Chronic hepatitis C virus (HCV) infection, an insidious disease of the liver affecting over 170 million people worldwide, is the leading cause of liver cancer and liver transplant in the Western world. Thanks to the concerted efforts of countless researchers and more than 30 biotechnology and pharmaceutical companies, the advent of new antiviral therapies has transformed chronic HCV infection into a curable disease for a substantial subgroup of patients.
Cure is measured as a sustained virologic response (SVR), defined as clearance of viral RNA from the blood as measured by sensitive PCR assay for a full six months after completing therapy. SVR has been shown to predict long-term clearance of virus, dramatically reduced rates of hepatocellular carcinoma, and reduced progression to cirrhosis and liver transplantation.
Two new HCV protease inhibitor agents, telaprevir (Vertex) and boceprevir (Merck), have increased SVR rates in genotype 1 HCV impressively from ~40% with pegylated interferon-α plus ribavirin (PegIFN/riba) to the mid-70% and mid-60% range, respectively. However, due to high rates of antiviral resistance these agents must be added to a therapy backbone of PegIFN/riba to be effective.
While telaprevir and boceprevir have improved the regimen by shortening the length of therapy for a substantial subset of patients (primarily treatment-naïve early responders), they have meaningfully added to the toxicity profile.
Telaprevir treatment resulted in an increase in the frequency of anemia of greater than twofold, and more than 50% of patients experienced a mild to moderate rash. There were also reports of serious cutaneous adverse reactions (SCAR) that occurred in 0.7% of treated patients that included potentially life-threatening conditions such as Stevens Johnson Syndrome (and a dermatologic eosinophilia syndrome that will likely require a vigorous pharmacovigilance program to insure the safety of patients.)
Boceprevir was shown to have bone marrow suppressive effects resulting in increased rates of anemia (49% vs. 29%), neutropenia (23% vs. 18%), and thrombocytopenia (4% vs. 1%). These effects will also require aggressive post- market pharmacovigilance to insure patient safety. These new protease inhibitors are also administered three times a day and must be taken with a meal, so patient compliance and the possible impact of poor dosing compliance on the emergence of resistance is going to be a tangible challenge in the post-approval setting.
Based on population sequencing data from the pivotal trials, the majority of patients who do not achieve an SVR on telaprevir or boceprevir triple therapy will have resistance to these agents. The impact on subsequent treatment options for these patients is unknown and potentially serious. Other patient groups that had lower response rates or were not sufficiently studied with the telaprevir and boceprevir regimens include patients with prior null response to IFN therapy, cirrhosis, black patients, and patients greater than 65 years of age.
In particular, the highly response-predictive IL28b host genotype testing was retrospective overall and insufficiently studied in black patients for the telaprevir and boceprevir programs.
Future clinical development is likely to proceed along two major courses: one tactical and one strategic. The tactical course will involve incremental improvements using a PegIFN/ribavirin backbone. Newer protease inhibitors and other more potent antiviral agents will be added to PegIFN/riba as second-generation triple therapies to improve SVR rates and tolerability profiles even further.
Data presented at the “European Association for the Study of the Liver (EASL)” described new antiviral agents that can be used with less frequent dosing, lower resistance rates, and less toxicity.
Noteworthy among them was the Phase II result from the Bristol-Myers Squibb (BMS) NS5a inhibitor (BMS-052) in combination with PegIFN/riba, which showed an SVR rate at 12 weeks post-treatment ranging from 83–92%. This agent is given once per day, and in this early-phase study appeared to be well tolerated.
Due to the higher predicted rate of response, the resistance rates will likely be lower for BMS-052 as well. A Phase II report from Pharmasset showed that its once-daily nucleoside polymerase inhibitor (PSI-7977) was associated with a 98% rapid virologic response at four weeks when combined with PegIFN/ribavirin compared to 19% for PegIFN/ribavirin alone. These agents, and others like them, will likely create better second-generation combination cocktails with PegIFN/riba over the next three to five years.
While important, the tactical improvements to the PegIFN/riba backbone will likely be overshadowed in the next five to ten years by strategic improvements in therapy. There are multiple new classes of agents in Phase II development that target various other functional components of HCV such as second-generation protease inhibitors (Boehringer Ingelheim, Abbott, BMS, Gilead, Roche, Achillion), nucleoside polymerase inhibitors (Pharmasset, Roche, Idenix), non-nucleoside polymerase inhibitors (Abbott, Anadys, Boehringer Ingelheim, Gilead), NS5a inhibitors (BMS), as well as host-targeted therapies such as cyclophilin inhibitors (Novartis, Conatus, Gilead, Scynexis, LG Life Sciences, DebioPharma Group), and therapeutic vaccines (GlobeImmune).
Elimination of PegIFN/riba appears to be an important goal and a likely outcome of development of combinations of these new classes of agents. Early data from Pharmasset presented at EASL showed a remarkably high viral clearance rate of 83% to 94% at 14 to 16 days of treatment, respectively, using just two antiviral agents in combination: PSI-7977 (a nucleoside inhibitor) and PSI-938 (also a nucleoside inhibitor).
Cure of chronic viral infections requires two key features—effective inhibition of viral replication and clearance of infected reservoirs. There are still no examples of a purely antiviral strategy leading to cures in any chronic viral infection (HIV, HBV, HCV), so it remains to be seen if a combination of two or more antiviral agents can deliver substantial rates of cure in the form of SVR.
However, newer immunomodulatory and host-targeted therapies such as innate immune modulators, cyclophilin inhibitors, and therapeutic vaccines could augment these purely antiviral approaches to deliver substantial SVR rates in the absence of PegIFN/riba.
The FDA should take a leadership role in facilitating both the tactical and strategic development paths highlighted in this article. The types of active controls, protocol designs, and analyses required for the second- and third-generation IFN-based regimens should be quite different from those utilized in programs for which the primary goal is delivery of SVR without PegIFN/ribavirin. Two distinct development pathways should be laid out clearly so the near-term period of tactical improvement in IFN-based therapy can proceed, and the longer term strategic development plans can flourish as well.
Approval of telaprevir and boceprevir will drive increased interest by patients and hepatologists in treating chronic HCV. For many patients the improvements in benefit/risk will be clear, but several patient types may be well served to wait for either better IFN-based regimens or IFN-free therapy.
SVR was not greatly improved in patients with IL28b C/C genotype in the boceprevir program and the remarkably low rate of response in the IL28b C/C PegIFN/ribavirin group in the telaprevir program adds some doubt as to the true magnitude of the treatment effect in this already favorable patient group. Cirrhotic HCV patients may be the most motivated patient group to seek treatment, but cirrhotic patients with prior null responses or prior partial responses had dramatically lower SVR rates with telaprevir (14% and 34% respectively) than were observed in prior relapsers or treatment-naïve patients (88% and 79% respectively).
While response rates in blacks were improved over PegIFN/riba in both programs, the response was not as good as that observed for Caucasian patients. Furthermore, the black subgroups were small and had inadequate IL28b analyses, leaving this an important area for continued study.
There is much to be excited about with the approval of telaprevir and boceprevir and for future drug development prospects in chronic HCV. One can expect continued improvements in IFN-based therapies over the next three to five years, including further improvements in SVR rates, more convenient dosing regimens, and reduced resistance.
The long view over five to ten years points to combinations of novel targeted agents of the antiviral, immune modulatory, and host targeted classes that can deliver meaningful SRV rates without the cost and toxicity of PegIFN/riba. With the arsenal now arrayed against it, chronic HCV will become a curable disease in the majority of patients over the next decade.