Hepatitis C Drug Development at a Crossroads†
Authors: David R. Nelson
Journal: Hepatology (2009)

The introduction of specifically targeted antiviral therapy (STAT-C) to peginterferon (PEG-IFN) and ribavirin (RBV) is soon at hand and will offer new treatment opportunities to patients infected with hepatitis C. The recently released Protease Inhibition for Viral Evaluation (PROVE, evaluating telaprevir) and Serine Protease Inhibitor Therapy (SPRINT, evaluating boceprevir) studies suggest that protease inhibitors in combination with PEG-IFN/RBV can produce sustained viral response rates (SVR) approaching 70% to 75% in genotype 1, treatment-naïve patients and the potential to shorten treatment duration in those with a rapid viral response.1-3 For previous nonresponders and relapsers to interferon (IFN)-based therapies, there is realistic hope for retreatment success (approximately 40% and 75% SVR, respectively, in PROVE 3 data).4 In addition, there is early indication that STAT-C drugs may help overcome negative host factors that have historically been associated with poor response rates (such as ethnicity, insulin resistance, steatosis, cirrhosis). A small cohort of African Americans included in PROVE-1 had a four-fold higher SVR rate with telaprevir (44% versus 11%), and the presence of cirrhosis did not negatively impact SVR rates in PROVE-3. FDA, Food and Drug Administration; HIV, human immunodeficiency virus; IFN, interferon; PEG-IFN, pegylated interferon; RBV, ribavirin; SPRINT, Serine Protease Inhibitor Therapy; STAT-C, specifically targeted antiviral therapy; SVR, sustained virological resistance. However, these trials also emphasize the limitations of protease inhibitors, and viral resistance data have provided important new lessons for small molecule drug development. The initial rapid drop in hepatitis C virus (HCV) viral levels on protease therapy is attributable to inhibition of the wild-type virus that then leads to the "uncovering" of preexisting resistant variants.5 The continued replication of these variants can then lead to a virological breakthrough (ranging from 2%-24% based on treatment regimen). Most reports have suggested that resistant variants are present at very low frequencies (<1%) and are usually detected after near complete suppression of the dominant wild-type virus. However, a recent analysis has suggested that naturally occurring drug resistance to protease and polymerase inhibitors can be seen almost 10% of patients with genotype 1.6 Another important finding with significant clinical implications from the PROVE trials is the different rates of resistance mutations detected between genotype 1a and 1b (much higher for 1a). The most likely explanation for these observations is a relative difference in the genetic barrier to resistance between subtypes. For example, the V36M or R155K mutation that can confer drug resistance to telaprevir requires only one nucleotide change from genotype 1a consensus sequence, whereas two substitutions are required in genotype 1b. Thus, it appears that HCV subtyping may play an important role in helping to select future treatment regimens and predict resistance development. Perhaps the most relevant conclusion of the PROVE and SPRINT trials is that PEG-IFN and RBV will remain critical elements in new treatment regimens. Patients who did not receive RBV in the PROVE trials and those with low-dose RBV (400-1000 mg) in the SPRINT-1 trial had increased viral breakthrough, higher relapse, and lower SVR. These data strongly indicate that standard-dose RBV is required to optimize response to these first-generation protease inhibitors. In addition, a 4-week lead-in phase of PEG-IFN/RBV in the SPRINT-1 trial led to a 50% reduction in viral breakthrough, likely because of the delivery of a more steady state of PEG-IFN/RBV and a lower viral load at the onset of protease inhibitor introduction. Lead-in phase approaches are now being extensively evaluated in other phase 2/3 programs, and its utility is still uncertain. Unfortunately, a common theme across all trials was that adverse events such as rash, pruritus, nausea, diarrhea, and anemia occurred more frequently in the protease-containing arms versus the standard of care arm. A higher proportion of both boceprevir-treated and telaprevir-treated patients discontinued treatment because of adverse events (1.5-fold to two-fold increase compared with control arm). The findings from the PROVE and SPRINT studies have dramatic implications, because these are the first extensive phase 2 data to suggest that a new treatment paradigm is on the horizon for HCV infection. Both protease inhibitors have fully enrolled phase 3 programs underway, and it is estimated that 2011 will bring approval of at least one of these agents. However, given the continued need for PEG-IFN and full-dose RBV, there are many HCV-infected groups that may not benefit from the addition of STAT-C agents, including decompensated cirrhosis, renal failure, posttransplantation, and the IFN-intolerant group (which may comprise as many as 50%-60% of all HCV-infected patients).7 Thus, what is desperately needed is the development of IFN-free regimens; in other words, a combination of small molecules similar to human immunodeficiency virus (HIV) therapy. The groundwork for this strategy has been set, but it is currently unclear whether HCV can be cured with direct-acting antiviral agents alone and without IFN-containing regimens. In vitro studies have confirmed additive/synergistic antiviral efficacy and the reduction of resistance with combinations of STAT-C agents, providing the biological plausibility to eradicate HCV with pure antiviral drug therapy.8 The first in vivo proof of principle has been generated in the chimpanzee model, in which HCV has been eradicated in one animal that was treated with dual antiviral therapy, including a protease and polymerase inhibitor.9 A novel study called INFORM-1 (Interferon-Free Regiment for the Management of HCV infection), the first dual-combination clinical trial with oral antivirals in patients with hepatitis C, is ongoing and evaluates the safety and combined antiviral activity of R7227 (ITMN-191), a protease inhibitor, and R7128, a polymerase inhibitor, in 14 days of combination therapy in treatment-naïve patients infected with HCV genotype 1.10 The initial cohorts of this study were recently reported and appear to lay the foundation for more aggressive and prolonged non-IFN trial designs. Patients receiving this combination for 14 days experienced a median reduction in viral levels of 4.8 log to 5.2 log IU in the higher doses tested. No treatment-related serious adverse events, dose reductions, drug–drug interactions, or discontinuations were reported. But, has this early "success" moved IFN-free regimens a step closer to reality for patients? The answer to this question depends largely on the Food and Drug Administration (FDA) reaction to these emerging data. The current regulatory climate in the United States is increasingly conservative, and there has been limited interest in early non-IFN regimens in HCV drug development. For an approval pathway, superiority to standard of care will be required, thus leading to "add-on" triple-therapy trial designs for most agents being tested. It is also clear that FDA concerns of resistance emergence will limit STAT-C monotherapy testing and place new challenges before non-IFN drug development pathways. Extensive preclinical resistance and safety testing are required before initiating human trials, while duration of exposure to monotherapy is being minimized (only 2-3 days of monotherapy allowed in phase 1/2). The Advisory Committee for the FDA has recommended that STAT-C agents should not undergo combination with other STAT-C agents until after phase 2b completion of each single agent.11 The result of this regulatory climate has led to the recent "outsourcing" of aggressive drug development to non-U.S. territories. The INFORM-1 trial is being enrolled exclusively in Australia and New Zealand, and one must assume that this is to bypass the strict FDA regulatory environment. Recently, this conservative approach for accelerated drug development has come under fire, and a large number of HCV-infected patients wonder why the hurdle appears higher than for HIV drug development. HIV was considered a deadly disease in which accelerated drug development was crucial, and the regulatory environment was friendlier to accelerated development. However, on the surface, HCV does not appear to present such a compelling argument. Data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) study suggests an annual death rate from those with advanced HCV-related disease of only 1%-2%.12 However, there are other select groups of patients who may suffer a much higher rate of mortality, including those with decompensated cirrhosis, HIV/HCV coinfection, and posttransplantation patients. Given recent data suggesting that SVR leads to an improvement in liver-related complications and mortality,13, 14 the addition of STAT-C agents has the potential for an immediate impact on morbidity and mortality in these special populations. However, most of these populations have not been included in the phase 2 and 3 clinical trials to date because of the need for extensive safety data and drug interaction studies. Lost in the excitement around new STAT-C therapies is the ever-growing list of HCV agents that have been removed from clinical development in the last few years. At least 15 drugs have had development halted during clinical trials, and there are likely many more that have not entered the public domain. Of note, most of these compounds have been discontinued not because of lack of antiviral activity, but rather because of unacceptable adverse event profiles (ranging from cardiomyopathy to hepatotoxicity). Thus, exposing these at-risk populations to early drug development may be associated with challenging adverse event profiles. Lastly, there is theoretical concern that early and ineffective combination of a protease and a polymerase inhibitor could lead to multidrug resistance and compromise future treatment regimens. In summary, potent viral suppression and shortened duration of therapy have been shown in the clinical trials with the addition of protease inhibitors to standard therapy. Although there is optimism surrounding the new STAT-C agents in the treatment of HCV, there is also concern regarding how resistance and new adverse events will impact future therapy. It also appears that the platform exists to begin to explore non–IFN-containing regimens, which would be an enormous step forward to accessing a large proportion of infected patients. However, this pathway forward is fraught with many hurdles and will need to be undertaken with deliberation and caution. We clearly stand at an important crossroads in treatment paradigms for HCV.