Focus on Hepatitis: Glimpses of Hope on a Distant Horizon
The success of protease inhibitors (PIs) in HIV treatment has generated attention and widespread optimism for their use in therapy for chronic infection with hepatitis C virus (HCV). The dramatic results of early research on the HCV PI, BILN 2061, led to enthusiastic predictions of a coming revolution in HCV treatment, even though the drug has now been shelved due to evidence of cardiac toxicity.
The promise of HCV PIs is in their potential to specifically target HCV, unlike pegylated interferon (PegIFN) and ribavirin (RBV), which work (or fail) through more general antiviral and immune-modulating mechanisms. An effective HCV PI would improve the chances of achieving viral clearance in patients who have not responded to treatment and in groups for whom current therapy is less likely to be successful (including patients with HCV genotype 1, African Americans, and patients with HIV/HCV coinfection).
An effective PI might also make treatment more attractive and tolerable by eliminating the need for RBV, shortening the length of treatment, and/or possibly enabling lower doses of PegIFN and, thus, fewer side effects.
But despite considerable research on HCV PIs over the past decade, it will require at least several more years before an HCV protease inhibitor will win FDA approval and reach the market. Only two HCV protease inhibitors are currently in human studies, and both are at the very earliest stage of clinical research.
Hepatitis C virus includes an enzyme, the NS3 serine protease, which is essential for viral replication. After HCV enters a cell, its RNA is translated into a long polypeptide, which is then cleaved into individual HCV proteins by enzymes -- until the individual proteins are separated, they cannot function.
The NS3 serine protease enzyme cleaves the virus's non-structural proteins, including the HCV polymerase enzyme. Viral replication can only begin after all the individual HCV proteins have been cleaved from the polypeptide chain.
Thus, a PI that could block the NS3 serine protease would prevent viral replication.
In 2003, researchers from the University of Texas reported another beneficial effect of blocking the activity of the NS3 serine protease. The HCV protease appears to inhibit cellular defenses against viral infection -- the interferon pathway.
Through an as yet unknown mechanism, the HCV protease inhibits the action of interferon regulatory factor-3 (IRF-3), preventing infected cells from triggering classical interferon defense pathways. The researchers demonstrated that an HCV protease inhibitor could reverse the blockade on cellular interferon defenses in cell culture models.
This work suggests that HCV PIs could work synergistically with PegIFN, boosting its effectiveness and possibly allowing for lower doses of interferon during treatment.
The structure of the HCV protease enzyme has posed significant challenges for drug development.
Research conducted by teams at Agouron and Vertex in the mid-1990s solved the three-dimensional crystal structure of the NS3 serine protease, enabling attempts to design drugs that would bind to the active site of the enzyme that catalyzed cleavage. But the active site has proven to be a difficult target, containing only a shallow pocket for binding.
Researchers at an Italian institute affiliated with Merck & Co. have proposed other strategies for designing PIs, including product-based inhibitors (compounds with structural properties mimicking the products of viral cleavage) and targeting the prime site of the HCV protease rather than the active site.
To date, a wide range of compounds showing in vitro activity against the HCV protease have been identified. The challenge lies in turning these compounds into drugs that work in humans.
A second challenge to PI development has been the lack of suitable laboratory and animal models for studying new drugs. Research in animals has been confined almost exclusively to chimpanzees, the only other species susceptible to HCV infection.
Recently, some progress has been made in studying marmosets, a small primate. Marmosets can be infected with GB virus B, a virus closely related to HCV. Indeed, researchers from GlaxoSmithKline recently published data evaluating an HCV PI in a marmoset/GB virus B model.
Some progress has also been made in developing models of mice implanted with human liver cells for the study of HCV drugs. New cell culture systems, using HCV replicon constructs that can replicate within certain types of cell lines, has enabled in vitro research that can measure the ability of a compound to inhibit viral replication.
The field of HCV PI development was poised to take off in the late 1990s, with a number of major companies working on compounds. But research was set back for several years when Chiron filed lawsuits against four companies working on PIs in 1998, claiming patent infringement.
Chiron holds patents on HCV, based on its researchers' identification of the virus in the late 1980s. Most of these lawsuits have been resolved, with companies agreeing to pay licensing fees to Chiron and royalties on sales of any marketed drug. But these legal and financial disputes had a chilling effect on research, slowing progress for several years.
In late 2002, Boehringer Ingelheim reported the first (and to date, only) results of studies of an HCV PI in patients with HCV infection. Patients who received a two-day course of treatment with BILN 2061, Boehringer Ingelheim's PI, experienced a rapid drop in their HCV viral loads of 2 to 3 logs (100-1,000 fold decreases).
These results were unprecedented, even with interferon-based treatment, and appeared to usher in a new era in HCV drug development and treatment. Most notably, BILN 2061 was particularly effective in patients with genotype 1 -- the strain of HCV least responsive to interferon-based treatment.
Boehringer Ingelheim announced plans to move BILN 2061 into larger phase II studies during 2003. The planned studies never materialized, and rumors spread that Boehringer Ingelheim had discovered unanticipated side effects in animals, specifically cardiac toxicity in monkeys.
In October 2003, Boehringer Ingelheim quietly announced on its Web site that, "Routine chronic safety testing of high, supra-therapeutic doses in animals did, however, show relevant side effects which need further analysis. Boehringer Ingelheim is currently studying the available pre-clinical data in order to decide on their impact on the clinical development of this substance. There are currently no trials ongoing with BILN 2061 and decisions about future trials will be made after thorough evaluation of toxicity findings in animal studies."
Boehringer Ingelheim's "thorough evaluation" failed to resolve toxicity concerns, and the company has quietly shelved the drug in favor of other compounds. The company has two follow-up HCV PIs under evaluation, though neither has been tested in humans.
Despite the disappointment surrounding BILN 2061's fate, two other PIs have advanced to human studies: VX-950, under co-development by Vertex and GlaxoSmithKline; and an as-yet unnamed compound from Schering-Plough. Both are in early phase I studies in humans, though neither has been researched yet in patients with HCV infection.
Several other companies have research programs focused on HCV PIs, including Gilead Sciences, Merck & Co., Pfizer, GlaxoSmithKline, and InterMune.
The initial reports of the BILN 2061 studies have been widely publicized; Boehringer Ingelheim's subsequent decision to halt further development of this compound has received less attention. Anecdotal reports suggest that many patients with HCV are choosing -- often based on the advice of their physicians -- to defer treatment due to the limitations of interferon and RBV, in the hopes that better options will become available in the next few years.
The issue of whether patients and physicians should base current treatment decisions on the future prospect of improved therapies is a critical one in the current clinical management of HCV.
In a recent commentary on BILN 2061 published in Gastroenterology, Stephen Zucker and Kenneth Sherman wrote:
"Although new therapies are clearly on the horizon, that horizon still remains at a substantial distance. Precisely how long is uncertain, but we venture to guess it will be a good [five] years before a novel small molecule or other pharmaceutical agent is available for clinical use. Until then, meticulous attention to compliance and adherence to optimal dosing regimens for [PegIFN] and [RBV] is the best way to achieve the most propitious outcome. While it certainly is reasonable to offer patients the anticipation of future treatment opportunities, hope is not a particularly effective method of viral eradication."
While pharmaceutical companies deal with development of HCV PIs and physicians and patients wrestle with treatment decisions based on available therapeutics, the field of HCV PI development raises a number of new challenges for research and policy.
The risk of viral resistance is likely to pose a major challenge to the development and clinical use of NS3 serine PIs, as it has with HIV PIs. in vitro studies using HCV replicons have identified mutations conferring drug resistance to BILN 2061 and VX-950. These findings were certainly not unexpected. Indeed, the potential for resistance is virtually guaranteed for compounds targeting the NS3 protease.
However, combinations of PIs could in theory offset the risks of resistance. Indeed, HCV strains containing mutations that rendered the virus resistant to BILN-2061 were still susceptible in vitro to VX-950, and vice versa. Ideally, companies with compounds in or approaching early clinical development -- such as Boehringer Ingelheim, Schering-Plough, and Vertex -- will collaborate on researching combination approaches after initial safety and efficacy has been demonstrated.
But the potential for resistance ultimately means that any PI will initially have to be used with PegIFN.
The pathway to US Food and Drug Administration (FDA) approval of an HCV PI is uncertain. What are the conditions for accelerated approval? Which groups -- for example, non-responders to standard therapy, cirrhotics, and/or patients coinfected with HIV -- should be prioritized in phase III research? Will a candidate need to be tested with both marketed PegIFNs (Pegasys and Peg-Intron) for full approval? What types of side effects will these compounds cause, and how will the risks and benefits be evaluated? What types of drug interaction studies will be necessary for approval?
HCV PI Effect on Treatment and Care
The advent of HCV PIs challenges us to imagine how their use will transform HCV care and treatment. A more effective (and, ideally, more easily tolerated) HCV treatment regimen would likely lead to hundreds of thousands of patients asking for treatment.
It may be too soon for the patient and medical communities to pin their hopes on an HCV PI. But it is not too soon to start asking these questions, and advocating creative solutions.
Daniel Raymond is Hepatitis C Policy Analyst at the Harm Reduction Coalition in New York.
This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication IAPAC Monthly.