Assistant Managing Editor

Impressive sustained viral response rates in a Phase II trial of Vertex Pharmaceuticals Inc.'s telaprevir sent shares of the Cambridge, Mass.-based company jumping Monday and boosted investor confidence for the ongoing pivotal program of the protease inhibitor in hepatitis C.

Emerging over the weekend as one of the highlights of this year's American Association for the Study of Liver Diseases meeting in Boston, data from the Phase II C208 study showed a greater than 80 percent SVR rate in all four treatment regimens of telaprevir plus ribavirin and interferon, including two arms that tested twice-daily dosing.

Trials to date - including the ongoing Phase III program - have tested three-times-daily dosing of telaprevir, and "we anticipate that is the regimen that would appear on the label," upon product approval, said Bob Kauffman, Vertex's chief medical officer. But the goal will be to ask regulators to sign off on the less-frequent regimen later.

"It was a small study," Kauffman told BioWorld Today. "Nevertheless, the results were fairly definitive, with a clear signal of twice-daily dosing."

The trial, conducted by European partner Tibotec Pharmaceuticals Ltd., enrolled 161 treatment-naïve patients with genotype 1 hepatitis C virus infection and tested four telaprevir-based regimens: two testing twice-daily treatments (every 12 hours), one with alfa-interferon-2a (Pegasys) and one with alfa-interferon-2b (Pegintron); and two testing thrice-daily treatments (every eight hours), one with alfa-interferon-2a and one with alfa-interferon-2b. All four treatment arms also included ribavirin.

In the telaprevir-ribavirin-Pegasys arms, SVR rates of 83 percent and 85 percent were seen in the two-times-daily and three-times-daily arms, respectively. Patients receiving telaprevir plus ribavirin and Pegintron treatment showed SVR rates of 82 percent and 81 percent for the twice-daily and three-times-daily arms, respectively.

For most of those patients - all but 18 percent - those responses came after 24 weeks of treatment in the 48-week trial.

"As far as the numbers are concerned, the SVR rates are as good as it gets and likely exceeded Street expectations," analyst Howard Liang, of Leerink Swann, wrote in a research note.

The C208 data also blew past previous SVR results from telaprevir - SVR rates were 61 percent in PROVE-1 and 68 percent in PROVE-2 - indicating the success of a response-guided treatment protocol, which Kauffman described as a "code word, in a way," that refers to a series of actions during the course of the trial, in this case better management of side effects, including rash, and better management of patients to reduce discontinuations.

Total discontinuation in the C208 trial was 5 percent (eight patients), and were mainly related to rash (four patients) and anemia (three patients), all at much lower rates than seen in earlier studies.

That bodes well for the ongoing Phase III program, which is being conducted using a similar response-guided protocol, and "could limit competitors' ability to claim better tolerability," noted analyst Michael Aberman, of Credit Suisse Securities.

Two Phase III trials - ADVANCE and ILLUMINATE - are testing telaprevir-based regimens in treatment-naïve patients. Data from that study are expected in the first half of 2010, Kauffman said. Data from a Tibotec-sponsored trial in nonresponders are expected around the middle of next year.

Deutsche Bank analyst Mark Schoenebaum believes there's a "good probability" that Phase III SVR rates will exceed those of Phase II. And if Phase III SVR rates top 70 percent, telaprevir's efficacy "will be hard to beat."

Vertex also reported data from Study 107, an open-label study involving patients from the PROVE trials who did not achieve SVR, with SVR rates among relapsing patients reaching as high as 90 percent and rates among partial responders reaching 55 percent.

Given its efficacy to date, along with tolerability and potential for twice-daily dosing, "telaprevir sets the bar high for itself and for competitors," wrote analyst Adam Cutler, of Canaccord Adams.

Shares of Vertex (NASDAQ:VRTX) gained $2.59 to close Monday at $36.15.

But coming up alongside telaprevir is boceprevir, a protease inhibitor from Kenilworth, N.J.-based Schering-Plough (about to be acquired by Merck & Co. Inc.). At AASLD, the company reported data from a response-guided therapy study in null responders, showing that 38 percent overall (19 of 50 patients) achieved SVR. Twenty-five percent (seven of 28) on 28 weeks of therapy reached SVR and 55 percent (12 of 22) who received 48 weeks of therapy reached SVR.

Boceprevir is in Phase III studies in treatment-naïve patients and in patients who have failed prior treatment. Studies are fully enrolled and Schering-Plough expects completion in mid-2010.

Other protease inhibitors in development include Whitehouse Station, N.J.-based Merck's MK-7009, which showed rapid viral response rates of 69 percent in the 600-mg arm to as high as 82 percent in the 800-mg arm in 12-week data presented at AASLD.

And Waltham, Mass.-based Avila Therapeutics Inc., which is developing its small-molecule protease inhibitor AVL-181, presented data showing that its drug promoted complete viral clearance in vitro when used in combination with other HCV therapies. Avila is set to move that program into clinical testing next year.

But one other piece of news coming out of this year's AASLD could be a good sign for the protease inhibitor space.

Analyst Brian Abrahams, of Oppenheimer & Co., pointed to a study by the University of Virginia, designed to explore the cost effectiveness of telaprevir and boceprevir, which found that even priced at a premium - $50,000 per course of treatment in the U.S. - the cost would still be lower in the long term, offset by savings preventing cirrhosis and transplant.

In other AASLD news:

• Alnylam Pharmaceuticals Inc., of Cambridge, Mass., said preclinical research findings showed that its transthyretin-mediated amyloidosis drug, ALN-TTR, demonstrated dose-dependent reduction of liver TTR messenger RNA and serum TTR protein levels by greater than 80 percent in transgenic mice and nonhuman primates, with gene silencing effects found to be durable for more than three weeks following a single-dose administration. ALN-TTR is a systemically delivered RNAi therapeutic targeting the TTR gene.

• Bristol-Myers Squibb Co., of New York, reported 48-week data from an ongoing study in chronic hepatitis B patients with decompensated cirrhosis showing that Baraclude (entecavir) resulted in greater viral suppression compared to adefovir (Hepsera, Gilead). The study met its primary objective, with Baraclude showing a viral load reduction of -4.48 vs. -3.40 for adefovir.

• Enzo Biochem Inc., of New York, reported results showing that treatment with EGS21, its oral beta glucosylceramide formulation, in patients with nonalcoholic steatohepatitis was associated with an improvement in the metabolic syndrome, decreasing HbA1c by 0.1 percent compared to 0.09 percent in the placebo group. Of secondary endpoints, glucose tolerance improved in 50 percent patients receiving EGS21 vs. 38 percent on placebo, and HDL levels increased 33 percent in treated patients compared to none in the placebo group.

• Gilead Sciences Inc., of Foster City, Calif., presented three-year, open-label data from two pivotal Phase III trials showing that the majority of patients with chronic hepatitis B virus infection receiving once-daily Viread (tenofovir disoproxil fumarate) experienced sustained suppression of HBV DNA levels in the blood to below 400 copies/mL (87 percent in Study 102 and 71 percent in Study 103). Additionally, 8 percent of all patients in Study 103 (HBeAg-positive) experienced "s" antigen loss, which can contribute to resolution of chronic HBV infection.

• GlobeImmune Inc., of Louisville, Colo., reported interim Phase IIb results showing that its Tarmogen GI-5005 for hepatitis C virus infection increased the end of treatment response in genotype 1 interferon-naïve patients to 74 percent when used in combination with standard of care, pegylated interferon plus ribavirin, compared to 59 percent of patients receiving standard of care alone. The GI-5005 treatment arm also showed a nearly twofold improvement in the proportion of patients achieving normalization of alanine aminotransferase levels vs. those receiving standard of care alone.

• Ocera Therapeutics Inc., of San Diego, reported Phase II data showing that AST-120 (spherical carbon adsorbent) reduced the severity of pruritis in patients with chronic liver disease. Patients treated with the drug had a statistically significant reduction in itching with a four-week treatment course, with a mean reduction by 100 mm VAS of 30 mm vs. 5 mm for placebo-treated patients. Those findings comprised a secondary endpoint of a study aimed at demonstrating the efficacy, safety and tolerability of the drug in cirrhotic patients with mild hepatic encephalopathy. A separate presentation showed that AST-120 statistically significantly reduced serum ammonia levels and brain swelling in a rat model of cirrhosis.

• Salix Pharmaceuticals Ltd., of Raleigh, N.C., presented results of an analysis showing the protective effect and durability of rifaximin treatment in the maintenance of remission in hepatic encephalopathy. The 299-patient study showed that rifaximin twice daily significantly reduced the risk of a breakthrough HE episode by 57.9 percent in cirrhotic patients with a history of two or more overt HE episodes. Data from a separate study showed that mean changes in baseline showed significantly improved critical flicker frequency response in the rifaximin group compared to placebo in patients with history of two or more episodes of HE within the prior six months and who were in remission at baseline.

• ZymoGenetics Inc., of Seattle, and Bristol-Myers Squibb Co., of New York, presented final results from a Phase Ib trial of PEG-Interferon lambda administered with ribavirin in relapsed and treatment-naïve hepatitis C virus patients, showing that antiviral activity was observed at all dose levels tested. Of the patients in the single-agent arm, all 12 receiving 1.5 mcg/kg and 3 mcg/kg weekly for four weeks achieved a greater than 2 log decrease in HCV RNA. Five of 12 patients receiving 1.5 mcg/kg and 3 mcg/kg every two weeks for four weeks achieved a greater than 2 log decrease.