Improved forms of interferon are being developed to extend the performance of existing hepatitis C therapies. Dr Sarah Houlton assesses the available treatments and those in development
Hepatitis C is a silent killer. Initial infection may cause no symptoms in about two-thirds of cases, and even when it does, they are often so mild that the infected person does not seek medical help. But if the body's immune system does not clear the virus, then it lies dormant, only to return years later and cause life threatening illness. It is a growing worldwide problem, with up to 200m people estimated to be infected, many of whom have no idea they have the virus.
It is spread by blood contact and, unlike hepatitis A and hepatitis B, there is no preventative vaccine. If the initial infection is noticed and diagnosed, then in many cases the virus can be cleared with a course of interferon alpha and ribavirin. But if the infection becomes chronic, the future prognosis for health is not good. The liver progressively becomes scarred; untreated, about a third of those with chronic infection develop cirrhosis within the first 20 years and a further third in the next decade, while the remainder are affected so slowly that they are unlikely to be affected significantly. There is also a high chance that they will develop liver cancer.
Because of the chronic nature of the disease and its poor prognosis, many drugs are in development to treat hepatitis C. It is further complicated by the fact that there are six major genotypes of the virus, which respond differently to treatment. Currently, the only real treatment is with interferon alpha, an antiviral protein that has to be administered by injection, along with the antiviral drug ribavirin, which is orally available. Two longer acting PEGylated versions of the interferon are available, Roche's PEG-interferon alfa-2a, and PEG-interferon alfa-2b from Schering-Plough. There is one amino acid difference between the two interferons, but their PEGylation is different. The Roche product is given in standard doses of 180µg once a week, whereas the Schering-Plough drug requires a slightly more complex regimen, and dosing at 1.5µ/kg.
undesireable side-effects
However, the regimen is not ideal. The main treatment limiting side effect is anaemia, because ribavirin can damage red blood cells; however, reducing or removing the ribavirin component also reduces the likelihood of success, and erythropoeitin can be used to combat the anaemia. Depression and suicidal thoughts have also been reported, and ribavirin is also teratogenic.
Numerous potential drugs to treat hepatitis C are under development, many of which are designed to be administered alongside the standard therapy, making it more effective or reducing the duration of treatment. As well as novel antiviral agents, investigational drugs in the pipeline include improved forms of interferon, which have reduced side effects. Furthest advanced of these is albuferon, being developed by Human Genome Sciences and Novartis, which is now in Phase III trials. It is designed to extend the half life of interferon alfa-2b in the body, which makes its therapeutic effect last for longer. The drug is a recombinant protein made by fusing the gene for the interferon with the gene for human serum albumin, which is naturally abundant in the blood and takes nearly three weeks to clear. By joining the albumin with the interferon, it slows the clearance of the interferon, and Phase II trials indicate that it can be dosed every two to four weeks, compared to the weekly dosing schedule that is required for the interferon alone.
OctoPlus is also working on a controlled release formulation of the same interferon in conjunction with US company Biolex Therapeutics. The formulation, Locteron, uses the Dutch company's biodegradable PolyActive drug delivery technology with BLX-883, Biolex's recombinant alfa interferon, which is made in duckweed cells. In a Phase IIa study in 32 patients with chronic hepatitis C genotype 1, all subjects achieved early virologic response in the two highest dose groups, and the tolerability profile was much better than for existing interferon products. It is also given every two weeks.
Interferons other than alpha are also being investigated. Intarcia Therapeutics" omega interferon has shown promise in combination with ribavirin in Phase II trials. It is being developed in a controlled release form, using the Duros device developed by Alza. This implantable osmotic mini-pump allows the interferon to be delivered continuously over three months, which gives a continuous level of the drug in the bloodstream, avoiding the peak drug levels that can lead to toxic effects, and also the sub-optimal levels that reduce therapeutic efficacy.
ZymoGenetics is looking at a PEGylated version of a third interferon, lambda, also known as interleukin-29. This native human protein is made by the immune system in response to viral infection, and acts through a different receptor to that of interferon alpha. In a Phase Ia trial, single doses of this interferon were well tolerated, and had the expected effect on interferon response markers. Trials on it continue.
interferon investigations
Interferons are still generally dosed with ribavirin, and Valeant Pharmaceuticals is working on a prodrug, taribavirin, which should reduce the side-effects. Preliminary results of a Phase IIb trial in combination with PEGylated interferon alfa-2b showed comparable reductions in viral loads for weight based doses of taribavirin and ribavirin, but the anaemia rate was significantly lower for those given taribavirin (figure 5). Mild diarrhoea was more common in the taribavirin group, but this was not treatment limiting.
Many other antiviral drugs are also under development, which act via a variety of different mechanisms. As with other viruses, a number of different points on the lifecycle provide potential targets for drugs. Its genome is a single strand of viral RNA, and this is translated in the liver into a protein. Protease enzymes in the liver cells and the polyprotein split it up into a number of smaller proteins; these are either structural proteins - the core shell protein and two surface glycoproteins, E1 and E2 - or non-structural proteins such as RNA polymerase that the virus needs for replication.
A target that has received a large amount of attention is the RNA-dependent RNA polymerase enzyme NS5B. This enzyme is not present in normal human cells, and thus agents targeting it should be specific for the virus. Both nucleoside and non-nucleoside polymerase inhibitors are being developed.
Roche has two nucleoside inhibitors in clinical trials, one of which is licensed from Pharmasset. R1626 is the furthest advanced, being in Phase II. Again being dosed alongside interferon and ribavirin, the first in class compound was given alongside the standard therapy for four weeks, and then the standard therapy continued for a further 44 weeks. After the treatment period, 84% of patients with genotype 1 virus had undetectable levels of HCV, compared to 65% for those give standard therapy for the whole 48 weeks. It also shows a high barrier to the development of resistance, and a large Phase IIb trial is now under way.
The second nucleoside drug, R7128, has showed promise in a four week Phase I trial. It demonstrated potent short-term antiviral activity, and was generally safe and well tolerated. A total of 50 treament naïve patients with chronic hepatitis C genotype 1 infection were given the drug plus standard therapy, and 85% of those given 1.5g doses twice a day achieved undetectable HCV levels by the end of the four week trial. It is a prodrug of the cytidine nucleoside analogue PSI-6130. Positive results have also been achieved in a Phase I study in subjects with genotypes 2 and 3 who did not respond to standard therapy.
Various non-nucleoside polymerase inhibitors are also being developed. Pfizer's PF-868,554 is in Phase II trials, as is ViroChem Pharma's VCH-759. This latter compound is orally available, and in one trial 32 subjects with genotype 1 infection were given the drug as monotherapy or placebo, and at the highest dose subjects experienced a two-log decrease in viral load, with the drug being well tolerated. Gilead Sciences" GS 9190 also showed promise in a Phase I study when dosed orally twice a day. Several other drugs are in preclinical studies, including compounds from Abbott, Anadys and Genelabs.
The protease activity responsible for the release of the non-structural proteins is another popular target. This activity is a result of host proteins and another non-structural protein, NS3, which complexes with a further protein, NS4A, to form a functional replicase complex, an essential step in the replication process which takes place before copying the viral RNA genome. Both of these proteins on their own are potential drug targets, as is the combination of the two.
Schering-Plough's boceprevir (fig.2) is specific for NS3, and is being evaluated in combination with PEG-interferon and ribavirin. The company recently reported initial results of a Phase II trial in treatment naïve hepatitis C patients. Twelve weeks after the 48-week treatment regimen, three quarters of the patients given the new drug as well as the standard therapy had a sustained virologic response, compared to 38% of those given interferon and ribavirin alone. It seemed more effective when given after a four-week lead-in of standard therapy.
anti-NS4A compound
A compound, which inhibits NS4A alone is ACH-1095 from Achillion Pharmaceuticals. Being developed in conjunction with Gilead, this is the second anti-NS4A compound it has brought into the clinic. The first ACH-806, (figure 1) failed in a proof of concept trial because it caused unacceptable levels of serum creatinine, a marker of kidney function, although it did show activity against HCV. It is early days for the new compound but it appears to have about 10 times higher antiviral activity than its predecessor.
Compounds that act on both proteins are also being investigated. Telaprevir (figure 6), previously known as VX-950 and being developed by Vertex and Tibotec, is again dosed with standard interferon and ribavirin therapy. Interim analysis of an ongoing Phase IIb study look good. Patients with genotype 1 chronic hepatitis C infection who did not respond adequately to interferon and ribavirin were given oral telaprevir plus standard therapy for 12 weeks, and then standard therapy alone for a further 12 weeks. Half of those given the new drug maintained undetectable levels of HCV 12 weeks after treatment, with a similar side effect profile to that seen with standard therapy. These results are similar to those seen in treatment naïve patients. A Phase III study in treatment naïve patients is under way, and the company is about to start a pivotal Phase III trial in patients who have failed to develop a sustained response in prior therapy. It is also being looked at in genotypes 3 and 4 of the virus, and with different dosing regimens.
A couple of other NS3/NS4A inhibitors that are being dosed alongside interferon and ribavirin are also in the pipeline. Medivir's TMC435350, also being developed in conjunction with Tibotec, is another orally available drug, currently in Phase II trials. And Intermune is developing ITMN-191 with Roche; this has reached Phase Ib and results suggest it is well tolerated.
Numerous other mechanisms of action are being investigated. The furthest advanced of these, SciClone Therapeutics" thymalfasin (Zadaxin), is a synthetic version thymosine alpha-1, a thyroid hormone. This hormone stimulates the T lymphocytes in the blood, which are thought to play an important role in clearing HCV from the system. Again, it is being tested alongside the standard interferon plus ribavirin therapy. A Phase III trial has been completed recently in patients who had not previously responded to standard therapy, and unblinded data should be released soon. Promisingly, interim blinded data indicated that a significant proportion of the subjects had responded, despite not having res-ponded to standard therapy in the past.
Migenix's celgosivir is in Phase II trials. This is an oral inhibitor of alpha glucosidase I, an enzyme that is involved in the formation of glycoproteins in human cells, and the idea is that by inhibiting it, the production of viral surface proteins E1 and E2 will be disrupted. In combination with standard therapy in non-responders, a significant reduction in viral load was seen in those given celgosivir (figure 3), and promising early results have also been reported in treatment naïve patients. It was well tolerated compared with standard therapy alone.
Another potential treatment from SciClone is SCV-07 (figure 4), the synthetic peptide gamma-D-glutamyl-L-tryptophan. It stimulates the immune system via T helper 1 cells, which are involved in the clearance of viral infections. The orally available drug is in Phase II trials, and a trial in patients who relapsed after standard therapy has recently been completed, with data due soon. The hope is that it will be able to replace interferon alpha in treating patients with HCV.
preventing replication
Swiss company DebioPharm is developing a cyclophilin, or Cyp, inhibitor. Cyp host cell proteins are thought to support the HCV replication process, and Debio 025 bonds strongly to them. In a placebo controlled Phase II trial, it was given alongside standard therapy to treatment naïve patients. After four weeks of treatment, it significantly reduced viral load compared with those given interferon and ribavirin alone. Novartis is also investigating a cyclophilin inhibitor; NIM811 is an analogue of cyclosporine that does not have immunosuppressive effects.
Various other drugs are also in earlier stage of development, as are a handful of therapeutic vaccines. But there remains no preventative vaccine, unlike for hepatitis A and B, for which extremely effective vaccines exist. It has not helped that until recently it was not possible to culture the virus in the lab, and a small animal model has only just been developed. Perhaps more importantly, not only does the virus replicate and mutate very quickly, the antibodies produced by the body do not protect against future infection.
Scientists now have a better idea of how antibodies can neutralise the virus and prevent infection; these can be produced naturally by the body in the early stages of infection and stop chronic disease developing. In particular, the interaction between the E2 glycoprotein on the virus surface to the CD81 receptor on the surface of liver cells can be blocked by neutralising antibodies, and Novartis has a vaccine, which acts in this way in Phase I trials. Genmab is developing an anti-E2 monoclonal antibody that could be protective.
Research is continuing to determine which are the most important interactions, and which are common to all genotypes of the virus. However, a vaccine is still a long way off, and in the nearer term improved drugs offer the best hope to those infected with the hepatitis C virus.