West Coast Editor

Positive interim Phase Ib data with VX-950, its oral protease inhibitor for hepatitis C, was enough to send Vertex Pharmaceuticals Inc. on an upward ride that left the company's shares 19.8 percent greater by the end of the day.

"It speaks volumes," said Michael Partridge, director of corporate communications for Vertex, regarding the data. "You're seeing a knockdown of the virus, and it's an unequivocal result."

Vertex's stock (NASDAQ:VRTX) closed Tuesday at $13.40, up $2.21.

The 14-day study enrolled 34 patients with chronic genotype 1 HCV - the most difficult strain to treat - who were given either placebo or one of three dose regimens of VX-950.

Those who got 750 mg of VX-950 every eight hours achieved a median reduction in HCV-RNA of greater than 4 log10, which is equivalent to a more than 10,000-fold decrease in viral levels, at the end of the period.

Investigators saw a median reduction in HCV-RNA of greater than 2 log10 in each of the other two VX-950 dose groups, and every patient given VX-950 achieved greater than a 2 log10 reduction within the first three days.

Ian Smith, chief financial officer of Vertex, said the firm "has always been looking at [the HCV protease] as a target."

Having solved the crystal structure, researchers faced the "very difficult challenge to design the chemistry that would cause a drug to lock on to the active site," he said. "The active site we've identified is flat. Fortunately, we were able to design a molecule that is very sticky."

They weren't alone in trying.

A few years ago, Ingelheim, Germany-based Boehringer Ingelheim GmbH published early stage work on a protease inhibitor for HCV dosed for 48 hours. Schering-Plough Corp., of Kenilworth, N.J., in October 2003 reported good in vitro results with an HCV protease inhibitor, called SCH6, exposed to cells at various concentrations during a 72-hour incubation period.

Smith acknowledged the Ingelheim results as "compelling," though both companies' studies were much briefer than Vertex's.

The tricky genotype 1 HCV successfully targeted by Vertex is the most prevalent strain of the virus in the U.S., Western Europe and Japan. VX-950 is partnered in Japan and the Far East with Tokyo-based Mitsubishi Pharma Corp., in a deal worth up to $33 million, signed last summer. (See BioWorld Today, June 15, 2004.)

Specifically, the VX-950 trial at three centers in Europe evaluated tolerability, pharmacokinetics and effect on viral kinetics of 450 mg every 8 hours, 1,250 mg every 12 hours, or 750 mg every 8 hours, with follow-up after the study period of 14 days. Included were patients who'd been treated previously and those who had not. Six patients got placebo and 28 patients were given VX-950.

Plasma HCV-RNA went down in all dose categories. Within three days of treatment, the median reduction was greater than 3 log10 in all three groups, and in the 750-mg arm, patients showed a further reduction in viral levels between days three and 14, with mean and median HCV-RNA reductions of greater than 4 log10 on the final day. Trough plasma concentrations of VX-950 were highest in that group.

In the 450-mg and 1,250-mg groups, maximal effects appeared between days three and seven of treatment. After that, between days seven and 14, there was an increase of about 1 log10 in median HCV-RNA in both groups.

"Of course we'll have to do much further work, but this is the kind of thing that hasn't been seen in [HCV]," Partridge said. Current treatment is interferon with ribavirin for a full year - an odious course of intravenous therapy that, Smith noted, has only a 40 percent to 60 percent likelihood of success and carries side effects such as anemia, flu-like symptoms and depression.

Given the odds and the side effects, many patients simply decline the drugs. If Vertex's compound reaches the market, they will have an apparently safe, well-tolerated pill. Interim data indicated VX-950 was well tolerated across all three dose groups with no serious adverse events and no treatment discontinuations.

Full analysis of the study, including a detailed pharmacokinetic and viral sequencing evaluation, is under way, and Vertex plans to offer more details from the study results at the Digestive Disease Week conference in Chicago. An embargo policy prevents the firm from disclosing anything further until then.

Meanwhile, Cambridge, Mass.-based Vertex will consult with the FDA and European regulators about how to proceed with development of the drug as monotherapy and in combination with other HCV therapies, with an investigational new drug application expected in the second half of this year to begin Phase II trials.

Credit Suisse First Boston in New York reiterated its "outperform" rating for Vertex and raised the target price from $16 to $20.