Proliferation of Polymerase Inhibitors and Other Tales From the HCV Crypt
Building a Better RibavirinLiver disease has become increasingly prominent in the HAART era. Hepatitis C progresses more rapidly in HIV-positive people, and is more difficult to treat. More effective, less toxic treatments for the hepatitis C virus (HCV) are urgently needed. Tracy Swan prepared this HCV pipeline report, with contributions from Daniel Raymond, exclusively for
The current standard of care for hepatitis C involves six to twelve months of combination treatment with pegylated interferon alfa, injected weekly, and ribavirin, a nucleoside analogue taken orally every day. Unlike HIV, successful hepatitis C treatment can result in viral clearance. The main goal of treatment is a sustained virologic response, when HCV remains undetectable six months after completion of therapy. More than 85% of people who have achieved an sustained virologic response remain free of HCV five years after completion of therapy. Secondary goals of treatment include normalization of liver enzymes and improvement in liver inflammation and fibrosis.
Hepatitis C treatment only succeeds in about half of people with hepatitis C. Various factors influence treatment outcome, including HCV genotype and viral load, HIV status, race, age, and body weight. Data from three pivotal coinfection trials, ACTG A5071, ANRS HC02 (RIBAVIC) and Roche's APRICOT (AIDS Pegasys and Ribavirin International Co-Infection Trial) are expected later this month. Preliminary data from A5071 and RIBAVIC indicate that pegylated interferon appears to be more effective than non-pegylated interferon in coinfected patients after both 24 and 48 weeks of treatment, but the response rates remain lower than those reported in HCV monoinfection treatment trials.
Pegylated interferon and ribavirin have several serious side effects, including depression, anemia, and neutropenia. Some of these side effects overlap with symptoms of HIV disease and side effects of certain HIV medications. Potentially dangerous drug interactions between ribavirin and other nucleoside analogues -- notably ddI (Videx) and d4T (Zerit) -- have also been documented.
Coinfected people often experience severe side effects during HCV treatment, making adherence difficult. In HCV treatment trials -- where monitoring and management of side effects and adverse events is generally most vigilant -- drop-out rates have been high. In ANRS HC02, only 224 of an original 416 completed 48 weeks of treatment. Severe adverse events -- psychiatric side effects, sepsis, pneumonia, hepatic failure, acute pancreatitis and hyperlactatemia -- were reported among 23% of the pegylated interferon group, and 19% of the interferon group, and four people died during the study.
The suboptimal efficacy and tolerability of HCV therapy does not bode well for coinfected persons for whom HCV has become a major medical concern. Hepatitis C is prevalent among people with HIV in the United States and Europe. In the United States, approximately 25% of HIV-positive people are coinfected with hepatitis C. Among those who attribute their HIV to injection drug use, HCV is far more prevalent: as many as 90% are coinfected. HIV infection accelerates HCV disease progression, increasing the risk for developing cirrhosis, hepatocellular carcinoma, and liver failure. End-stage liver disease resulting from HCV coinfection has become a leading cause of death among HIV-positive people in the developed world.
Coinfected people and their clinicians must weigh current HCV treatment options against the immediacy of the need for treatment. Over the short term, until new therapies become available, researchers and clinicians are trying to optimize HCV treatment outcomes among coinfected people by various strategies, which include extending the duration of therapy by an additional six months, using growth factors instead of dose reductions to manage anemia from ribavirin and neutropenia from pegylated interferon, and using induction therapy with high-dose interferon. For virologic non-responders, researchers are exploring whether long-term maintenance therapy with low-dose pegylated interferon may prevent progression of liver disease.
Over the longer term, improvements in HCV treatment will require drugs with one or more of the following characteristics:
While no single drug may meet all of these criteria, combinations of new drugs may ultimately bring dramatic improvements in the efficacy and tolerability of HCV treatment. As with HIV, combination treatment will remain the standard, since viral resistance to most single-drug therapy is likely. In the near future, any new drug will need to be used in combination with pegylated interferon (and, in some cases, ribavirin) until enough new agents are available for novel combinations.
The most exciting new antiviral treatments target HCV directly by inhibiting viral proteins such as the hepatitis C protease and polymerase enzymes. This approach parallels the development of antiretrovirals used in HIV treatment. Alternative forms of interferon and ribavirin, along with other immunomodulatory drugs, are also in development. However, strategies aimed at stimulating the immune system to fight HCV could in theory be less effective in people with impaired immune responses due to HIV infection.
A New Class of HCV Drugs: Serine Protease Inhibitors
Many companies have pursued drugs designed to inhibit the HCV serine protease enzyme, based on the success of protease inhibitors in HIV treatment. As with HIV, the hepatitis C virus encodes a protease enzyme essential for viral replication. However the HCV protease has proven a more difficult target due to the shape of the molecule. While many compounds have demonstrated antiviral efficacy in vitro, few have moved into human studies.
Early excitement was generated from proof-of-concept reports on Boehringer Ingelheim's serine protease inhibitor, BILN-2061. In small phase I studies, BILN-2061 reduced HCV viral load by 2-3 logs during two days of treatment in people with HCV genotype 1. Despite these promising results, Boehringer Ingelheim has temporarily halted development of BILN-2061, pending evaluation of animal toxicity data. After four weeks of BILN-2061 at much higher doses than those used in humans, monkeys developed cardiac lesions. No similar toxicities have appeared in humans over shorter dosing intervals, though long-term safety data has not been reported.
Two other HCV protease inhibitors have moved into early clinical development. In mid-2004, Vertex will open a phase I study of their HCV serine protease inhibitor, VX-950. According to Vertex's in vitro data, VX-950 is active against HCV that has developed resistance to BILN-2061 (and vice versa, according to BI). Schering has an as yet unnamed HCV protease inhibitor in early phase I research. Other companies are developing HCV serine protease inhibitors, but none has entered testing in humans.
Several other drugs in development are targeting other aspects of HCV replication, such as the HCV RNA-dependent RNA polymerase (roughly analogous to HIV reverse transcriptase). Idenix Pharmaceuticals has an oral HCV polymerase inhibitor, NM283, in phase I/II. A phase I/II trial of Rigel's HCV oral polymerase inhibitor, R803 will open in mid-2004. Japan Tobacco is developing two oral HCV polymerase inhibitors, JTK-109 and JTK-003. In Japan, JTK-003 has moved into phase II; both drugs are in phase I studies outside of Japan. Several other companies have compounds in pre-clinical development.
Other strategies target HCV RNA rather than viral proteins. Antisense oligonucleotides bind to HCV RNA and prevent synthesis of HCV's viral proteins. Isis Pharmaceuticals has developed ISIS-14803, an injectable antisense oligonucleotide. Initial phase II studies have demonstrated safety and efficacy. ISIS-14803 is being evaluated in non-responders to prior HCV therapy with pegylated interferon and ribavirin; trial participants will receive all three drugs.
Drugs to Replace or Potentiate Ribavirin
Viramidine is a pro-drug of ribavirin that becomes active in the liver. Anemia, the major dose-limiting toxicity of ribavirin, may not occur as frequently with viramidine as with ribavirin, because less of viramidine's active form enters red blood cells. At the end of 2003, Valeant Pharmaceuticals (formerly ICN) opened VISER1 (Viramidine's Safety and Efficacy vs. Ribavirin), an international phase III study of 1,000 persons, combining pegylated interferon alfa-2b with ribavirin or viramidine. Another international phase III study, VISER2, combining pegylated interferon alfa-2a with ribavirin or viramidine, is expected to open in mid-2004.
Ribavirin may partially function as an IMPDH (inosine-5'-monophosphate dehydrogenase) inhibitor. Inhibition of IMPDH may help block HCV production by decreasing levels of guanosine triphosphate, one of the four essential components of RNA strands. Other IMPDH inhibitors may work in synergy with ribavirin, increasing its other antiviral effects. Vertex's oral IMPDH inhibitor, merimepodib, will enter phase III in 2004. It is being used in combination with pegylated interferon and ribavirin.
Several drugs that may alter or enhance immune responses are under investigation as HCV treatments. In general, compounds with immunomodulatory properties may have unexpected or unintended consequences in people with HIV, either harmful or benign. The effects of immunomodulators must be carefully evaluated in coinfected people.
Zadaxin, or thymosin alfa, is an injectable synthetic peptide based on substances found in thymus gland extracts. It may enhance immune responses through various mechanisms. Zadaxin has not been approved as part of hepatitis C therapy in the United States or Europe, although it has been approved in other countries. Currently, phase III studies are evaluating responses to treatment with pegylated interferon alfa-2a, with or without thymalfasin, in non-responders.
Isatorbine, an injectable drug from Anadys Pharmaceuticals, elicits innate immune responses (natural killer cells, interferon-alfa and tumor necrosis factor) via Toll-like receptor 7, a white blood cell receptor. Phase II trials combining isatorbine with interferon are planned for 2004, as are phase I studies of an oral pro-drug of isatorbine, ANA 971. Coley Pharmaceuticals recently initiated phase I studies of Actilon, a drug that stimulates similar effects by targeting Toll-like receptor 9.
Maxim Pharmaceuticals' injectable histamine dihydrochloride (Ceplene) may protect and stimulate immune system cells. A phase II study in Europe and Canada has enrolled 302 non-responders to prior interferon and ribavirin therapy. This trial will compare efficacy of pegylated interferon alfa-2b and ribavirin with or without histamine dihydrochloride.
Preventing Recurrent Infection After Transplantation
Two novel approaches are being evaluated in liver transplant recipients, as hepatitis C almost always recurs after transplantation. HepeX-C, an infusible monoclonal antibody made by XTL Pharmaceuticals, targets the envelope proteins of HCV. If successful, this approach will neutralize the virus before it infects cells. HepeX-C has entered phase II studies in liver transplant recipients. Civacir, an infusible HCV immunoglobulin made from pooled antibody-positive blood, is being evaluated in a NIAID-sponsored phase I/II trial. Immunoglobulins have been used to prevent recurrent hepatitis B in liver transplant recipients.
The Interferon Menu
In addition to the new classes of HCV drugs, other types of interferon are in development, including a pegylated "consensus" interferon made from a sequence of twelve interferon subtypes (Peg-Alfacon from InterMune) and an interferon-alfa fused to albumin (which enables less frequent injections) by Human Genome Sciences.
Several therapeutic vaccine candidates are in development. Chiron and CSL Limited have a therapeutic vaccine in phase I, and Intercell has launched a multi-center dose-ranging study for its therapeutic vaccine in Europe. Innogenetics has completed small phase II studies of their vaccine candidate and are planning a larger, placebo-controlled phase II study in 150 non-responders. If therapeutic vaccination proves to be a successful approach in HCV monoinfection, efficacy in HIV-positive persons will need to be evaluated.
Challenges in HCV Drug Development
Many additional compounds are in pre-clinical development, and new approaches, such as RNA interference, appear promising. However, some of these drugs may never make it into human trials, and others may take years to develop.
Currently no trials are open to HIV-positive participants. The design of clinical trials often restricts participation to those most likely to show good responses to treatment. People with HIV may be on medications whose interactions with a new drug have not been studied. The symptoms or side effects that an HIV-positive person may experience during a clinical trial could be due to antiretroviral therapy and concomitant medications, HIV disease itself, or the investigational HCV drug, thus complicating evaluation of the new drug's safety profile. In addition, people with HIV comprise about 10% of all people with chronic hepatitis C infection in the United States, a relatively small market. However, coinfected people make up a greater proportion of those in most need of HCV treatment due to increased risk of disease progression. Many will not have the luxury of deferring treatment until more data becomes available when a new HCV drug receives FDA approval.
Trials of current therapies in coinfected people have opened years after pivotal monoinfection treatment studies used for FDA approval. This situation has left coinfected people and their doctors without a solid evidence base for making treatment decisions in the three years since the first pegylated interferons reached the market. This pattern must not continue; coinfected people should be included in HCV treatment trials as soon as safety and dose-finding studies have been completed.
Several issues related to the development and approval of new HCV therapies require attention:
HCV and HIV advocates need to expand their focus on HCV drug development, and work with companies and the FDA on development plans and approval requirements.
This article was provided by Treatment Action Group. It is a part of the publication TAGline.