Hepatitis C: Another Protease Revolution

Dec 01, 2010



The providential similarities between HIV and the Hepatitis C virus (HCV) have enabled researchers at the level of viral dynamics to apply their crisis-driven know-how about designing drugs to target specific proteins and enzymes on the first retrovirus to that of the second. And as with HIV in the mid-'90s, the launch of a new class of protease inhibitors is set to transform HCV treatment over the next decade, with kinder, gentler oral antiviral cocktails that will increase success rates from 50 percent to 75 percent while halving the current onerous course of treatment. "The pipeline has about 100 molecules designed to hit all these new targets—protease, polymerase, RNA-binding proteins," says Matthias Gotte, a virologist whose lab at McGill University tests old compounds for their prowess at outwitting the replication and resistance of HIV, HCV, and herpes.



Vertex's telaprevir is expected to be the first protease out of the FDA gate early next year, followed by Merck's boceprevir by late 2011. Both drugs boast superior efficacy, and their side effects are modest compared to the standard of care: a 24- to 48-week course of weekly injections of interferon boosted by ribavirin, with its 50 percent cure rate due in part to the severe malaise triggered by the immune stimulator. Telaprevir has not only the front-runner's advantage but a slight edge in efficacy. Analysts anticipate a breathless launch by Vertex and Merck alike, and projections of $2.5 billion in annual sales by 2013 for telaprevir are widely shared.

As second fiddle, boceprevir will require standout post-marketing data to grab a heaping piece of a global HCV market expanding to $8 billion by 2014 as a growing number of the 220 million people infected with the virus access diagnosis and treatment. Still, a physician survey by Datamonitor found that 46 percent expect to prescribe telaprevir (with standard of care) to newly diagnosed patients, compared to 26 percent who will choose boceprevir.



"There is still big room for improvement in this class because both drugs have to be dosed three times a day," says Mansi Shah, a Datamonitor analyst. Nipping at their heels is J&J's Phase II protease, TMC435, poised to become the first once-daily treatment. Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, and Roche all have promising protease in Phase II. Because HCV is quick to develop resistance to this class, the most potent, fastest-clearing molecule is likely to seize first-line status.



But the HCV treatment revolution will be in full swing only when an all-oral combination retires IV interferon for good. To that end, each of these six Big Pharmas are also chasing a first-in-class polymerase inhibitor—last month, Roche took the lead by licensing Pharmasset's midstage polymerase, RG7128—and are already testing protease/polymerase dual therapies in Phase II. But the polymerase class poses its own drug-design challenges: Although it is almost free of resistance, one after another targeted molecule has been doomed by high toxicities.

After preliminary data was recently released by BMS at the annual liver-disease conference, Gilead and Vertex stirred worries that a protease/polymerase duo alone lacks sufficient potency for sustained viral control, suggesting that the addition of ribavirin for a triple-drug viral punch will be the gold standard until a third viral protein is pierced or an inhaled—and much milder interferon—comes along. Still, the progress in HCV will bring the pharmaceutical industry glowing global headlines in 2011. Right now thousands of patients with chronic infection and failing livers are literally counting the days until their doctors can write their first scrip for these likely lifesaving drugs.