Assistant Managing Editor

Less than a month away from FDA advisory panels on hepatitis C virus (HCV) candidates telaprevir and boceprevir, the two protease inhibitors met up again at the European Association for the Study of the Liver meeting in Berlin, as analysts continued trying to figure out which one will have an edge over the other in the marketplace.

Heading into EASL, Vertex Pharmaceutical Inc.'s telaprevir appeared to be winning in terms of cure rate data. Results from two Phase III studies in combination with the standard of care (SOC), ribavirin and interferon, showed a 75 percent and a 72 percent cure rate, respectively, in patients treated with telaprevir. Two Phase III trials of boceprevir plus SOC yielded cure rates of 66 percent. (See BioWorld Today, May 27, 2010, and Aug. 11, 2010.)

Updated data from the REALIZE study in previously treated patients during the conference last week also seemed to bode well for telaprevir, which produced viral cures in 83 percent of prior relapsers, 59 percents of prior partial responders and 29 percent of null responders. The drug also did well across all patients tested for the IL28B genotype. Those analyses "continued to demonstrate telaprevir's advantages," Wells Fargo analyst Brian Abrahams wrote in a research note.

Yet boceprevir, branded Victrelis, from Whitehouse Station, N.J.-based Merck & Co. Inc., has performed well in treatment-experienced patients, too. Data presented at EASL showed that 64 percent in the boceprevir plus SOC group achieved sustained virological responses (SVR) vs. 21 percent in the SOC group. And fewer patients receiving boceprevir relapsed after the end of treatment, 12 percent vs. 33 percent. Plus, early consensus seems to indicate that boceprevir might be easier for patients to take.

Differences in trial design make a straight head-to-head comparison between telaprevir and boceprevir a difficult proposition, but John M. Vierling, professor of medicine and surgery at the Baylor College of Medicine in Houston, who has worked with both candidates – a Phase III trial in previously treated patients with boceprevir (those data recently reported in The New England Journal of Medicine) and a Phase III trial of telaprevir in treatment-naïve patients – said he thinks both have merit against HCV.

The two drugs represent a major advancement in treatment, shortening treatment duration and significantly boosting efficacy compared to existing SOC, which is known for only a 40 percent to 50 percent cure rate. But, even with the protease inhibitor triple-drug combo, roughly a fourth of patients still are not responsive to treatment, and it's those cases that might deserve the most attention.

"You have to turn around the look at the non-SVR [patients]," Vierling told BioWorld Insight. Those comprise a number of subtypes, such as patients intolerant to interferon, those who fail to complete a full course of treatment due to side effects and even those who complete a full course, but still are unable to reach SVR status.

There's also the issue of resistance. Protease inhibitors can confer resistance-associated variants (RAV), though patients experiencing a rapid SVR on the triple-drug therapy don't have to worry about resistance. "You cannot develop resistance if there is no replication," Vierling said. Those who are slow, partial or nonresponders, however, can develop resistance. Since both telaprevir and boceprevir have identical resistance profiles, development of resistance to one drug will render a patient unlikely to respond to the other.

That means physicians will be tasked with monitoring patients, and Vierling said he would not be surprised to see the upcoming FDA advisory panels look at determining a standardized method for that monitoring. The telaprevir and boceprevir programs both involved different methods of measuring virus detectability and virologic effect, "so they will need guidance on the level of quantification," such as a standard PCR assay, he said.

Guidance likely would also include a treatment stopping point based on futility for patients who are slow or nonresponders to minimize the chance of RAV.

But there was some good news about resistance coming out of EASL. Unlike HIV, which can produce subsequent transmission of resistant virus following treatment with protease inhibitors, HCV RAVs generated appear to spontaneously decrease when patients are off treatment. So patients don't have to worry that treatment with telaprevir or boceprevir "could cause worse disease or wild-type disease," Vierling said.

Though he warned that it's hard to predict the outcome of an FDA review, Vierling said he thinks it's "likely" telaprevir and boceprevir will end up winning approval. But, while, those first-generation protease inhibitors will improve the treatment paradigm but "they do not completely solve the problem," he added.

That means plenty of room for up-and-coming competitors in the HCV space.

One of those contenders is a four-drug regimen from Cambridge, Mass.-based Vertex that combines telaprevir with earlier-stage polymerase inhibitor VX-222 plus SOC. Data at EASL showed a 12-week response rate of 90 percent with no viral breakthrough, with half of those patients able to stop all therapy at 12 weeks.

Piper Jaffray analyst Edward Tenthoff viewed those data as a good sign, since triple-drug therapy likely will convert into a four-drug cocktail "before interferon-sparing, all oral triple therapy ultimately emerge as standard of care," he noted in a research report.

And getting rid of interferon is a long-term goal in HCV, though it's proven tricky. Vertex, for example, previously discontinued an arm in its trial testing telaprevir and VX-222 without SOC after patients in the study experienced viral breakthroughs. So far, Pharmasset Inc. and partner Roche AG have made the most noise with an interferon-free regimen. Combining nucleotide drugs PSI-7977 and PSI-938 produced a 94 percent response in HCV patients in an early trial.