Washington Editor

Although no protease inhibitor has yet to be approved for hepatitis C, the new class of drugs is already changing the landscape for hepatitis C virus (HCV) therapies.

While Merck & Co. Inc. and Vertex Pharmaceuticals Inc. prepare to make the case for their protease inhibitors before the FDA's Antiviral Drugs Advisory Committee this week, analysts, physicians and competitors are already looking to the next horizon in HCV treatment.

Merck's boceprevir and Vertex's telaprevir could play a big part in that development. If they are approved, they will become the new standard of care (SOC) by which future HCV therapies will be measured.

With a market estimated at $3.3 billion a year and more than 170 million people worldwide infected with HCV, the space is an attractive destination for start-ups and big biopharma alike. Since it has changed little over the past 15 years, the sector has plenty of opportunity.

For patients, the current SOC, a combination of pegylated interferon and ribavirin, offers a 35 percent to 40 percent cure rate and a year of living with flu-like symptoms, Vertex spokeswoman Dawn Kalmar told BioWorld Today. As a result, a large number of patients forgo treatment.

Both boceprevir and telaprevir, used in conjunction with SOC, increased cure rates dramatically and reduced the duration of treatment for many subjects. Boceprevir produced a 66 percent cure rate in both treatment-naïve and treatment-failed patients. (See BioWorld Today, Nov. 2, 2010, and Aug. 11, 2010.)

Telaprevir produced cure rates of 75 percent in its ADVANCE trial and 72 percent in its ILLUMINATE trial, both with treatment-naïve patients. In treatment-failed patients, it had a 65 percent cure rate. (See BioWorld Today, May 27, 2010, and Sept. 9, 2010.)

The advisory committee will consider each drug on its own merits, discussing boceprevir Wednesday and telaprevir Thursday.

The Phase III program for boceprevir was unique because of a response-guided therapy arm that personalized the treatment according to response markers throughout the trial, Eliav Barr, vice president of the infectious diseases unit at Merck Research Laboratories, told BioWorld Today.

"Health care, and medicine as a whole these days, is focusing more and more on personalized medicine," Barr said. In trying to find the right "cocktail" that works for each HCV patient, personalized medicine becomes a reality, he added.

However, in the briefing documents the FDA released Monday for boceprevir's hearing, the agency questioned the strength of the evidence to support response-guided therapy in certain groups of patients, such as late responders, African-Americans who typically do not respond well to SOC, or patients with advanced fibrosis or cirrhosis.

A request by the Whitehouse Station, N.J.-based Merck to include null responders in the indication also raised a flag since the trial didn't specifically test boceprevir in that group. One of the questions the committee will discuss is whether a postmarket study is needed in null responders, patients who did not respond to SOC.

Based on the briefing documents for boceprevir, most analysts Monday expected the committee to recommend approval for both drugs. And although the FDA had yet to release the briefing documents for telaprevir, analysts continued to give the marketing edge to the Vertex drug, developed in conjunction with a Johnson & Johnson subsidiary, which has marketing rights outside North America.

The FDA's concerns about the null responders for boceprevir indicated "telaprevir may ultimately receive a broader label," Wells Fargo Securities analyst Brian Abrahams said. "The documents also highlighted other areas where we believe the telaprevir data are stronger."

Vertex, of Cambridge, Mass., has been developing telaprevir for the past 15 years, Kalmar said. Approval of the drug would mark the first candidate the company has taken from development to launch.

Approval of both, or either, of the HCV treatments would be a scene changer for the disease. The "Holy Grail" in HCV therapy, up until now, has been improving cure rates, Kalmar said. But looking ahead, the goal will shift to eliminating or reducing the need for interferon.

Several biotechs are already planning those next steps. A number of companies, including J&J subsidiary Tibotec BVBA and Boehringer Ingelheim, have protease inhibitors in Phase III.

Others, like San Diego-based Anadys Pharmaceuticals Inc., are waiting to see if the Merck and Vertex drugs are approved so they can use the new SOC in combination with their candidates. A combination could shorten the duration of treatment and possibly lead to the elimination of interferon, Anadys CEO Steve Worland told BioWorld Today.

Biolex Therapeutics Inc. also is hoping to include boceprevir or telaprevir in a Phase III trial next year, but the Research Triangle Park, N.C.-based company is taking a different tack. It doesn't want to eliminate interferon; it wants to improve it.

"The next Holy Grail is not to get rid of interferon," Biolex CEO Jan Turek told BioWorld Today. "The next Holy Grail is to get cure rates of 90 percent." In a Phase IIb study, Biolex's Locteron, a controlled-release interferon alpha, showed a significant reduction in flu-like adverse events and depression, both common side effects of interferon.