatment-experienced patients were retreated with either boceprevir or telaprevir in combination with PEG IFN/riba. 54–76% of patients with previous relapse 38–40% of partial responders and 0–19% of previous null responders were cured. 49% of patients experienced a serious adverse event (SAE), 21% of patients discontinued treatment due to SAEs and 2.2% 278
of patients died whilst receiving treatment [10]. By contrast, a landmark IFN-free study of 380 patients with compensated HCV cirrhosis has demonstrated cure rates in excess of 90% with a three-drug IFN-free regimen, with remarkably good tolerability [14]. This tolerability is substantiated by a reduction in resource utilization whilst on treatment, even in this historically difficult to treat cohort. 15–30% of patients infected with HIV are co-infected with HCV [15,16]. This prevalence is even higher in HIV-positive intravenous drug users. HIV appears to have multiple permissive effects on HCV infection, with lower rates of spontaneous resolution of infection, higher HCV viral loads and low success rates with IFN-based treatment regimens. Meta-analysis suggests that HIV co-infection doubles the likelihood that an individual will progress to cirrhosis and makes it up to six-times more likely that an individual will develop decompensated liver disease. Immune reconstitution with highly active antiretroviral treatment only partially ameliorates these effects [17]. Cure rates with PEG IFN/riba treatment are as low as 21–29% [18,19] in genotype 1 HCV. Even in affluent countries, only a small proportion of co-infected patients are treated for HCV. Data here also suggest that IFN-free treatment will be an effective strategy [20]. HCV infection is now the commonest indication for liver transplantation in the USA and western Europe. HCV recurrence in LTRs is universal. Progression to cirrhosis thereafter is accelerated. Between 20 and 30% of LTRs will have graft cirrhosis at 5 years after liver transplantation. In LTRs with genotype 1 HCV, only 13–30% of patients will be cured with PEG IFN/Riba [21]. Coilly et al. have reported a multicentre cohort study in which a first-generation protease inhibitor (boceprevir or telaprevir) was used in addition to PEG IFN/riba in 47 patients [22]. The observed SVR rate was 50%. However, 43% of patients discontinued treatment and three patients died whilst receiving treatment. Current EASL guidelines do not advocate the use of telaprevir or boceprevir after liver transplantation. It is clear that more tolerable and effective treatments for LTRs is a key area of need, and this is one of the patient groups that should be prioritized for early access to new agents. Furthermore, Curry et al. have demonstrated that the combination of sofosbuvir and riba prevents graft orthotopic liver transplantation (OLT) recurrence when given to patients waitisted for OLT [23]. HCV is a common cause of morbidity in the hemodialysis population. Its prevalence varies between 5 and 80 % in hemodialysis patients in different countries [24,25]. HCV treatment with PEG IFN, with or without riba, is often poorly tolerated and much less effective with overall SVR rates of 38% and treatment discontinuation rates as high as 15% [26]. DAAs that can be used in end-stage renal failure will thus have an important role to play. As 50% of patients treated with PEG IFN/riba will not be cured, a significant pool of patients that have failed treatment has accumulated. These patients can be characterized as: Expert Rev. Gastroenterol. Hepatol. 9(3), (2015)
Faldaprevir for the treatment of genotype-1 HCV
.
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.
Relapsers: Patients who had an undetectable HCV RNA viral load at the end of PEG IFN/riba treatment, but subsequently had a detectable HCV viral load. Partial responders: Patients who demonstrated some response to PEG IFN/riba treatment, but were never HCV RNA negative on treatment. Null responders: Patients who did not demonstrate virological response to PEG IFN/riba treatment, as defined by a less than two log decline in HCV RNA 12 weeks after starting antiviral treatment.
Studies including all three groups will be discussed
The greatest challenge in HCV is in making effective treatment and well-tolerated treatments available to all patients. Screening, referral and treatment rates remain low, despite guidelines. After referral, the upfront costs of DAA treatment are high, but need to be balanced against long-term outcomes. Faldaprevir Faldaprevir
Faldaprevir is a non-covalently binding, linear HCV NS3/4a protease inhibitor. In vitro, it has potent antiviral activity and is highly specific to HCV genotypes 1, 2, 4 and 6 [27]. Faldaprevir has a pharmacokinetic profile that makes oncedaily dosing a feasible option, unlike both boceprevir and telaprevir. In a double-blind multiple-rising dose Phase I study, its half-life was 20–30 h and steady state was reached in 120 h [28]. When faldaprevir is given as monotherapy, its trough concentration correlates well with both dosage and decrement in viral load in the first 6 days of treatment. The relationship between dose exposure and plasma serum concentration is moderately variable. The measured coefficient of variation for AUC (0-t) is as high as 65%. Pharmacokinetic parameters for faldaprevir are similar in patients without cirrhosis and those with compensated cirrhosis. There do not appear to be significant drug–drug interactions between faldaprevir and PEG IFN/riba. A single-dose phase one study has suggested that faldaprevir dose adjustment is not required in severe renal impairment [29]. Faldaprevir is a moderate inhibitor of cytochrome p450 3A4. It also has inhibitory effects on cytochromes CYP2C9 and UGT1A1. It does not have significant interactions with methadone or buprenorphine or naloxone [30]. However, exposure to the combined oral contraceptive, more specifically the combination of ethinyloestradiol and levonorgestrel, is moderately increased by faldaprevir [31]. Faldaprevir is also a substrate of CYP3A4 and may need dose adjustment with highly active antiretroviral treatment in co-infected patients. In patients treated with efavirenz, faldaprevirhas been studied at the higher dose of 240 mg once daily, whereas a 120 mg daily dose has been studied in patients being treated with the HIV protease inhibitors daurunovir/ritonovir, or atazanavir [32]. TABLE 1 summarizes clinical trial data for faldaprevir in PEG IFN/ribaregimens. informahealthcare.com
Drug Profile
Summary of Phase I & II data Phase I BI1220.2
Unpublished work suggested that in doses between 20–240 mg once daily, faldaprevir would be well tolerated for up to 28 days. In a Phase Ib dose finding study (BI1220.2), 34 treatment naı¨ve patients received either placebo or faldaprevir at doses of 20–240 mg once daily for 14 days. Nineteen treatment-experienced patients received faldaprevir at doses of 48–240 mg once daily, with PEG IFN/riba for 28 days [28]. Viral load reduction in the monotherapy group was highest in the 240 mg group with a medium of decline of 4.4 log 10 IU/ml. Most patients experienced viral breakthrough during the 14 days of monotherapy. In the treatment-experienced arm, where a three-drug regimen was used, five of the six patients treatment with faldaprevir 240 mg once daily had an undetectable viral load 28 days after starting treatment. There was no virological breakthrough on treatment in the 240 mg dosage group. However, two of the six patients treated with the 48 mg dose and one of the seven treated with 120 mg of faldaprevir once daily developed virological breakthrough on treatment. Based on these data, further studies have investigated 120 and 240 mg once-daily doses. Phase II Silenc1
The SILEN-C1 study (n = 429) was a Phase IIb double-blind trial of faldaprevir in 120 mg and 240 mg once-daily doses, with PEG IFN/riba, in comparison to a PEG IFN/riba control group [33]. In an attempt to minimize resistance to faldaprevir developing, this study incorporated a 3-day ‘lead-in’ of PEG IFN/riba dual therapy before their first dose of faldaprevir. Patients with cirrhosis were excluded from this study. All patients received 24 weeks of either faldaprevir or placebo. All patients received PEG IFN/riba for 24 to 48 weeks. In both 120 mg and 240 mg faldaprevir groups, 50% of patients were allocated to receive a 3-day lead-in of PEG IFN/rib and placebo before receiving their first dose of faldaprevir. 50% of patients allocated to 240 mg dosage arms were randomized to discontinue all treatment at week 24 if they had a maintained rapid virological response on treatment (mRVR). This was defined as a viral load below the lower limit of quantification at week 4, which remained undetectable thereafter up to week 20. Patient randomization was not stratified by HCV G1 subtype, due to laboratory limitations. At the time of study design, the relevance of IL-28B genotyping was not known, and this was also not included in randomization criteria. 56% of patients who received PEG IFN/riba and placebo achieved an SVR 24. 73% of patients in the 120 mg dose group achieved an SVR 24. 72% of patients who received a 3-day PEG IFN/riba lead-in, followed by 240 mg of faldaprevir daily, achieved an SVR 24. 84% of patients who received 240 mg of faldaprevir without a lead-in had an SVR 24. 279
Drug Profile
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Table 1. Outcomes of interferon-containing regimens with faldaprevir. Study
Comment
Subjects enrolled
Doseage arms
Duration of PEG IFN/riba (weeks)
SVR
SVR in G1a vs G1b
BI1220.2
Phase Ib dose-finding study
Silen-C1
Phase IIb double blind placebo controlled study
429 all treatment naı¨ve and non-cirrhotic
1:1:2:2 placebo 24 weeks + PEG IFN/riba 48 weeks
24–48 weeks (response guided in 240 mg faldaprevir arm)
Silen-C1
Phase IIb double blind placebo controlled study
71
Placebo 24 weeks + PEG IFN/riba 48 weeks
48
56.00%
not assigned at randomization
Silen-C1
69
FDV 120 mg q.d. 24 weeks (after 3 day LI) + PEN IFN/riba 48 weeks
48
73.00%
not assigned at randomization
Silen-C1
143
FDV 240 mg q.d. 24 weeks (after 3 day LI) + PEN IFN/riba 48 weeks
24–48
72.00%
not assigned at randomization
FDV 240 mg q.d. 24 weeks (no LI) + PEN IFN/riba 48 weeks (no RGT)
24–48
84.00%
not assigned at randomization
Silen-C1
Phase IIb double blind placebo controlled study
146
Silen-C2
Phase IIb double blind study
290 non-cirrhotic patients with previous null or partial response to PEG IFN/riba
Silen-C2
142 (40% previous null response)
FDV 240 mg q.d. 24 weeks (after 3 day LI) + PEN IFN/riba 24–48 weeks
24–48
40.00%
Silen-C2
76 (53%previous null response)
FDV 240 mg q.d. 24 weeks (no LI) + PEN IFN/riba 48 weeks (no RGT)
48
31.00%
Silen-C2
70 (54% previous null response)
FDV 240 mg BID 24 weeks (after 3 day LI) + PEN IFN/riba 24–48 weeks
48
22.00%
81
FDV 120 mg q.d. for 12 weeks (after 3 day LI) + PEG IFN/riba for 24–48 weeks
24–48
67.00%
53 vs 82%
79
FDV 120 mg q.d. for 24 weeks 9 after 3 day LI) + PEG IFN/riba for 24–48 weeks
24–48
74.00%
72 vs 75%
Silen-C2 Silen-C3 Silen-C3
Phase IIb open label study
Silen-C3
160
Silen-C3 Silen-C3 StartVERSO 1 and 2 StartVERSO 1 and 2
Phase III reported pooled analysis
1309 264
40 vs 23% Placebo + PEG IFN/riba 48 weeks
48
50%
PEG IFN: Pegylated interferon; riba: Ribavirin.
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Faldaprevir for the treatment of genotype-1 HCV
Drug Profile
Percentage of patients with mRVR eligible for 24 weeks total treament
SVR in patients with cirrhosis
SVR in preious relapsers (Telaprevir/ boceprevir)
SVR in partial responders
SVR in null responders
Overall discontinuation rates due to adverse events
SAE rate
Discontinuation rate due to rash
NA
NA
NA
NA
NA
4.00%
3.00%
0.00%
NA
NA
NA
NA
NA
6.00%
4.00%
0.00%
77.00%
NA
NA
NA
NA
13.00%
13.00%
4.00%
85.00%
NA
NA
NA
NA
9.00%
8.00%
3.00%
43.00%
NA
32.00%
21.00%
6.00%
0.00%
NA
NA
50.00%
35.00%
4.00%
0.00%
NA
NA
42.00%
29.00%
23.00%
10.00%
70.00%
3 out of 10
NA
NA
NA
6.00%
12.00%
0.00%
83.00%
4 out of 10
NA
NA
NA
6.00%
9.00%
1.00%
4
6
84%
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Table 1. Outcomes of interferon-containing regimens with faldaprevir (cont.).
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Study
Subjects enrolled
Doseage arms
Duration of PEG IFN/riba (weeks)
SVR
StartVERSO 1 and 2
521
FDV 120 mg q.d. for 12–24 weeks + PEG IFN/riba 24–48 weeks (RGT)
24–48%
73%
StartVERSO 1 and 2
524
FDV 240 mg q.d. for 12 weeks + PEG IFN/riba 48 weeks (RGT)
48%
72%
StartVERSO 3
Comment
Phase III, partially placebo controlled
677
StartVERSO 3
99 previous relapsers
FDV 240 mg q.d. for 12 24 weeks + PEG IFN/riba 48 weeks (RGT)
70%
StartVERSO 3
49 previous relapsers
placebo for 12 weeks + PEG IFN/riba 48 weeks (RGT)
7%
57 previous partial responders
FDV 240 mg q.d. for 12 weeks + PEG IFN/riba 48 weeks (RGT)
53%
29 previous relapsers
placebo for 12 weeks + PEG IFN/riba 48 weeks (RGT)
3%
145 previous null responders
FDV 240 mg q.d. for 12 weeks + PEG IFN/riba 48 weeks (RGT)
33%
StartVERSO 3
SVR in G1a vs G1b
PEG IFN: Pegylated interferon; riba: Ribavirin.
78 and 87% of patients in the 240 mg/LI and 240 mg/no LI groups, respectively, had an mRVR and qualified to consider stopping all treatment after 24 weeks. Shortening treatment duration did not compromise efficacy in the 240 mg/no LI arm as the SVR rate (91%) was identical in both groups. However, in the 240 mg/LI arm, SVR was 96% in patients who received 48 weeks of total treatment, versus 81% in those who shortened treatment to 24 weeks (p = 0.051) Overall, 9% of patients treated with faldaprevir/PEG IFN/ riba had a SAE in association with antiviral treatment. Only 3% of patients in the placebo/PEG IFN/riba group had an SAE. Patients who were allocated faldaprevir were likely to discontinue treatment due to an adverse event (4–11 vs 1%). 3% of patients who received 240 mg of faldaprevir daily developed a rash that led to treatment discontinuation, whereas no patients treated with a 120 mg dose or placebo did so. However, there were no reported cases of severe cutaneous adverse reactions (SCAR) such as Stevens–Johnson syndrome, erythema multiforme or drug rash with erythema and systemic symptoms (DRESS) in any patient in this study. The addition of faldaprevir, in this study, to PEG IFN/riba did not increase the incidence or severity of anemia on treatment. Both telaprevir and boceprevir are often associated with significant treatmentrelated anemia. 282
Virological breakthrough whilst receiving faldaprevir was reported to be associated with the development of NS3 mutants encoded for R155K in genotype 1a and D168V in genotype 1b. However, five of the six patients with these mutations present at baseline achieved SVR. Thus in non-cirrhotic, treatment-naive patients, faldaprevir improved HCV treatment efficacy when added to PEG IFN/ riba. 120 and 240 mg doses of faldaprevir appeared to of equivalent efficacy. Response-guided therapy allowed most patients to shorten treatment without compromising efficacy. A 120 mg dose might lead to fewer dose-related side effects, in particular fewer cutaneous and gastrointestinal side effects than a 240 mg dose. Treatment efficacy may be compromised by a 3-day ‘lead-in’ of pegylated IFN a 2a and riba, although this duration is considerably shorter than that required to approach steady state for either riba or pegylated IFN a-2a. Trials of other protease inhibitors given with a 4 week lead-in do however support the conclusion that HCV treatment efficacy is not improved by a PEG IFN/riba lead-in. SILEN-C2
The SILEN-C2 study included 290 patients who had previous null or partial response to PEG IFN/riba [34]. Patients with cirrhosis were not included in this study. All patients received at Expert Rev. Gastroenterol. Hepatol. 9(3), (2015)
Faldaprevir for the treatment of genotype-1 HCV
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Percentage of patients with mRVR eligible for 24 weeks total treament
SVR in patients with cirrhosis
SVR in preious relapsers (Telaprevir/ boceprevir)
SVR in partial responders
least 24 weeks of PEG IFN/riba in combination with the study medication. Patients received 240 mg once daily of faldaprevir with a 3-day PEG IFN/riba lead-in (240/LI), 240 mg once daily with no lead-in (240/no LI) or 240 mg twice daily of faldaprevir with a 3-day PEG IFN/riba lead-in(480/LI). In order to assess the usefulness of response-guided treatment in treatmentexperienced subjects, in the 240/LI group, 50% of patients with an mRVR were allocated to 24-week total treatment duration. All other patients received 48 weeks of PEG IFN/riba. 35% of previous null responders and 50% of previous partial responders had an SVR with faldaprevir. In similarity with SILEN-C1, a 3-day PEG IFN/riba lead in to a ±10% reduction in SVR rate. A 240 mg bd dose also did not improve SVR rate, but did lead to more treatment discontinuation. 4% of patients in 240 mg groups discontinued treatment due to adverse events, whereas 23 % did so in the 480/LI group. 19% of patients in the 480/LI group experienced a SAE on treatment, against 7% in the 240 mg groups. Response-guided treatment in patients with mRVR in the 240/LI arm leads to a reduction in SVR rates, 42 vs 73% (p = 0.035). 24 % of patients experienced viral breakthrough on faldaprevir. SVR rates tended to be lower in patients with HCV genotype 1a than 1b. informahealthcare.com
SVR in null responders
Overall discontinuation rates due to adverse events
SAE rate
5
7
8
8
5% in cohorts 1 and 2 combined, 6% in cohort 3
9% in FDV treated patients
Drug Profile
Discontinuation rate due to rash
In summary, SILEN-C1 and SILEN-C2 trials demonstrated that faldaprevir was potentially at least as potent as other protease inhibitors in late stage development at the time. A 3-day ‘lead-in’ was not of utility. Dose-related side effects were considerable at 240 mg dosage, although this dose may be more effective in treatment-experienced patients. Response-guided treatment appeared justifiable in treatment-naive patients with an mRVR and 24 weeks of total treatment duration appears feasible. However, patients with previous partial or null response would require 48 weeks of PEG IFN/riba. Discontinuation rates were relatively high in this study. SILEN-C3
The SILEN-C3 study was a Phase IIb open label study which investigated the possibility of further shortening faldaprevir treatment [35]. Patients received 120 mg of faldaprevir once daily for either 12 or 24 weeks, along with PEG IFN/riba for 24 or 48 weeks. 160 treatment-naı¨ve patients were enrolled. Patients with compensated cirrhosis were also eligible and constituted 12% of the study population. Patients with mRVR in this study had 24 weeks of PEG IFN/riba, whilst those without early treatment success (ETS) continued PEG IFN/riba for 48 weeks. The study design specified a 3-day lead-in of PEG IFN/riba prior to receiving faldaprevir. An initial ‘loading dose’ 283
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Drug Profile
Agarwal & Barnabas
dose of faldaprevir 240 mg was given as a first dose of faldaprevir after completion of the lead-in phase. 77% of patients had ETS and stopped all treatment at week 24. Overall, 67 and 74% of patients in the 12- and 24-week faldaprevir treatment arms achieved an SVR 24. This was not a statistically significant difference and was felt to be related to imbalances in IL-28B genotypes between the two study groups. IL28 B genotyping was assessed in retrospect as the utility of IL28B genotyping had not been established at the time of study design. The overall early discontinuation rate was 11% (15% in the 24-week group and 7% in the 12-week group). Discontinuations consequent to treatment-related adverse events occurred in 6% of patients overall. 4% of patients reported SAEs on treatment. 11% of patients experienced viral breakthrough on treatment. In the group that received 12 weeks of faldaprevir, 50% of viral breakthroughs occurred after faldaprevir treatment has been completed, whereas in the 24-week group viral breakthrough was always seen whilst on faldaprevir. As in SILEN-C1, virological breakthrough whilst on faldaprevir associated with the development of NS3 mutants encoding for R155K in genotype 1a, in 79% (15/19) patients. In genotype 1b, 59% (10/17) showed a D168V mutation. One patient had a GT-1g R155K mutation. The authors concluded that faldaprevir was effective at a 120 mg once-daily dose when given for either 12 or 24 weeks, with most patients being able to shorten PEG IFN/riba to 24 weeks duration. Phase II- IFN-free
The most recent advance in HCV studies has been the rapid emergence of a series of studies in which an NS5-B inhibitor (most often sofosbuvir) is used with either an NS 5A inhibitor and/or an NS 3/4A protease inhibitor. Riba may also be incorporated into treatment. Multiple studies show that in combination, these drugs exceed the potency of PEG IFN/riba-based regimens, with SVR 12 rates >90% being reported in multiple Phase II and III studies, even in difficult-to-treat populations such as previous null responders. The investigational non-nucleoside 5B polymerase inhibitor deleobuvir was investigated in the SOUND C and HCV Verso study series. In January 2014, Boehringer Ingelheim announced that it was halting further development of deleobuvir following interim analysis from the HCV Verso study series, which showed an unacceptably high rate of virological breakthrough. Faldaprevirpotency may be inadequate for further development in IFN-free regimens.
patients would be allocated to a riba-free arm, but recruitment to this arm was discontinued at FDA request following poor reported outcomes from other clinical trials where neither PEG IFN nor riba was used. Treatment duration was between 16 and 40 weeks. All patients received faldaprevir 120 mg once daily. Deleobuvir was dosed at 600 mg two- or three-times per day. All patients received a loading dose of 1200 mg deleobuvir and 240 mg of faldaprevir at baseline. 9% of patients had cirrhosis. The reported SVR12 in this trial was 52–69%. Published data do not specifically discuss the SVR rate in patients with cirrhosis. 16% of patients experienced virological breakthrough on treatment. Overall, prolongation of treatment to 28 and 40 weeks did not improve its efficacy. Increasing the dose of deleobuvir from 600 mg BID to 600 mg TID did not improve treatment outcomes but did appear to increase the premature discontinuation rate. A post hoc subgroup analysis showed much improved SVR rates in patients treated with patients with genotype 1b infection (57–85%), compared to genotype 1a (11–47%). 9% of patients had severe adverse events on treatment. 13% of patients discontinued study medication prematurely, comparable to trials that include PEG IFN. Overall, the authors concluded in post-hoc analysis that the combination of deleobuvir, faldaprevir and riba appeared to be highly effective HCV genotype 1b when given for 16 weeks. SOUND-C3
SOUND-C3 enrolled 32 previously untreated patients, 12 of whom had genotype 1a infection and an IL28B CC Genotype. The remaining 20 had HCV 1b and varying IL28 B genotypes. All patients received faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily and weight-based riba. 95% of genotype 1b and 17% of genotype 1a patients had an SVR 12. One patient had an SAE. 9% of patients discontinued treatment due to adverse events. This discontinuation rate is comparable to several IFN-containing regimens. PPI668 as third agent
PPI-668 is an investigational NS 5A inhibitor. Lalezari et al. reported preliminary data in an initial cohort of 37 HCV genotype 1a patients treated with the combination of faldaprevir 120 mg daily, deleobuvir 400–600 mg twice daily and PPI-668 200 mg daily and weight-based riba [37]. All patients were treatment naive. One patient discontinued treatment due to adverse events. At the time of their report, 100% of the 27 patients who completed treatment were still HCV RNA negative 4 weeks after stopping treatment. Further follow-up data are awaited.
SOUND-C2
Phase III START Verso 1–4
The first Phase II study to be published which uses faldaprevir in an IFN-free regimen is the SOUND-C2 trial [36]. 362 treatment-naı¨ve patients received a combination of faldaprevir and deleobuvir, along with riba. Patients with cirrhosis were included in this study. It was initially planned that 20% of
START Verso is a series of four Phase III clinical trials of faldaprevir. STARTVerso 1 and 2 assessed the efficacy of a faldaprevir-based regimen in treatment-naive patients with genotype 1 HCV. In START-Verso3, however, the study population had previously received PEG-IFN/riba for HCV.
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START Verso 1 & START Verso 2
START Verso 1 and 2 are multicentre Phase III placebocontrolled studies of identical design. Response-guided therapy was used in one arm. ETS was defined as HCV unquantifiable or undetectable at week 4 and undetectable at week 8. This qualified patients to be considered for treatment abbreviation. Pooled analysis data from this study have been presented [38]. 1314 patients were recruited. 9% had cirrhosis. All patients were treatment naive and received one of: .
.
.
faldaprevir 120 mg once daily for 12 to 24 weeks, with PEG IFN/riba for 24–48 weeks in a response-guided manner (patients with ETS stopped all treatment at 24 weeks); faldaprevir 240 mg once daily for 12 weeks, with PEG IFN/ riba for 24–48 weeks (patients with ETS stopped all treatment at 24 weeks); placebo + PEG IFN/riba for 48 weeks.
The overall SVR rate was 73%, against 53% in the placebo group. A 240 mg faldaprevir dose was not more effective than 120 mg. 84% of patients on either dose of faldaprevir had ETS. Patients with ETS stopped faldaprevir at week 12 and PEG IFN/riba at week 24 and had an 83% SVR rate. Patients without ETS had an 84% overall SVR rate. When a 120 mg dose of faldaprevir was used, adverse events leading to discontinuation of all treatment were similar to the placebo/PEG IFN/riba arm (5 vs 4%), but a 240 mg faldaprevir dose resulted in numerically higher discontinuation rates (8%). Virological failure was more common in genotype 1a than 1b (40 vs 23%).The presence of a Q80 K mutation at baseline did not affects treatment efficacy in this study, unlike the effect seen with simeprevir. Phase III: START Verso 3
START-Verso 3 assessed the efficacy of faldaprevir 240 mg in 678 treatment-experienced patients, when administered with PEG IFN/riba [39]. This was a double-blind, partially placebocontrolled study. Previously treated patients were characterized as previous relapsers, partial responders or null responders. Previous relapsers and partial responders received 48 weeks of PEG IFN and either placebo or 12–24 weeks of faldaprevir 240 mg once daily. In this cohort, patients with ETS could stop all treatment at week 24. Previous null responders received 48 weeks of PEG IFN and either placebo or 12–24 weeks of faldaprevir 240 mg once daily. No response-guided therapy was allowed in this study cohort. Partial responders showed a 53% response rate and previous relapsers had a 70% SVR rate. This was a marked improved on patients treated with placebo and PEG IFN/riba in these cohorts. In comparison to historical data of null retreated with PEG IFN/riba alone, the addition of faldaprevir leads to a significant increase in SVR rate to 33%.Cirrhosis was present in 21% of patients. In previous relapsers, the presence of cirrhosis did not affect treatment efficacy, but in both null and partial informahealthcare.com
Drug Profile
responders, cirrhosis markedly reduced treatment efficacy. Regardless of previous treatment history, faldaprevir appeared to be less effective in genotype 1a infection. Overall, adverse events rates were similar to PEG IFN/riba, but gastrointestinal side effects were more frequent. Phase III: START Verso 4
Following this series, START Verso 4 was initiated to assess the use of faldaprevir in patients with HIV co-infection [32]. This study included either treatment-naive patients, or those who had relapsed on previous PEG IFN/riba treatment. 310 patients were enrolled in this study. 45 patients had cirrhosis. Only interim data up to 4 weeks post cessation of treatment are available. Patients received either 120 mg/day of faldaprevir for 24 weeks, or 240 mg/day of faldaprevir/day for either 12 or 24 weeks, in addition to PEG IFN/riba for up to 48 weeks. At 24 weeks, patients with ETS across all arms were randomized 1:1 to stop all medication at 24 weeks or continue with PEG IFN/riba for a further 2 weeks. Allocation to 120 and 240 mg arms was random unless patients were on efavirenz (allocated 240 mg dosage arm) or daurunovir/atazanavirbased regimens (allocated 120 mg dosage arm). Overall, 74 % of patients achieved SVR 4. There was similar efficacy across all dosage arms. 80% of patients had ETS, and treatment efficacy was similar between 24- and 48-week PEG IFN/riba arms. SVR 4 rates were similar in G1a and G1b (74 and 77%). 89% of Il28b CC genotype patients had an SVR4, whereas SVR was only achieved in 67% of non-CC genotype patients. The 45 patients with cirrhosis had similar SVR4 (76%) to non-cirrhotic patients. In keeping with previous similar studies, patients with previous relapse had an improved SVR compared to treatment-naive patients (87 vs 71%). 80% of patients achieved early treatment success and 88% of these had an SVR4. In the ETS group that stopped all medication at 24 weeks, the SVR4 comparable to the ETS group extended PEG-IFN/riba treatment to 48 weeks. 8–10% of patients experienced viral breakthrough on treatment. 7% of patients discontinued treatment due to adverse events. 10% of patients had an SAE on treatment, and there was one death, in a patient who received 240 mg of faldaprevir. This death was adjudged to secondary to Stevens– Johnson syndrome. Phase III: HCVerso1 & HCVerso2
Based on data from STARTverso 4, HCVerso 1 and 2 studies were designed to assess the safety and efficacy of a faldaprevircontaining, IFN-free regimen in patients infected with HCV genotyping 1b. These studies completed recruitment in August 2013. In January 2014, Boehringer Ingelheim announced that it was halting further development of deleobuvir. Preliminary data from HCVerso 1 and 2 have been reported to have shown a high discontinuation rate due to inadequate virological response. 285
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Agarwal & Barnabas
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Safety & tolerability
Unlike the first-generation PIs, telaprevir and boceprevir, faldaprevir does not appear to exacerbate the anaemia caused by PEG IFN/riba. However, newer IFN free regimens have far fewer side effects/faldaprevir does not appear to be more well tolerated than first-generation PIs. GI side effects and rash appear to be particularly important side effects. Regulatory status
In April 2011, the US FDA granted fast track designation for the development of regimens containing faldaprevir and PEG IFN/riba, and faldaprevir and deleobuvir. In March 2014, the FDA accepted a new drug application for filing, for faldaprevir in combination with PEG IFN/riba. This is targeted for the fourth quarter of 2014. In November 2013, the European Medicines agency granted an accelerated assessment for faldaprevir. On 20 June 2014, BI announced that it was halting further development of all investigational agents for HCV, including of course faldaprevir. Conclusions & five-year view
The treatment of HCV is a rapidly changing and highly competitive field. Ciluprevir, the first clinically important DAA against HCV, was developed by BI. Initial published data in 2004 showed that it was a ground-breaking agent in HCV. Although ciluprevir’s development was halted because of concern of its potential cardiotoxicity, faldaprevir appeared to be a promising substitute. In early clinical trials, faldaprevir seemed to offer incremental benefit over other DAAs. Since then, it has become one of the most widely studied DAAs across Phase I, II and III clinical trials. The potential advantages of faldaprevir, in comparison to first-wave DAAs, included: .
Early potency against HCV; Once-daily dosing; Safety in renal failure; Reduced on-treatment anemia, and thus greater tolerability.
. . .
Newer competitors have overtaken it in all these areas however, and it is no surprise that product development was terminated. Discontinuation rates are significantly higher than its competitors, and SVR rates at best are similar. One is forced to speculate that BI does not feel that faldaprevir is potent enough a DAA to be used in an IFN-free regimen. With IFNcontaining regimens, breakthrough on faldaprevir occurs frequently, which is indicative of its relatively low genetic barrier to resistance. Several new DAAs appear to be potent enough to consider an IFN-free regimen for as little as 6 weeks. A pan-genotypic, fixed dose two-drug combination pill, in a riba-sparing regimen appears entirely feasible from clinical trial data. Drug–drug interactions with immunosuppressants in the OLT population, and highly active antiretroviral treatment medication in co-infected patients, may be far less of a problem than at present. Newer regimens also have the potential to be equally effective and well tolerated. As drugs become more potent, response-guided therapy also becomes less relevant. In 5 years therefore, it is entirely possible that patients will only need a qualitative HCV PCR at diagnosis and 12 weeks after stopping treatment to confirm cure. It is foreseeable that for most patients, monitoring of viral load on treatment will be undertaken only to confirm adherence, as efficacy will be near-universal. Faldaprevir, and indeed BI’s HCV entire program was strategically flawed in two ways. First, faldaprevir had a slow development program in relation to its competitors. Second, unlike its competitors, BI did not widely explore the potential for a three-DAA regimen inclusive of an NS 5A inhibitor. In a rapidly changing field, therefore, its first mover advantage was rapidly lost. Financial & competing interests disclosure
K Agarawal and A Barnabas have been principle investigators and subinvestigators in clinical trials of faldaprevir, respectively. 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.
Key issues .
Faldaprevir, a protease inhibitor, showed initial promise as a potent DAA for the treatment of hepatitis C, when used in combination with PEG IFN/riba.
.
From phase 2 and 3 trial clinical data, however, it emerged that competing direct acting antiviral agents offer significant advantages in terms of both tolerability and efficacy.
.
Further trial data showed that in interferon-free regimens incorporating faldaprevir, efficacy appeared to be inferior to emerging DAAs.
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Further development of faldaprevir was discontinued on 20 June 2014.
286
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Faldaprevir for the treatment of genotype-1 HCV
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