Editor

Vertex Pharmaceuticals Inc.'s unveiling last week of the Phase III program for the protease inhibitor telaprevir - the latest volley in the battle for a better hepatitis C virus therapy - brought cheers, muted somewhat by the inclusion of a 48-week treatment study, added to the larger test lasting half that long.

Shooting for a label that calls for 24 weeks of treatment, Vertex apparently faces the chance that regulators here and overseas will cling to their preference for a longer spell of therapy, even as telaprevir remains bedeviled by its main side effect (rash) and would-be competitors jostle for position in the HCV space.

And it's a busy arena. The drugs of choice for genotype 1 HCV (the most prevalent subtype) are pegylated interferon plus ribavirin, making Schering-Plough Corp.'s Pegintron or F. Hoffmann-La Roche Ltd.'s Pegasys - even though the combo works only in about 50 percent of patients, as measured by a sustained virologic response (SVR) six months after treatment. Best bets for improved efficacy call for an oral drug (such as telaprevir) added to an interferon.

In its Phase III program, which starts enrolling in March, Vertex will run a three-arm pivotal trial testing two, 24-week regimens in about 1,050 treatment-naive patients, and will use rapid viral response (RVR) criteria to determine which participants can quit at the end of the period. A second study in 400 to 500 patients will try the 48-week regimen, aiming to confirm positive results from Phase II studies.

Specifically in Phase III, one arm will get 24 weeks of therapy, with telaprevir dosed at 750 mg every eight hours for 12 weeks in combination with standard doses of pegylated interferon alfa-2a and ribavirin for 12 weeks, following by another 12 weeks of the same regimen without telaprevir.

Another arm gets 24 weeks of therapy, with telaprevir dosed at 750 mg every eight hours for just for eight weeks in combination with standard doses of the other two drugs for eight weeks, followed by 16 weeks with the regimen minus telaprevir. A control arm will take the no-telaprevir therapy for 48 weeks.

Vertex shares weakened on the Phase III news in pre-market trading, but perked later, as Wall Street digested the news after a conference call with management.

The slow start to enthusiasm recalled the reaction to word of interim results from Phase IIb trials in November, when Vertex dipped despite news that telaprevir beat standard of care. Investors apparently didn't like the marginally lower than expected SVR in data from PROVE 1, offered at the American Association of the Study of Liver Diseases meeting in Boston.

In PROVE 1, Vertex said, 61 percent of 79 patients in the U.S. trial called PROVE 1 gained undetectable viral levels at 24 weeks after stopping therapy (telaprevir plus pegylated interferon plus ribavirin). In the European study, PROVE 2, 65 percent of 81 patients on the "12 plus 12" regimen - 12 weeks of telaprevir pill three times daily, followed by 12 weeks of the standard of care - got rid of their HCV and stayed clear of disease when tested 12 weeks later. (Later the rate was updated to 67 percent.)

The Phase III program falls in line with Vertex's plan, disclosed earlier. In the larger study, patients need to hit RVR at 4 weeks in order to qualify for stopping at the 24th week, and the test is mainly designed to show a 15 percent difference in the SVR between drug and placebo at week 24.

But the Phase III approach has an important edge over PROVE 1, since patients who don't show an RVR and who continue therapy at 48 weeks can count as wins in Phase III. This means the SVR rate at 24 weeks stands a handsome chance of beating the 61 percent in PROVE 1's "12+12" arm.

Meanwhile, up and comers in HCV include Roche's nucleoside polymerase inhibitor R1626, which knocked the virus down to undetectable levels in 81 percent of patients after 4 weeks in a Phase IIa study. Another, earlier-stage drug in the same class: Pharmasset Inc.'s R7128, tested in 50 patients - 85 percent of whom saw their virus fall below the radar after four weeks.

Schering-Plough has the protease inhibitor boceprevir in Phase II trials. The drug has been shown to work (with pegylated interferon) in 79 percent of patients at the top dose, after 12 weeks.

Until last summer, yet another strong player was ViroPharma Inc., with its non-nucleoside polymerase inhibitor HCV-796. Reports of elevated liver enzymes in treated patients caused the firm, with partner Wyeth Pharmaceuticals Inc., to suspend dosing in a Phase II trial in August.

Among the firms venturing into new approaches for HCV, Human Genome Sciences Inc., with its long-acting interferon called Albuferon (albumin-interferon alpha 2b), reported a significant development last week in its Phase III push called ACHIEVE. The data monitoring committee recommended that HGS modify the protocol, lowering the dose of Albuferon in the 1,200-mcg arm to 900 mcg, and not wait for adverse effects before cutting back.

Wall Street slammed HGS on the news, taking away 45 percent of the stock's value - pretty severe, considering that Phase IIb results showed 900 mcg equaled or beat pegylated interferon, the endpoint for Phase III. A lesson in trial design, maybe: If you don't need that higher-dose cohort (and you'll probably have to change it later anyway), leave it out. Phase II data already had suggested the 1,200-mcg dose might be less than optimal, and both marketed pegylated interferons are labeled for pulmonary risk.

Also striving for a better interferon is the French firm Flamel Technologies SA, which reported positive preliminary data in October with its Phase I-stage IFN-alpha-XL, when compared to pegylated interferon in chronic HCV. Flamel is hunting for a partner.

Flamel, though, is far behind Vertex, whose telaprevir could "transform therapy in two major dimensions," said Kurt Graves, the company's chief commercial officer and head of strategic development, during the conference call: an SVR superior to standard of care, achieved in half the treatment time.