New US hepatitis C treatment guidelines

The American Association for the Study of Liver Diseases (AASLD), the Infectious Diseases Society of America (IDSA) and the International Antiviral Society USA jointly issued new guidelines for the treatment of hepatitis C this week. The guidelines recommend how the newly licensed direct-acting antivirals sofosbuvir and simeprevir should be used in the treatment of all hepatitis C virus (HCV) genotypes. The guidelines will be updated regularly as new data and agents become available. New sections on eligibility for treatment, monitoring of treatment and management of acute infection will be added soon.

New European hepatitis C treatment guidelines

The European Association for the Study of the Liver (EASL) issued new hepatitis C treatment guidelines in December 2013. These guidelines were compiled prior to the licensing of sofosbuvir in the European Union.

Sofosbuvir approval in European Union

Gilead Sciences announced on 17 January 2014 that sofosbuvir (Sovaldi), a nucleotide polymerase inhibitor for the treatment of hepatitis C, has received marketing approval in the European Union.

The European licence allows sofosbuvir to be used for treatment of all hepatitis C genotypes (1-6), according to the following dosing schedules:

Sofosbuvir will be available for prescription in the EU as soon as reimbursement agreements have been reached in member states. The length of time it takes for the drug to be assessed will vary from one country to another. In a few member states such as Germany, the drug is already available (in France it is already available through the Temporary Authorisations for Use [ATU] programme). The cost of the drug is likely to be a barrier to availability in many countries. A 12-week course of sofosbuvir treatment will cost US$84,000 in the United States, not including the cost of combination drugs such as ribavirin or pegylated interferon. The European price of a 12-week course of treatment has not yet been confirmed.

Sofosbuvir/ledipasvir results

Gilead Sciences will also seek approval in Europe for a fixed-dose combination of sofosbuvir and the NS5A inhibitor ledipasvir, following the announcement of results of the ION studies in December. The ION-3 study showed that eight weeks of treatment with the combination was sufficient to cure 94% of previously untreated people with hepatitis C genotype 1 infection. A 12-week course of treatment cured 93.6% of previous non-responders with genotype 1 infection, and 97.7% of patients in a second study of previously untreated people with genotype 1 infection.  These levels of treatment response were achieved without the use of ribavirin or interferon.

Further results from these studies, in particular the details of performance of the combination in patients with advanced liver disease, will be presented at scientific conferences in the next few months. The combination may receive marketing approval towards the end of 2014 or in early 2015, just ahead of AbbVie’s interferon-free drug combination.

Daclatasvir filing in European Union

Sofosbuvir/ledipasvir is not the only interferon-free combination that includes sofosbuvir. Final results of a study first presented in 2012 were published last week, showing that the combination of sofosbuvir and the NS5A inhibitor daclatasvir also achieves a very high cure rate in people with hepatitis C genotypes 1, 2 or 3. The study included both previously untreated people and people who had failed to respond to a previous course of treatment with pegylated interferon, ribavirin and either telaprevir or boceprevir.

Research into this combination was stalled in 2012 because daclatasvir is being developed by Bristol-Myers Squibb while sofosbuvir is owned by Gilead Sciences. Gilead chose to develop sofosbuvir with another drug in its pipeline, ledipasvir, rather than allow further studies with daclatasvir.

Now that sofosbuvir is licensed and available for purchase, Bristol-Myers Squibb has announced that it is launching three new studies of the combination of daclatasvir and sofosbuvir, and has already applied for marketing approval of daclatasvir in the European Union. The results of the daclatasvir/sofosbuvir study published this month form part of that application, so it is possible that daclatasvir will be approved for use in Europe in combination with sofosbuvir, not just for genotype 1 but also for genotypes 2 and 3.

Daclatasvir has also been studied in combination with pegylated interferon and ribavirin for treatment of genotypes 2 and 3. It is being studied in combination with the protease inhibitor simeprevir for interferon- and ribavirin-free treatment of genotype 1 hepatitis C.

In a press release announcing its European marketing application, a Bristol-Myers Squibb spokesman stated: “If daclatasvir is approved, we would focus on helping to ensure its availability to patients with limited treatment options and would work with EU health authorities to ensure access is achieved as quickly as possible.”

Other new drugs news

Several other companies also made announcements about their development plans for hepatitis C treatments in January, showing how quickly the drug pipeline is changing.

Boehringer-Ingelheim announced that it is halting development of an interferon-free combination that includes deleobuvir, a non-nucleoside NS5B polymerase inhibitor. The decision was taken after it became clear that the combination was unlikely to perform as well as interferon-free combinations being developed by other companies. Boehringer-Ingelheim will press ahead with its plans to seek marketing approval in Europe and the United States for its protease inhibitor faldaprevir.

Two other companies, Vertex and Idenix, announced phase 2 study results of interferon-free combinations. In both cases, the SVR4 results (sustained virological response four weeks after the end of treatment) fell below 90%, raising the question of whether these combinations will be considered sufficiently potent in comparison with the interferon-free combinations from Gilead Sciences and AbbVie that are likely to be approved within the next year.

Achillion announced that it is preparing to initiate trials of three different interferon-free combinations in 2014, and also hopes to restart development of its protease inhibitor, sovaprevir, which was placed on clinical hold by the US Food and Drug Administration.

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