Therapeutic focus - Hepatitis C waits for better treatments

Novartis snapped up the leading candidate of an emerging class of hepatitis C drug when it licensed the cyclophilin inhibitor Debio-025 from Swiss compatriot, Debiopharm, even before it could report phase II trial results. A review of the R&D pipeline shows, however, that neither cyclophilin inhibitors nor Debio-025, now dubbed alisporivir, are likely to be the first new class to hit a market in which an estimated half of patients do not respond to the current standard of care.

Should they succeed, two hepatitis C protease inhibitors now in phase III trials would be more likely to hit the market first and take their places alongside pegylated interferon alpha and ribavarin treatments that are now the standard of care. It is an area of significant need; an estimated 170 million people worldwide are estimated to be infected with the hepatitis C virus, many co-infected with HIV, and current treatments can result in severe side effects and adverse reactions.

Still, as the Novartis-Debiopharm deal demonstrates, cyclophilin inhibitors are generating increasing levels of interest. Novartis also has in phase II trials Nim811, Scynexis has a candidate in phase I trials for hepatitis C prophylaxis as well as a cyclophilin inhibitor research project, and Biotica Technology has undertaken a research project.

Cyclophilin inhibitors in the hepatitis C pipeline
Status Name Pharmacological class Company Indications
 Phase II Debio-025 (UNIL-025) Anti-virals Debiopharm Hepatitis C treatment [Phase II]; HIV treatment [Phase I]
Nim811 Anti-virals Novartis Hepatitis C treatment [Phase II]; HIV treatment [Phase I]
 Phase I SCY-635 Anti-virals Scynexis Hepatitis C prophylaxis [Phase I]
Research project Cyclophilin Inhibition research project Immunosuppressants Scynexis Immune suppression [Research project]; General viral indications [Research project]; Other neurological indications [Research project]
nPT-CyP project Anti-virals Biotica Technology Hepatitis C treatment [Research project]

Race to market

The most likely entrant to break the interferon-ribavarin dominance will be the protease inhibitor VX-950, also known as telaprevir, which Vertex Pharmaceuticals has developed and will market in North America and has licensed to Johnson & Johnson in Europe, the Middle East, South America and Australia, and Mitsubishi Tanabe Pharma in Asia. Its fate rests on a series of three phase III trials scheduled to finish in March, May and July. If those are successful, look for a worldwide launch in 2011.

Expectations for the drug are high. Consensus forecasts from EvaluatePharma’s show it to be a blockbuster for both Vertex and J&J in 2014, with $2.77bn in sales for Vertex and $1bn for J&J. But even with a market capitalisation of $7.67bn Vertex is a mere minnow against J&J, as such telaprevir’s success is much more important to Vertex. EvaluatePharma’s NPV Analyzer estimates telaprevir to be woth $9.02bn to Vertex, or 118% of the Massachusetts company’s market cap (Event - Vertex, Schering-Plough line up hep C data as pivotal results loom, October 29, 2009).

If Vertex is first to market, rival Merck & Co will have some consolation in the form of more shots on goal in the hepatitis C protease inhibitor class thanks to its acquisition of Schering-Plough. Boceprevir is also set to launch in 2011 should its phase III trials prove successful, while narlaprevir is in phase II trials. For the moment however analysts have clearly picked telaprevir as the winner, given that consensus sales for boceprevir in 2014 sit at $491m, a respectable level but dwarfed by the telaprevir forecasts.

Different approaches

If the hepatitis C protease inhibitors are the first to market, they are only the first drops from an R&D pipeline that is a confluence of multiple streams. The table below summarises the leading classes of new candidates in a pipeline containing 89 products overall, across 26 different targets.

Clinical phase hepatitis C candidates 
Pharmacological Class Number of candidates
Protease inhibitor  18
Interferon approach  12
Polymerase inhibitor  10
Therapeutic vaccine  6
Anti-viral  5
Nucleoside modulators  5
Hepatitis C agent  4
Anti-infective  3
Cyclophilin inhibitor  3

The recent entrants to the race, cyclophilin inhibitors, were discovered when cyclosporine, the immunosuppressant used in organ transplants, was found to bind to cyclophilins, a cellular protein that is thought to aid in the virus’ replication, and thus suppressed virus spread.

The first partnered drug in the cyclophilin inhibitor category, Debio-025 was licensed for undisclosed fees and milestones to be paid to privately held Debiopharm. With NIM811, an organic Novartis candidate, the Basel-based company appears to have locked up the franchise ahead of Scynexis and Bioteca.

Some crucial dates are coming up for Debio-025. Debiopharm has two ongoing phase II trials with a total of 340 patients testing sustained viral response with the drug. The larger of the two, with 290 patients testing Debio-025 in combination with interferon and ribavarin against the stand of care alone, is expected to be completed in November.

Behind that is NIM811, which is in phase II trials in 250 patients to assess its safety and tolerability in combination with interferon and ribavarin, versus interferon and ribavarin alone. That trial is not expected to finish until 2013, however.

The need for more effective hepatitis C treatments is clear. With pivotal trial results nearing on some new treatments and an abundance of shots on goal to come, it is likely that coming years will see the emergence of better drugs with fewer side effects. The question for pharmaceutical manufacturers is which shots will hit the back of the net and which will go wide.

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