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Disease area focus: Hepatitis C

Looking at the challenges, goals and developments for the pharma industry within specific disease and therapy areas

Therapy area focus: Hepatitis CHepatitis C is a viral liver disease which causes inflammation of the liver. While it has always been regarded as a liver disease, it has also been associated with numerous haematological, renal, dermatological, rheumatic, autoimmune and brain disorders. Hepatitis C has six identified genotypes and more than 50 subtypes, with genotype 1 being the most common in Europe and most difficult to treat. The economic burden of chronic hepatitis C is high, largely due to the management of its long-term consequences, including cirrhosis, liver cancer and liver transplant. Patients who go untreated or fail treatment are at risk of developing severe liver problems or primary liver cancer.

Globally, approximately 170 million people are infected with the virus, an estimated five million sufferers located in Western Europe, with numbers expected to be even higher in Eastern Europe. Despite the fact that infection rates are decreasing, the clinical and economic impact of chronic hepatitis C will grow considerably in the next decade as a large population of individuals who were infected with the virus in the 1960s-1980s begin to develop health issues associated with the disease, especially cirrhosis and liver cancer.

Hepatitis C is a curable chronic disease. It is a rare example of a chronic viral infection that can be completely cured, while hepatitis B, HIV and herpes cannot. However, only 3.5 per cent of people with the disease are currently receiving treatment in Europe. This is because the treatment is gruelling: it takes a year; it makes the sufferer feel ill and there is only a 40-50 per cent chance of being cured.


Estimated current prevalence of HCV infection in Europe

Estimated current prevalence of HCV infection in Europe

 

Historic developments
Before widespread screening of blood supplies began in the 1990s, hepatitis C was most commonly spread through contaminated blood transfusions and organ transplants. Today, most people become infected by sharing needles or other equipment used to inject drugs. The development of drugs to combat the disease started in the early 1990s with standard interferon, a naturally occurring protein that is produced by the immune system in response to
viral infections. The patient had to take it three times a week, for 24 weeks. However, the monotherapy only cured 5 per cent of patients. Patients with chronic hepatitis C were treated for one year on the same medication and up to 10 per cent were cured.

The end of the 1990s saw the next advance in treatment, which involved the use of interferon with ribavirin, a compound that was first synthesized in the 1970s. The mode of action is still unknown, but if used on its own, it does not cure hepatitis C. However, when used with interferon, the success rate rises from 10 per cent to approximately 30-40 per cent because of the synergistic effect. Ribavirin is an oral treatment, but is associated with anaemia as a side effect.

The next development was a new formulation of interferon, pegylated interferon, which breaks down slowly to produce a long-lasting effect. It has two advantages: the patient only has to use it once a week and it has a long-lasting anti-viral effect.

However, interferon has many side effects: flu-like symptoms, depression, hair loss and anaemia. It has to be administered by injection once a week over the course of a year.

Using pegylated interferon and ribavirin together has became the current standard of care, with a cure rate of 40-50 per cent. However, the success rate depends on what HCV genotype the patient has. Genotype 1 has a lower success rate. Treatment takes place over 48 weeks and has a 40 per cent success rate, while genotypes 2 and 3 patients are treated for 24 weeks, with a success rate of 80 per cent.

One of the main challenges that the pharmaceutical industry faces is in developing drugs with reduced side effects, which are often the reason patients refuse to come forward for treatment or later abandon it. Meanwhile, others are not allowed to take the drugs currently available because they already have a history of depression or anaemia.

The industry also needs to make treatments more convenient for patients because research has shown that treatment adherence is key in success rates. Currently interferon-based hepatitis C drugs are given by injection, which does not fit in with patients' lifestyles. For some patients, it is also necessary to have supportive medicines, such as anti-depressants, to help patients manage side effects.

Another challenge that the pharma industry will face in the area is getting drugs approved by regulators. At phase III companies have to prove that their drug works better than those already on the market, but as other drugs get approved, the bar will be raised, making it harder to enter the market.

Future treatments
There is a need for medications that inhibit the replication of the virus, a compound to block the activity of the virus, and there are currently more than 30 drugs being studied in phased trials. These Direct Acting Antivirals (DAAs), a class of drugs that target the viral enzymes critical to hepatitis C virus replication, include: protease inhibitors, polymerase inhibitors and NS5A inhibitors (see table 1).

 

Table 1: Types of Direct Acting Antivirals

Drug class

How it works

Protease inhibitors

Protease inhibitors block an important stage of viral replication and are being explored in conjunction with pegylated interferon-alpha and ribavirin to enhance its efficacy and shorten treatment regimens

Polymerase inhibitors

Polymerase inhibitors disrupt the action of the enzyme that copies viral genetic material needed for viral replication

NS5A inhibitors

NS5A inhibitors target a protein that is essential for viral replication

 

These drugs were initially tested in monotherapy and have resulted in a sharp and rapid decline of the viral load within a few days. However, the virus can develop resistance through viral mutants. These new drugs have been studied in combination with interferon and ribavirin over longer periods of time, up to 48 weeks. Two of these drugs have now completed development – boceprevir and telaprevir – and are currently being reviewed by the European Medicines Agency and the US Food and Drug Administration. The results of phase II and phase III clinical trials for these treatments suggest that triple combination therapy results in approximately 30 per cent more patients who achieve sustained virologic response, compared to the current standard of care. It is believed that in the future a combination of small molecules with complementary mode of action could be administered orally to combat the disease.

Other new therapies in early stage development focus on increasing a patient's natural immune response to the virus. These include new interferons that aim to increase the amount of time interferon is active in the body, improving its efficacy and reducing side effects, and also toll-like receptor agonists that
aim to prompt the body to produce high levels of interferon.

However, the ultimate goal remains to develop an oral 'interferon free' regimen, which reduces side effects, works in a short period of time and has a cure rate of more than 80 per cent.

The Author
Liz Wells
is deputy editor of PME. She compiled this article from interviews with Kenny Simmen, vice president of research and early development at Tibotec in Belgium, one of the Janssen Pharmaceutical Companies and with Fabien Zoulim, director of the hepatology department at the Lyon University Hospital and scientific director of the INSERM Viral Hepatitis Research Laboratory, France.

Related links:

Further background information about hepatitis C

7th April 2011

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