Therapeutic focus - Novel hep C class get another big backer

With the protease inhibitors already blazing a trial, a number of new classes of direct acting anti-virals designed to fight hepatitis C are progressing through trials in a fiercely fought race to prove that the current standard of care, interferon and ribavirin, can eventually be eliminated.

With its acquisition of Anadys, Roche has bought into the non-nucleoside polymerase inhibitors, a fairly widely studied class, the potential of which has yet to be determined. None have made it into phase III yet and tolerability issues have emerged; their future at this stage seems to lie as add-ons to more potent agents. However, with a number of big hep C players showing an interest and at least six having made it into mid-stage testing, Roche clearly sees this as a class worth considering (see table below).

Transforming treatment

Data from an ongoing phase II study of Anadys’ non-nucleoside, setrobuvir, failed to set the company’s shares alight last week (Anadys data encouraging but stronger signals needed, October 13, 2011).

However Roche was obviously already interested, snapping up the company for $230m in a deal announced today. The Swiss pharma giant noted that setrobuvir provides it with an additional mode of action that will hopefully lead to interferon-free regimens – the company’s pipeline already encompasses nucleoside polymerase inhibitors and a protease inhibitor (Roche making up for lost time with Anadys purchase, 17 Oct 2011).

The first generation protease inhibitors – Vertex’s Incivek and Merck & Co’s Victrelis – are already transforming the treatment of hep C - the clinical trials that won these agents approval suggest cure rates should double.

However the newer classes of anti-virals, which also include the NS5A and cyclophilin inhibitors, are believed to be much more potent. Hence the hope for eventually eliminating interferon and ribavirin backbones, something not possible with the first generation protease inhibitor agents.

Many believe the nucleoside polymerase inhibitors hold the most potential for supplanting current standard of care – and possibly even the protease inhibitors - largely because their mechanism of action should raise barriers to resistance developing. Acting against the NS5B polymerase in the HCV genome, these agents target the catalytic sites of the enzyme, preventing the virus from replicating.

The non-nucleoside polymerase inhibitors also target the NS5B polymerase, inhibiting its ability to replicate. However these agents do not bind to active sites that are important to the function of the enzyme, they bind to non-active or allosteric sites. This means viral resistance is more likely to build, a factor that has dented enthusiasm for the class.


This resistance issue was seen with Vertex’s non-nucleoside candidate, VX-222, gained through its $370m takeout of ViroChem in 2009 (Vertex strengthens hold on hepatitis C field, March 4, 2009).

In December last year viral breakthrough forced Vertex to scrap the arm of an ongoing phase II study examining a dual combination of Incivek and VX-22. The study continued with three arms, testing the agents plus current standard of care, and in July announced encouraging interim results from the arm which pitted the experimental agent in combination with Incivek, interferon and ribavirin.

Part of the company’s strategy to fend off future competitive threats to its flagship drug Incivek, analysts believe the VX-222 containing 'quad' regimen holds potential. However tolerability issues – renal failure and GI toxicities – and the multitude of other agents in development means hopes have dimmed. Data has yet to emerge on an arm of the study testing the all oral regimen of VX-222, Incivek and ribavirin.


Despite this perceived lower potency, others are also pushing on with this class. In June, Johnson & Johnson started a trial of its non-nucleoside candidate in combination with TMC435, a phase III protease inhibitor that is emerging as the biggest competitive threat on the horizon for Incivek and Victrelis.

Boehringer Ingelheim, which earlier this year started an extensive phase III programme with its protease inhibitor, BI 201335, also has a non-nucleoside in phase II studies. BI 207127 is being studied in combination with BI 201335 in interferon free regimens, with and without ribavirin.

Abbott has not said too much about its internally discovered non-nucleosides, ABT-333 and ABT-072, although both have been through a series of phase I and early phase II studies – ABT-333 is part of an ongoing mid-stage study being also conducted with ABT-450, another oral protease inhibitor.

Pfizer has also said little about its efforts with filibuvir, although according to a fairly large phase II trial, seeking to recruit almost 300 patients, is ongoing. Testing the agent in combination with interferon and ribavirin, results could emerge next year.

Meanwhile Idenix’s hep C pipeline – over which Novartis owns rights to first refusal - contains a non nucleoside that completed proof of concept tests earlier this year.

Role to play

In another sign that the road is unlikely to be smooth for this class, last month Gilead Sciences said that as a result of two serious adverse events dosing would cease in trials of GS 9190 in combination with interferon and ribavirin and other direct acting agents.

Toxicity issues have been seen with other agents - including rash with Roche's newly acquired setrobuvir. Combined with lower potency and barrier to resistance compared to other novel hep C classes, this means researchers do not believe that the non-nucleosides have the potential to supplant the first-generation protease inhibitors in the new interferon and ribavirin triple therapy regimen.

But should effective combinations of other direct acting anti-viral agents manage to remove the need for the interferon and ribarivin components, they could still have a role to play.

Selected non-nucleoside polymerase inhibitors
Status Product Generic Name Company Originator First Introduction
Phase II ABT-072 Abbott Laboratories Abbott Laboratories  2016
ANA598 setrobuvir Roche Anadys Pharmaceuticals
PF-00868554 filibuvir Pfizer Pfizer  2016
ABT-333 Abbott Laboratories Abbott Laboratories  2015
VX-222 Vertex Pharmaceuticals ViroChem Pharma  2015
BI 207127 Boehringer Ingelheim Boehringer Ingelheim
GS 9190 tegobuvir Gilead Sciences Gilead Sciences
Phase I TMC647055 Johnson & Johnson Tibotec
IDX-375 Idenix (Novartis has option) Idenix Pharmaceuticals

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