Risk Of Developing Liver Cancer After HCV Treatment

Sunday, January 6, 2013

HCV: second-generation protease inhibitors

Liver InternationalLiver International

Special Issue: Proceedings of the 6th Paris Hepatitis Conference, International Conference on the Management of Patients with Viral Hepatitis
Volume 33, Issue Supplement s1, pages 80–84, February 2013
 

New therapeutic strategies in HCV: second-generation protease inhibitors

Virginia C. Clark,
Joy A. Peter,
David R. Nelson*

Article first published online: 3 JAN 2013

DOI: 10.1111/liv.12061

Keywords:
Hepatitis C;
protease inhibitors;
ACH 2684;
MK 5172

Abstract
Telaprevir and boceprevir are the first direct-acting antiviral agents approved for use in HCV treatment and represent a significant advance in HCV therapy. However, these first-generation drugs also have significant limitations related to thrice-daily dosing, clinically challenging side-effect profiles, low barriers to resistance and a lack of pan-genotype activity. A second wave of protease inhibitors are in phase II and III trials and promise to provide a drug regimen with a better dosing schedule and improved tolerance. These second-wave protease inhibitors will probably be approved in combination with PEG-IFN and Ribavirin (RBV), as well as future all-oral regimens. The true second-generation protease inhibitors are in earlier stages of development and efficacy data are anxiously awaited as they may provide pan-genotypic antiviral activity and a high genetic barrier to resistance.

Abbreviations
AEs adverse effects
cEVR complete early virological response
PIs NS3-4A protease inhibitors
RVR rapid virological response
SVR sustained viral response

A large number of NS3-4A protease inhibitors (PIs) have reached clinical development, including two drugs, telaprevir and boceprevir, that have already been approved for use in combination with pegylated IFN-α (PEG-IFN) and ribavirin (RBV) in patients infected with genotype 1 hepatitis C virus. Telaprevir and boceprevir significantly improve virological outcomes in both treatment-naїve [1, 2] and -experienced genotype 1 patients [3, 4]. However, the clinical utility of these first-generation PIs is limited by a thrice-daily dosing schedule (with food), increased rates of adverse effects (AEs) (anaemia and rash), a low genetic barrier to resistance and extensive drug–drug interactions. These limitations highlight the opportunities for improvement in protease inhibitors. This review will discuss the newer protease inhibitors under late-stage development, which should be more potent, with higher barriers to viral resistance, and improved dosing regimens.

Second-wave protease inhibitors
 
Second-wave protease inhibitors offer several advantages over currently available drugs. Improved pharmacokinetics will allow a once-a-day dosing schedule and the side-effect profiles are more tolerable. However, these agents have similar genotype coverage and similar resistance profiles to telaprevir and boceprevir, and do not represent true second-generation PIs. The improved PIs have been referred to as second-wave PIs. They will probably replace first-generation PIs in combination with PEG-IFN/RBV to become the initial partners in the first generation of all-oral regimens. The following drugs are currently in phase II and III development (Table 1).

Table 1. HCV protease inhibitors
 
TelaprevirApprovedFirst generation
BoceprevirApprovedFirst generation
SimeprevirPhase 3Second wave
BI1335Phase 3Second wave
AsunaprevirPhase 3 (all oral)Second wave
Danoprevir/rPhase 2Second wave
SovaprevirPhase 2Second wave
ABT450/rPhase 2Second wave
MK 5172Phase 2Second generation
ACH 2684Phase 2Second generation

Simeprevir (TMC435; Tibotec, Beerse, Belgium; Medivir Pharmaceuticals, Stockholm, Sweden; Janssen, Beerse, Belgium) is a once-a day-oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection. Phase I and II trials have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once-a-day dosing, and demonstrates potent antiviral activity and efficacy [5]. The final results of two phase IIb trials of TMC435 with PEG-IFN/RBV in naïve and treatment-experienced populations have been completed [6]. PILLAR study enrolled 368 treatment-naïve subjects with genotype 1 and compared two different doses (75mg vs 150 mg) and durations (12 weeks vs 24 weeks) of simeprevir therapy in combination with PEG-IFN/RBV for either 24 or 48 weeks. A sustained viral response (SVR) was achieved in 68–76% of patients with this triple therapy regimen and approximately 80% of subjects were eligible to receive shortened 24 weeks of therapy with very high SVR (93–96%). Adverse effects were similar to standard therapy, and the lowest rate of relapse was found in the study arm receiving 150 mg daily TMC435 in addition to PEG-IFN/RBV for 24 weeks (8%). In addition, SVR rates in the 150-mg dosing arms did not differ according to HCV subtype (1a vs 1b), but as expected, SVR was highest in the IL28B CC genotype.
 
ASPIRE was a randomized, double-blind, placebo-controlled phase IIb trial, which assessed the efficacy and safety of simeprevir in combination with PEG-IFN/RBV in 462 patients with genotype 1 HCV who had failed a previous PEG-IFN/RBV regimen. The ASPIRE study randomized patients to seven treatment arms, each of which was given simeprevir in combination with 48 weeks of PEG-IFN-2a/RBV. SVR rates were significantly higher in all simeprevir-containing treatment arms compared with PEG-IFN/RBV alone. The best results were obtained in the 150-mg dosing groups with a SVR of 85% vs 37% in prior relapsers, 75% vs 9% in partial responders and 51% vs 19% in prior non-responders. It is also important to note that higher 24-week SVR rates were observed with simeprevir-containing therapy in difficult-to-treat patient subgroups, including patients with cirrhosis and a previous non-response (31% SVR in non-response cirrhotics). As has been seen with most PI-based studies, breakthrough or relapse was associated with a resistant virus (42/43 people who experienced breakthrough and 34/36 who relapsed). Subjects with HCV genotype 1a were more likely to have the R155K mutation alone or with additional mutations, whereas people with HCV genotype 1b had the D168V mutation [7].
 
In both the naïve and treatment-experienced trials, TMC435 was generally well tolerated with no evidence of significant safety signals related to rash, anaemia or neutropaenia. However, transient elevations of direct and indirect bilirubin were seen in subjects who took a 150-mg dose of simeprevir. Elevations in bilirubin were not associated with an elevation of AST or ALT, returned to baseline with the cessation of therapy and are believed to be related to interference with bilirubin transporters.
 
Finally, simeprevir may also provide opportunities for use in non-genotype 1 patients. A phase IIa proof-of-concept trial provided evidence that TMC435 has a broad spectrum of activity against multiple HCV genotypes except for genotype 3 [8]. Monotherapy with oral TMC435 200 mg q.d. for 7 days was associated with potent antiviral activity in patients infected with genotypes 2, 4, 5 and 6. The greatest antiviral activity was observed among patients infected with genotypes 4 and 6, followed by genotypes 2 and 5. Of note, no antiviral activity was seen against genotype 3. Thus, simeprevir seems to offer significant improvement over boceprevir and telaprevir: once-a-day dosing, improved safety profile (lack of rash and anaemia) and expanded antiviral activity across more genotypes.

BI201335 (Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany) is another NS3/4A protease inhibitor with once-a-day dosing that has completed phase 2 testing. SILEN-C1 study reported the efficacy data from a randomized phase II trial with 429 genotype 1 treatment-naïve patients [9]. The treatment regimen included BI201335 in addition to PEG-IFN/RBV for 24 weeks at doses of 120 and 240 mg, followed by another 24 weeks of standard therapy. Response-guided therapy was evaluated and achievement of an eRVR (HCV-RNA negative at week 4 and week 12) resulted in randomization to stop therapy at week 24 or continue with PEG-IFN/RBV for a total of 48 weeks. The overall SVR rate was 83% for the 240-mg dose (lower for the 120-mg dose), and 92% of the patients with an eRVR achieved a SVR regardless of the subsequent duration of PEG-IFN/RBV. Adverse events (mostly gastrointestinal) resulted in drug discontinuation in 7.3% of subjects. SILEN-C2 study evaluated 288 partial or non-responders and evaluated the 240-mg dose, either once or twice daily in combination with PEG-IFN/RBV for 24 weeks [10]. The highest SVR was achieved in the once-a-day dosing groups: it was 50% in partial responders and 35% in non-responders. It should be noted that patients with cirrhosis were not included in this study. Both SILEN-C1 and C2 tested the efficacy of a 3-day lead-in with PEG-IFN/RBV. The expectation was that the lead-in would limit the development of resistance by providing better antiviral drug coverage when the PI was introduced. For unknown reasons, the lead-in arms in both trials showed a significant decrease in efficacy, and this strategy to limit resistance has been abandoned. SILEN-C3 evaluated treatment-naïve, genotype 1 patients and randomized them to either 12 or 24 weeks of once-a-day 120 mg BI 201335. Both groups received PEG-IFN/RBV for 24 weeks and patients who did not achieve an eRVR continued PEG-IFN/RBV until week 48. SVR rates were similar for both durations, 65% vs 73% overall and 82% vs 81% in those with eRVR respectively. Through all of the SILEN-C phase 2 trials, the adverse-event profile of BI 201335 appeared to be mild rash and photosensitivity along with some GI toxicity (nausea, diarrhoea and vomiting). As with a few other PIs under development, BI 201335 is associated with a transient rise in indirect or unconjugated bilirubin that is related to inhibition of the bilirubin transporter (inhibition of hepatic uptake of uridine diphosphate glucuronosyl transferase 1 family polypeptide A1, UGT1A1)[11]. The once-per-day dosing regimen that is moving forwards into phase 3 trials has fewer adverse events than the twice-per-day dosing regimen.

Danoprevir/r (RG7277; Roche, Basle, Switzerland; Intermune Pharmaceuticals, Brisband, CA) is a twice-a-day, ritonavir-boosted HCV protease inhibitor with good antiviral activity against genotypes 1, 4 and 6. Of note, the early hepatotoxicity signals of the drug were virtually eliminated by the addition of ritonovir boosting, which leads to strong inhibition of CYP3A and increased through concentrations of the PI. DAUPHINE is a large phase 2 trial in naïve patients that evaluated three different doses (50, 100 and 200 mg danoprevir, boosted with 100 mg ritonavir, twice daily) and response-guided therapy in combination with PEG-IFN/RBV [12]. Twelve weeks after stopping therapy, antiviral negativity (SVR12) was 93% in the 200-mg dosing arm, 83% in the 100-mg arm and 67% in the 50-mg arm. At the 200-mg dose, the response was not influenced by either HCV subtype (1a vs 1b) or IL28B genotype (CC vs non-CC), suggesting that this regimen leads to potent viral suppression. Of note, genotype 4 patients had a 100% SVR 12 across all dosing arms. Danoprevir is also being evaluated in IFN-free regimens combined with the nucleoside inhibitor, Mercitabine (RG7128) [13].
 
Asunaprevir (BMS-650032; Bristol-Myers Squibb, New York, NY) is a twice-daily protease inhibitor being developed in both IFN-containing and free regimens with daclatasvir, an NS5A inhibitor and BMS 791325, a non-nucleoside inhibitor. Asunaprevir was initially studied at a dose of 600 mg twice per day, but was decreased to 200 mg twice per day because of increased liver enzymes. The combination of asunaprevir and daclatisvir was the first regimen to successfully cure HCV-infected patients without the use of IFN [14]. Despite potential approval in an IFN-free combination in genotype 1b patients and a potential quad regimen, asunaprevir is not likely to become the PI of choice for this second wave of PIs because of the twice-per-day administration and potential association with hepatotoxicity.
 
Sovaprevir (ACH-1625; Achillion Pharmaceuticals, New Haven, CT) is another NS3 protease inhibitor with very high potency, reporting a half-maximal inhibitory concentration of ~1 nm. A phase IIa study reported that ACH-1625, with PEG-IFN/RBV, resulted in a RVR in 75–81% of subjects compared with a RVR of 20% in patients receiving PEG-IFN/RBV alone [15]. A phase IIb study is under way at this time, but given the true second-generation PI also from Achillion (see below), it is less likely that this PI will be carried through to phase III trials.
 
ABT-450/r (Abbott, Abbott Park, IL; Enanta Pharmaceuticals, Watertown, MA) ABT-450 is being evaluated with ritonavir boosting to increase plasma concentrations and enable once-a-day dosing. A recent analysis included 35 treatment-naїve chronic hepatitis C patients randomly assigned to receive ABT-450/ritonavir or placebo [16]. Participants received ABT-450/ritonavir at doses of 50/100 mg, 100/100 mg or 200/100 mg once daily, or placebo, as monotherapy for 3 days, followed by 12 weeks of ABT-450/ritonavir or placebo at the same dose in combination with PEG-IFN/RBV. During the 3 days of monotherapy, the response was similar in all three ABT-450/ritonavir dose arms, with a mean maximum HCVRNA decrease of around 4 log IU/ml, compared with 0.36 log IU/ml in the placebo group. In an intent-to-treat analysis at 4 weeks, 88% of patients receiving ABT-450/ritonavir plus PEG-IFN/RBV had achieved a RVR (RVR; HCV RNA <25 IU/ml) compared with only 9% in the placebo arm. At 12 weeks, 92% receiving ABT-450/ritonavir vs 18% receiving placebo had achieved a complete early virological response (cEVR, again HCV RNA <25 IU/ml). HCV sub-genotype (1a or 1b), baseline HCV RNA and IL28B gene pattern were not associated with differences in virological response. ABT-450/r is also being studied in all-oral regimens and is more likely to receive approval in this IFN-free pathway.

Second-generation protease inhibitors
 
Two second-generation protease inhibitors, MK-5172 and ACH-2684, are in various stages of clinical development. These true second-generation PIs are expected to have broader genotype coverage and higher barriers to resistance, which represents a significant shift from the second-wave PIs.
 
MK-5172 (Merck & Co., Inc, Whitehouse Station, NJ) is a novel macrocyclic NS3/4a protease inhibitor under phase II clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major HCV genotypes, notably variants resistant to earlier protease inhibitors. R155 is the main overlapping position for resistance and different mutations at this amino acid site within NS3 protease confer resistance to nearly all protease inhibitors in development. However, MK-5172 exhibits potent antiviral activity against variants carrying mutations at position R155. Thus, based on its preclinical profile, MK-5172 is expected to be broadly active against multiple HCV genotypes, including genotype 3 as well as clinically important resistance variants making it highly suited for incorporation into newer all-oral regimens. MK-5172 was given in doses of 50–800 mg QD (monotherapy) to 48 men with HCV genotype 1 and 30 HCV genotype 3 patients for 7 days [17]. There were six arms (including a placebo arm). The maximum change in HCV levels was a decrease of −5.37 IU/ml in HCV genotype 1 and −4.41 IU/ml in genotype 3 patients. In the genotype 1 patients, 75% (30 of 40 pts) were below the level of HCVRNA quantification (25 IU/ml). The drug was generally well tolerated. In early-stage studies, MK-5172 in various doses has been shown to work across different genotypes [18] and can be dosed once a day, which makes it an attractive candidate for future clinical development.
 
ACH-2684 (Achillion Pharmaceuticals) is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and a safety profile at high drug exposures that strongly supports once-a-day dosing. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. It has preclinical activity against the six known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b at an IC50 of approximately 100 pm [19]. Achillion Pharmaceuticals, Inc reported proof-of-concept data from a Phase 1b clinical trial demonstrating that patients with HCV genotype 1 treated with ACH-2684 achieved a mean maximum 3.73 log10 reduction in HCV RNA after 3-day 400-mg monotherapy with once-a-day dosing. The compound also demonstrated good safety and tolerance both in healthy volunteers and in patients with HCV. This PI seems to represent an ideal partner for all-oral regimens that can help deliver pangenotypic activity with a high barrier to resistance.

Conclusion
 
The development of protease inhibitors represents a significant milestone in improving the efficacy of HCV treatment. However, the limitations of first-generation PIs have opened the door for continued drug development in this class. Several other direct-acting antivirals are under development [20]. Simeprevir, asunaprevir and BI are second-wave PIs in phase III trials, and will probably obtain approval with PEG-IFN/RBV in 2014. To be used in an all-oral regimen, second-wave PIs will need to be used in combination with other direct-acting antivirals to overcome the low genetic barrier to resistance. These combinations could include PIs and a nucleoside inhibitor with a high genetic barrier to resistance or PIs with a non-nucleoside inhibitor (or NS5A inhibitor) with a non-overlapping resistance profile. The future of protease inhibitors lies in the further development of second-generation drugs with a broad genotypic coverage and a high genetic barrier for resistance, which may be the ideal backbone for an all-oral HCV treatment regimen.

Disclosure
 
The authors have no disclosure.

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