Bob Roehr

November 08, 2010

November 8, 2010 (Boston, Massachusetts) — Proof of concept for the therapeutic vaccine GI-5005 (GlobeImmune) against hepatitis C virus (HCV) infection, used in combination with standard of care (pegylated-interferon alfa-2b plus ribavirin), was presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. Results were presented by Paul J. Pockros, MD, from the Scripps Clinic in San Diego, California.

One novel approach to treating hepatitis C is to stimulate the immune system to better attack and clear the infection, Dr. Pockros explained. This approach contrasts with most interventions currently in development that use small molecules to directly attack the virus.

The vaccine strategy incorporates HCV nonstructural protein 3 (NS3) and core antigens into recombinant Saccharomyces cerevisiae, a family of budding yeast, and expresses those proteins on the surface of the yeast cell. Dr. Pockros said the mechanism of action is not completely clear, but it is thought that subcutaneous injection of the yeast "stimulates a danger signal, which in turn brings antigen-presenting cells like dendritic cells to the surface."

"Those quickly phagocytose the inactivated yeast. The proteins are broken down, and NS3 and core proteins are expressed on the surface of the dendritic cell. This then stimulates helper and killer T cells," which identify and attack hepatocytes infected with hepatitis C.

"If you give this to patients who are chronically infected, it mimics patients who are acutely infected with HCV — they clear the virus," Dr. Pockros explained. Typically, chronically infected patients do not mount a T cell response against the core, envelop, or nonstructural proteins of HCV, whereas patients who clear the virus "mount a modest response against the envelop proteins and a robust response against nonstructural proteins NS3 and NS5," he added.

The phase 2 study was conducted in 133 patients infected with HCV genotype 1 who were randomized in a 1:1 manner to the vaccine or standard of care. Those assigned to active treatment received 40YU GI-5005 monotherapy (1 YU = 107 yeast particles) 5 times a week, then twice monthly during a 12-week lead-in period before adding standard of care (pegylated-interferon alfa-2b plus ribavirin) and reducing the vaccine dosing to once a month. Treatment-naïve patients followed this regimen for 48 weeks, and nonresponders followed it for 72 weeks. The principle end point was end-of-treatment response/sustained viral response (SVR).

Dr. Pockros said that "there was a slight benefit [from the vaccine] in the treatment-naïve and nonresponders; this was numerical only and was not statistically significant. However, when you added the 2 groups together, it became statistically significant" (P = .037).

Stratifying by IL28B gene status in the standard of care group, 2 of 5 patients with the more difficult to treat T/T allele cleared the virus at some point, but 1 subsequently had viral breakthrough while on therapy, and the second relapsed, "so none of the patients had an SVR."

However, "of the T/T patients who received the vaccine, all 5 cleared the virus. Two had to be taken off therapy because of the side effects of [pegylated-interferon alfa-2b plus ribavirin], but the remaining 3 had a sustained virologic response," according to Dr. Pockros.

He said there was only a modest response among those who were previous virologic nonresponders.

There was a statistically significant difference in those whose alanine transaminase (ALT) levels normalized. "Some of these responses were durable, although this did not quite reach significance" in this study, which was underpowered for subset analysis. Biopsy of 32 patients strongly suggests that the normalization of ALTs seen in some patients "is associated with the reduction in necroinflammation."

Perhaps the most interesting response among those who received the vaccine was the T cell, measured by ELISPOT assay. "It mimicked what you saw with a virologic response," Dr. Pockros said. "Four of 5 T/T allele patients had a T cell response; 1 did not actually get treated. But none of the patients who received standard of care had a T cell response." During the discussion, Dr. Pockros said the vaccine is likely to be genotype specific.

Adverse events mirrored those seen with standard of care, with the addition of some modest reactions at the site of injection for the therapeutic vaccine. The product has currently been administered to more than 250 study subjects.

Session cochair Douglas R. LaBrecque, MD, director of liver services at University of Iowa Health Care in Iowa City, told Medscape Medical News that the data "are so preliminary and in such small numbers that all you can say is it wasn't a total failure."

But he does see a benefit to the approach "if it would allow you to eliminate some of the medications [in a regimen], be it the interferon or small molecules, which have their own side effects."

The private biopharmaceutical company GlobeImmune sponsored the trial. Dr. Pockros reports ongoing research ties with the company. Dr. LaBrecque has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-6. Presented November 1, 2010.


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