Staff Writer

As the 44th annual meeting of the European Association for the Study of the Liver (EASL) wrapped up over the weekend, all eyes turned to the INFORM-1 study, the first to combine two direct antivirals for hepatitis C.

INFORM-1 combined the protease inhibitor R7227 (InterMune Inc. and F. Hoffmann-La Roche Ltd.) with the polymerase inhibitor R7128 (Pharmasset Inc. and F. Hoffmann-La Roche Ltd.).

Unlike HCV trials conducted to date, INFORM-1 did not include concomitant treatment with the HCV standard of care, ribavirin plus pegylated interferon, which often comes under fire for its 40 percent to 50 percent cure rate and significant side effects.

Principal investigator Ed Gane of Auckland Clinical Studies said the INFORM-1 trial was "based on the rationale from the HIV treatment paradigm."

In a conference call with investors, he explained that combining different antiviral agents that target different steps in the viral replication process should not only increase the antiviral effect but also delay or prevent development of antiviral resistance.

Credit Suisse Securities LLC analyst Michael Aberman called the INFORM-1 results the "most eagerly anticipated" data of the conference. Leerink Swann LLC analyst Howard Liang wrote in a research note that the study "underscores the importance and hope the HCV field has placed on the combination of direct antivirals."

INFORM-1 is an ongoing randomized, double-blind, placebo-controlled, ascending dose Phase I trial.

Initial data presented at EASL showed that various combinations of R7227 and R7128 resulted in median viral load reductions between 3.9 log10 and 5.2 log10 after 14 days of dosing in treatment-naïve HCV patients.

Specifically, the first cohort of the trial looked at 500 mg R7128 twice daily and 100 mg of R7227 every eight hours first individually as monotherapies and then in combination.

Once the safety of the combination was established, patients received one of four combination regimens for 14 days: 500 mg bid R7128 plus 100 mg q8h R7227, which resulted in a 3.9 log10 median viral load reduction; 500 mg bid R7128 plus 200 mg q8h R7227, which resulted in a 5.2 log10 median viral load reduction; or 1,000 mg bid R7128 plus either 100 mg or 200 mg q8h R7227, both of which resulted in a 4.8 log10 median viral load reduction.

Like the viral load data, absolute virus levels and the number of patients achieving undetectable virus levels were similar at the three highest doses. Gane suggested that could be due to the fact that the majority of patients in the study reached undetectable virus levels, creating a plateau.

However, Liang noted that R7227 combined with the standard of care has achieved median viral load reductions of 5.7 log10, and he said the lack of dose-response could be due to the small sample size and narrow dose range.

Regardless, Liang wrote that the INFORM-1 data showed "combinability, lack of resistance, the ability to achieve undetectability in some patients, and continued downward viral trajectory at the end of treatment" - none of which is trivial. He predicted the trial will encourage further antiviral combination studies.

Aberman predicted that Vertex Pharmaceuticals Inc. will take a similar approach, combining its protease inhibitor telaprevir with the polymerase inhibitor VCH-222, which it gained last month through the acquisition of ViroChem Pharma Inc. (See BioWorld Today, March 5, 2009.)

There were no serious adverse events in the INFORM-1 trial. Subsequent cohorts looking at higher doses of R7227 in treatment-experienced HCV patients are under way.

In other EASL news:

• Avila Therapeutics Inc., of Waltham, Mass., presented preclinical data showing that its oral protease inhibitor, AVL-181, binds covalently and irreversibly to HCV protease and has activity against mutant strains of HCV. Avila plans to start clinical trials in 2010.

• Dynavax Technologies Corp., of Berkeley, Calif., presented new details from the Phase III PHAST trial, which compared Dynavax's hepatitis B vaccine Heplisav to GlaxoSmithKline plc's marketed hepatitis B vaccine, Engerix-B. As previously announced, the trial met its primary endpoint, with Heplisav inducing a noninferior antibody response (95 percent) compared to Engerix-B (81.1 percent, p < 0.0001). New data showed that Heplisav also induced a faster response, with a seroprotection rate of 24 percent at month one, 95 percent at month three and 98 percent at month seven. The seroprotection rate for Engerix-B was 4 percent at month one, 23 percent at month three and 81 percent at month seven. Heplisav, which combines HBV surface antigen with Dynavax's immunostimulatory sequence (ISS) technology, remains on clinical hold in the U.S. thanks to a case of vasculitis that emerged last year. Merck & Co. Inc. bailed out of its partnership for the vaccine, but Dynavax said discussions with regulators indicated there may be a path forward. Shares of Berkeley, Calif.-based Dynavax (NASDAQ:DVAX) rose 24 cents, or 26 percent, to close at $1.15 on Monday. (See BioWorld Today, March 19, 2008, Aug. 7, 2008, Dec. 22, 2008, and Feb. 10, 2009.)

• Human Genome Sciences Inc., of Rockville, Md., presented the final results from two Phase III trials, ACHIEVE 1 and ACHIEVE 2/3, comparing ribavirin plus Albuferon (albinterferon alfa-2b) dosed every two weeks to ribavirin plus Pegasys (pegylated interferon alfa-2a, F. Hoffmann-La Roche Ltd.) dosed weekly in hepatitis C. As previously announced, both trials met their primary endpoint of a noninferior sustained virologic response (SVR). In ACHIEVE 1, 48.2 percent of Albuferon patients achieved an SVR compared to 51 percent of Pegasys patients; in ACHIEVE 2/3, 79.8 percent of Albuferon patients achieved an SVR compared to 84.8 percent of Pegasys patients. Despite Albuferon's less frequent dosing, analysts had raised concerns about the inability to establish superiority and adverse events seen at higher doses. HGSI said a pooled analysis showed the rate of serious/severe adverse events was 21.2 percent for Albuferon patients and 20.8 percent for Pegasys patients, while the discontinuation rate due to adverse events was 8.1 percent for Albuferon patients and 3.9 percent for Pegasys patients. HGSI and partner Novartis AG plan to submit global marketing applications in the fall. (See BioWorld Today, Jan. 24, 2008, Dec. 9, 2008, and March 10, 2009.)

• Vertex Pharmaceuticals Inc., of Cambridge, Mass., presented additional data from PROVE3, a Phase IIb trial of protease inhibitor telaprevir in treatment-experienced HCV patients. The final data were similar to previously presented interim data, with 51 percent of patients achieving a sustained viral response (SVR) after 24 weeks of treatment with telaprevir plus ribavirin plus pegylated interferon and 52 percent of patients achieving an SVR after 48 weeks of the same regimen, compared to 14 percent of patients receiving ribavirin plus pegylated interferon alone. Phase III studies in both treatment-experienced and treatment-naïve HCV patients are ongoing.