The Next Generation of DAAs: What's on the Horizon?

Hi Folks,
This month, Medscape added a couple hepatitis C learning activities for physicians, physician assistants, nurse practitioners, and nurses. Links to two activities are provided below, a third "The Next Generation of DAAs: What's on the Horizon?" has been added to the blog.  

The "Continuing Medical Education (CME)" is technical, but the participant can walk away gaining knowledge of this disease and the new HCV drugs making their way down the pipeline. In any event it can be worth taking advantage of these excellent learning opportunities. 

View CME available at Medscape

First CME

CME A New Era of HCV Treatment and Management CME
Dr Donald Jensen chronicles the past 2 decades of HCV infection therapy from mono and dual therapies to triple therapy with DAAs.

Medscape Education Oncology, March 27, 2012

 

Second CME

 

Addressing the HCV Referral and Treatment Bottleneck CME

In this exclusive interview, Dr Fried provides insight into the evolving HCV treatment model.

Medscape Education Infectious Diseases, March 28, 2012

 

*Free registration is required

 

The Next Generation of DAAs: What's on the Horizon?

Drugs in 4 classes of second-generation DAAs have entered phase 3 trials with the hope of eradication chronic HCV infection

 

The CME below covers the following:

 

Improve awareness and understanding of emerging therapies for HCV

Upon completion of this activity, participants will be able to:

1. Identify the limitations and unaddressed needs associated with current treatments
2. Describe how new agents in development may address these issues

 From Medscape Education Infectious Diseases

The Next Generation of DAAs: What's on the Horizon?

Paul Y. Kwo, MD; Marco A. Lacerda, MD

Faculty and Disclosures

CME Released: 03/28/2012; Valid for credit through 03/28/2013

Introduction

Until mid-2011 the standard treatment regimen for chronic hepatitis C virus (HCV) infection was pegylated interferon (PEG-IFN) and ribavirin (RBV). Although this regimen improved treatment success rates and shortened duration of treatment, it left many gaps in the treatment and outcomes of chronic HCV infection, which have been the focus of numerous clinical trials over the past decade. In May 2011 the approval by the US Food and Drug Administration (FDA) of 2 direct-acting antiviral agents (DAAs), the first-generation NS3/NS4a protease inhibitors telaprevir (Incivek, Vertex)^[1] and boceprevir (Victrelis, Merck)^[2], heralded a new era in this field. The introduction of DAAs for the treatment of HCV infection is the most significant development since the pegylation of interferon (INF) and the addition of RBV to PEG-IFN in the late 1990s.^[3]

Triple therapy, consisting of an NS3/NS4a protease inhibitor (boceprevir or telaprevir), PEG-IFN (alfa-2a or alfa-2b), and RBV is now the standard of care for genotype 1 HCV infection. The upside is that sustained virologic response (SVR) rates improved significantly (from 63% to 75%)^[1,2] and the duration of treatment decreased from 12 months to 6 months.^[1,2] The downside is that these regimens:

• are only applicable to patients with genotype 1 chronic HCV infection;
• are currently not indicated for some genotype 1 patient populations (eg, elderly patients, patients with HIV/HCV coinfection or cirrhosis);
• increase the patient's treatment burden (ie, pill burden, dosage and administration requirements for telaprevir);
• are more complex to administer than the standard regimen;
• have significant drug-drug interactions; and
• are more toxic.^[4]

Importantly, for the first time, clinicians administering HCV therapy must be aware of generating resistant-associated variants (RAVs) in patients who fail to achieve SVR. The highly replicative HCV presents a significant challenge for the DAAs. A high degree of viral sequence diversity leads to the generation of large numbers of potentially DAA-resistant virus, variant-bearing amino acid substitutions that preexist as minor populations within a patient's quasispecies. Resistance to DAAs is conferred by a single amino acid substitution in the NS3 protease that has only a moderate impact on viral fitness; it will allow resistant variants to become dominant within the viral quasispecies within days of initiating DAA therapy unless combined with another agent. Thus, selection of RAVs is an inherent characteristic of DAAs; therefore, monotherapy with DAAs results in rapid development of RAVs, rebound, and treatment failure. As exciting as the debut of the first DAAs was, further drug development is needed to address these gaps. The ideal regimen would be one that is:

• safe;
• highly effective in all patients, regardless of genotype;
• subject to minimal drug-drug interactions;
• simple to administer for both the clinician (simple stopping rules) and the patient (all-oral regimen [INF and/or RBV free] with a lesser pill burden); and
• more tolerable.

This article will discuss clinical trials of investigational agents used with or without approved agents for the treatment of chronic HCV infection.

Targets for Anti-HCV Therapy

The HCV replication cycle is complex (Figure 1) and thus, provides several targets for anti-HCV therapy. All of the HCV enzymes are essential for HCV replication and are potential targets for new drug discovery. The milestones in HCV research have been detailed in the literature.^[5] The development and approval of the DAAs evolved from a greater understanding of the HCV replication cycle, in particular, the nonstructural proteins.

Figure 1. HCV enters the hepatocyte and generates structural and nonstructural proteins that are potential targets because they support viral RNA replication. The NS3 and cofactor NS4a serine protease catalyze posttransitional processing of all nonstructural proteins as well as cleave the NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B junctions, leading to the formation of a replicative complex. Kwo PY, et al. Gut Liver. 2011;5:406-417. Republished with permission.

DAAs

There are 3 classes of DAAs: (1) protease inhibitor, (2) polymerase inhibitor, and (3) NS5A replication complex inhibitor; the key characteristics of these classes are summarized in Table 1.

Nucleoside inhibitors of NS5B RNA-dependent RNA polymerase are nucleos(t)ide analogues that target the active site of the polymerase and are incorporated by the polymerase into the RNA, leading to the chain termination.

Table 1. Characteristics of the Anti-HCV Drug Classes

DAA Class	Potency Against Antiviral Replication	Genotypic Coverage	Genetic Barrier to Resistance
NS3/NS4A protease inhibitor*[6]	High	Limited (genotype 1)	Low
Polymerase inhibitor[7] NS5B nucleoside inhibitor† NS5B nonnucleoside inhibitor††	Intermediate Intermediate	Pangenotypic (genotype 1,2,3) Limited (genotype 1)	High Low
NS5A replication complex inhibitor§[3]	High	Pangenotypic (genotype 1,4)	Low

*Inhibitor of NS3 serine protease
^†Nucleoside inhibitor of NS5B RNA-dependent RNA polymerase
^††Nonnucleoside inhibitor of NS5B RNA-dependent RNA polymerase
^§Inhibitor of NS5A replicase protein

Beyond Telaprevir and Boceprevir: Second-Generation DAAs Combined With PEG-IFN/RBV

The DAA pipeline is robust. As with the first-generation DAAs, the next DAAs approved for the treatment of chronic HCV infection will likely also require the addition of the PEG-IFN/RBV backbone. The investigational DAAs that are in phase 3 or are moving into phase 3 studies as of March 2012 are listed in Table 2.

Table 2. Phase 2 Studies* of DAA Therapy Combined With PEG-IFN/RBV (as of March 2012)

Investigational Agent and Clinical Trial Name	Manufacturer	Class	Preliminary Efficacy Results (Cure Rates)	Current Study Phase
Simeprevir (TMC435) PILLAR trial (phase 2b)[8]	Tibotec, Inc.	NS3/NS4A	75% to 86%	Phase 3
BI 201335 SILEN-C1 trial (phase 2b)[9]	Boehringer Ingelheim Pharmaceuticals, Inc.	NS3/NS4A	71% to 83%	Phase 3
BMS 790052† (daclastavir plus asunaprevir)[10]	Bristol-Myers Squibb Company	NS5A	36% to 90%	Phase 3
PSI-7977 (now GS-7977) PROTON Study (phase 2)[11]	Genentech, Inc./ Pharmasett, Inc.	NS5B nucleoside polymerase	88% to 91%	Entering phase 3

*The SILEN-C3 and COMMAND-1 trials are not included because the SILEN-C3 trial did not include a control group that received the previous standard of care and the cure rates for the COMMAND-1 trial have not been reported.
^†This phase 2b study randomized patients to receive daclatasvir and asunaprevir alone or in combination with PEG-IFN/RBV.

The PILLAR Trial

The PILLAR trial was an intention-to-treat analysis of treatment-naive patients with genotype 1 chronic HCV infection who received 12 weeks or 24 weeks of once-daily TMC435 and PEG-IFN/RBV. Preliminary data suggest comparable or superior efficacy with similar or improved side-effect profiles and easier dosing schedules compared with the currently approved DAAs; after 24 weeks of treatment 75% to 86% of patients treated with TMC435 had undetectable HCV RNA, depending on the dose (75 mg vs 150 mg).^[8] In addition, 79% to 86% of the patients receiving TMC435 qualified for a shortened (24-week) duration of therapy; of those, 85% to 96% had undetectable HCV RNA at week 24.^[8]

The SILEN-C1 Trial

The SILEN-C1 trial compared SVR rates in treatment-naive patients with genotype 1 chronic HCV infection who received once-daily BI 201335 (120 mg vs 240 mg) with a 3-day lead in of PEG-IFN/RBV with patients who received once-daily BI 201335 (240 mg) without a lead in PEG-IFN/RBV.^[9] Preliminary data suggest comparable or superior efficacy with similar or improved side-effect profiles and easier dosing schedules compared with the currently approved DAAs. The majority of patients with more difficult-to-treat HCV types (genotype 1a and IL-28B non-CC allele) achieved SVR. In the group that received 240 mg BI 201335 without a lead in of PEG-IFN/RBV, SVR rates were as follows: overall, 83.1% (genotype 1a [82.4%], genotype 1b [84%]); IL-28B non-CC alleles (70.8%); and IL-28B CC alleles (100%).^[9]

The PROTON Trial

The PROTON trial was an intention-to-treat analysis of treatment-naive patients with genotype 1 chronic HCV infection who received a 24-week treatment regimen incorporating 12 weeks of the once-daily, second-generation nucleoside polymerase inhibitor PSI-7977 (Pharmasset) (200 mg vs 400 mg) in combination with PEG-IFN/RBV.^[11] The SVR rate at 12 weeks after treatment was 88% in the 200-mg cohort and 91% in the 400-mg cohort.

Study to Determine the Effectiveness of Antiviral Combination Therapy to Treat HCV-Infected Patients Who Have Previously Failed Standard of Care

The combination of the once-daily NS5A inhibitor (daclatasvir, Bristol-Myers Squibb) combined with the protease inhibitor asunaprevir (BMS-650032, Bristol-Myers Squibb) was given to noncirrhotic, genotype 1 null responders to PEG/IFN.^[10] The regimen consisted of daclatasvir (60 mg, once daily) and asunaprevir (600 mg, twice daily) for 24 weeks. The group that received daclatasvir and BMS-650032 in combination with PEG/RBV (genotype 1 and 1 genotype 1b) achieved an SVR rate of 90%.

Quadruple Therapy

Lessons learned from the experience of treating HIV-infected patients led researchers to investigate combining DAAs that target different steps of viral replication to increase potency and lower the genetic barrier to resistance. The addition of 2 DAAs to the PEG-IFN/RBV backbone is referred to as quadruple or "quad" therapy. Two quad therapy regimens are in phase 2 clinical trials. The clinical trial of the aforementioned daclatasvir plus asunaprevir also randomized nonresponder patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg, once daily) and the NS3 protease inhibitor asunaprevir (600 mg, twice daily) in combination with PEG-IFN/RBV for 24 weeks. The SVR rate was 90%.^[10]

The ZENITH Trial

The ZENITH trial evaluated a quad regimen consisting of 2 DAAs (the NS5b polymerase inhibitor VX-222 [100 mg vs 400 mg] and telaprevir) and PEG-IFN/RBV.^[12] This study was designed with stopping rules (ie, undetectable HCV RNA levels at week 2 and week 8) to determine whether a patient was eligible to stop all treatment at 12 weeks. Patients with detectable HCV RNA levels at week 2 and/or week 8 received an additional 12 weeks of PEG-IFN/RBV (for a total of 24 weeks). Overall SVR rates were 83% (100 mg) and 90% (400 mg). SVR rates after 12 weeks of treatment in patients eligible to receive only 12 weeks of therapy were 82% (100 mg) and 93% (400 mg). SVR rates after 12 weeks of treatment in patients eligible to receive 24 weeks of therapy were 83% (100 mg) and 87% (400 mg).

INF-free DAA Therapy

Preliminary data from phase 2 clinical trials demonstrate that DAA combinations with or without RBV and without INF achieve viral clearance and SVR. This is an important step in the evolution of HCV therapy, as many HCV-infected persons are unable to tolerate INF-based therapies. Moreover, combination DAA regimens are more likely to reduce the emergence RAVs. As of March 2012, multiple studies of INF-free combination DAA therapy (ie, NS3/NS4a, NS5a, NS5b, nonnucleoside NS5b inhibitors) with and without RBV are ongoing.

The INFORM Trial

The INFORM trial evaluated 5 INF-free treatment regimens of the NS3/NS4 oral protease inhibitor danoprevir (InterMune/Genentech) combined with the NS5B polymerase inhibitor mericitabine (Roche) for 14 days in treatment-naive and nonresponder patients. In the treatment-naive cohort, 87.5% persons achieved viral suppression at day 13; this was the first proof-of-concept study showing antiviral efficacy of an all-oral regimen.^[13]

Daclatasvir Plus Asunaprevir

The clinical trial of the aforementioned daclatasvir plus asunaprevir also showed that null responders who received asunaprevir plus daclatasvir achieved an SVR rate of 36%, with 2/2 genotype 1b null responders achieving SVR.^[10] These results were replicated in study of 10 Japanese noncirrhotic null responders with genotype 1b chronic HCV infection, who received daclatasvir plus asunaprevir without PEG-IFN/RBV for 24 weeks. The SVR rate was 90%, although 1 patient who achieved SVR stopped therapy early due to adverse events.^[14]

The SOUND-C2 Trial

The SOUND-C2 trial evaluated 5 INF-free regimens using the combination of the NS5B nonnucleoside polymerase inhibitor BI 207127 (600 mg, 3 times daily) with the NS3/NS4a protease inhibitor BI 201335 (120 mg) plus RBV in genotype 1 treatment-naive patients.^[15] Preliminary data were reported for persons randomized to 16 weeks of therapy. The SVR rate was 76% at week 12 and 59% (43% in genotype 1a- and 69% in genotype 1b-infected patients) at 12 weeks after completion of 16 weeks of treatment.

Interim data from 2 of the treatment arms of the ZENITH trial showed that viral loads were below the lower limit of quantification (<25 IU/mL) in 80% of patients at week 2 and 83% of patients at week 12.^[12]

Genotype 2 and Genotype 3

The ELECTRON trial combined PEG-IFN for a duration of 0, 4, 8, and 12 weeks with the nucleoside polymerase inhibitor PSI-7977 with RBV for 12 weeks in patients with genotype 2 and genotype 3 HCV infection.^[16] The SVR rates were 100% in all arms at 12 weeks after completion of treatment, including the INF-free cohort receiving only PSI-7977 and RBV. These results suggest that extremely high response rates can be achieved with 12 weeks of INF-free therapy in patients with genotype 2 and 3 HCV infection.

The VITAL 1 Trial

A planned interim (12-week) analysis of the VITAL 1 trial in patients with genotype 2 and 3 HCV infection examined alisporivir (an oral cyclophilin inhibitor [Novartis]) monotherapy with or without RBV and with or without pegylated INF.^[17] There was a >3 log₁₀ reduction in the mean HCV RNA levels over the first 4 weeks of treatment with the INF-free alisporivir regimen. Rapid virologic response was achieved by 28%, 36.9%, and 41% of patients in the alisporivir 1000 mg, alisporivir 600 mg plus RBV, and alisporivir 800 mg plus RBV groups, respectively; from week 4 to week 6, the proportion of patients with undetectable HCV RNA increased to 31.7%, 48.8%, and 46.2% in these same groups, respectively. Overall, extended rapid virologic response with INF-free alisporivir and alisporivir with add-on INF treatment from week 6 was achieved in 92.7%, 95.2%, and 90.3% in the alisporivir 1000 mg, alisporivir 600 mg plus RBV, and alisporivir 800 mg plus RBV groups, respectively. Interim response rates were also similar among patients with genotype 2 and genotype 3 chronic HCV infection.

Summary

Triple therapy with a protease inhibitor and PEG-IFN/RBV will likely remain the standard of care for patients with genotype 1 chronic HCV infection through 2014, although it is possible that the once-daily protease inhibitors (ie, TMC435, BI 201335) and/or the NS5A inhibitor daclatasvir will be FDA-approved during this time period. The NS5B inhibitor PSI-7977 also has been associated with high SVR rates when added to PEG-IFN/RBV. By 2014 the era of combination DAA therapy -- more than 1 DAA -- with or without INF and RBV should commence.

Preliminary data from phase 2 studies suggest that RBV will remain a part of some oral regimens because breakthrough/relapse rates appear to be lower when RBV is added to DAAs, particularly in patients with chronic genotype 1a HCV infection. Also, combination DAA regimens (some INF-free) show increased efficacy, good safety profiles, shorter duration of therapy, and lower resistance. In addition, some investigational agents (eg, PSI 7977 in combination with RBV) have achieved high SVR rates in patients with genotype 2 and 3 chronic HCV infection.

In the future chronic HCV infection may be treated much like Helicobacter pylori: a finite duration (12 weeks to 24 weeks) of an all-oral therapy with subsequent eradication or cure. The role of PEG-IFN/RBV in DAA regimens (especially in in treatment-naive patients who achieve rapid clearance and patients most refractory to PEG-IFN/RBV) remains to be defined, but given the impressive results reported with quadruple therapy, this combination may be required for refractory chronic HCV infection. Promising results, however, require confirmation in larger studies, and in more diverse patient populations.

Supported by an independent educational grant from Genentech.

Disclaimer

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.
Medscape Education © 2012 Medscape, LLC

References

1. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416. Abstract
2. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206. Abstract
3. Poordad F, Khungar V. Emerging therapeutic options in hepatitis C virus infection. Am J Manag Care. 2011;17:S123-S130. Abstract
4. Vachon ML, Dieterich DT. The era of direct-acting antivirals has begun. Semin Liver Dis. 2011;31:399-409. Abstract
5. Moradpour D, Penin F, Rice CN. Replication of hepatitis C virus. Nat Review Microbiol. 2007;5:453-463.
6. Lange CM, Sarrazin C, Zeuzem S. Review article: specifically targeted anti-viral therapy for hepatitis C - a new era in therapy. Aliment Pharmacol Ther. 2010;32:14-28. Abstract
7. Kwo PY, Vinayek R. The therapeutic approaches for hepatitis C virus: protease inhibitors and polymerase inhibitors. Gut Liver. 2011;5:406-417. Abstract
8. Fried M, Buti M, Dire GJ, et al. TMC435 in combination with peginterferon and ribavarin in treatment-naïve HCV genotype 1 patients: Final analysis of the PILLAR Phase IIB study. In: Program and Abstracts From the 62th Annual Meeting of the American Association for the Study of Liver Diseases; November 6-9, 2011; San Francisco, CA. Abstract LB-5.
9. Sulkowski MS, Emanoil C, Asselah FA, et al. Treatment with the 2nd generation HCV protease inhibitor BI 201335 results in high and consistent SVR rates -- Results from SILEN-C1 in treatment-naïve patients across different baseline factors. In: Program and Abstracts From the 62th Annual Meeting of the American Association for the Study of Liver Diseases; November 6-9, 2011; San Francisco, CA. Abstract 226.
10. Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216-224. Abstract
11. Lawitz E, Lalezari JP, Hassanein T, et al. Once-daily PSI-7977 plus Peg/RBV in treatment-naive patients with HCV GT1: Robust end of treatment response rates are sustained post-treatment. In: Program and Abstracts From the 62th Annual Meeting of the American Association for the Study of Liver Diseases; November 6-9, 2011; San Francisco, CA. Abstract 225.
12. Nelson DR, Jacobson IM, Di Bisceglie AM, et al. VX-222/telaprevir in combination with peginterferon-alfa-2a and ribavirin in treamtent naïve genotype 1 HCV patients treated for 12 weeks: Zenith study, SVR12, SVR12 interim analysis. In: Program and Abstracts From the 62th Annual Meeting of the American Association for the Study of Liver Diseases; November 6-9, 2011; San Francisco, CA. Abstract LB-14.
13. Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose- escalation trial. Lancet. 2010;376:1467-1475. Abstract
14. Chayama K, Takahashi S, Toyota J, et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology. 2012;55:742-748. Abstract
15. Zeuzem S, Soriano V, Asselah T, et al. Virologic response to an interferon-free regimen of BI201335 and BI207127, with and without ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: week 12 interim of the SOUND-C2 study. In: Program and Abstracts From the 62th Annual Meeting of the American Association for the Study of Liver Diseases; November 6-9, 2011; San Francisco, CA. Abstract LB-15.
16. Gane EJ, Stedman CA, Hyland RH, et al. Once daily PSI-7977 plus RBV: Pegylated interferon-ALFA not required for complete rapid viral response in treatment-naive patients with HCV GT2 or GT3. In: Program and Abstracts From the 62th Annual Meeting of the American Association for the Study of Liver Diseases; November 6-9, 2011; San Francisco, CA. Abstract 34.
17. Pawlotsky JM, Flisiak R, Rasenack J, et al. Once daily alisporivir interferon (IFN)-free regimens achieve high rates of early HCV clearance in previously untreated patients with HCV genotype (G) 2 or 3. In: Program and Abstracts From the 62th Annual Meeting of the American Association for the Study of Liver Diseases; November 6-9, 2011; San Francisco, CA. Abstract LB-11.