Further info on the GI-5005 HCV vaccine study presented at AASLD... hope for those with the IL28 T/T allele?

Synopsis of the GI-5005 study presented at AASLD 2010. Overall, the numbers for GI-5005 aren't extraordinary, but certainly worth further studies. The true benefit for this vaccine may be how it appears to illicit a T-cell response in patients carrying the T allele of the IL28 gene, which didn't occur when the same patients were given standard of care

By: DIANA MAHONEY, Internal Medicine News Digital Network

12/01/10

BOSTON – A therapeutic vaccine against the hepatitis C virus was associated with a significantly higher sustained virologic response rate when added to standard-of-care treatment, and the findings justify further development of the vaccine, Dr. Paul Pockros reported at the annual meeting of the American Association for the Study of Liver Diseases.

In the proof-of-concept trial, 133 patients infected with hepatitis C virus (HCV) genotype 1 were randomized to either triple therapy comprising the experimental GI-5005 vaccine, which is designed to elicit a T-cell response specific to HCV, along with pegylated interferon alfa-2b plus ribavirin (P/R), or the standard P/R therapy alone.

The primary outcome measure was sustained virologic response (SVR), defined as undetectable HCV RNA at 6 months after treatment, said Dr. Pockros of the Scripps Clinic in La Jolla, Calif.

The 68 patients in the experimental group initially received monotherapy with the vaccine, consisting of five weekly injections followed by two monthly injections for a 12-week lead-in period, before progressing to the standard-of-care P/R treatment and once-monthly injections. The 65 patients in the control group received standard-of-care P/R treatment alone.

In both groups, the treatment duration was 48 weeks for treatment-naive patients and 72 weeks for those who had a poor or partial response to prior P/R treatment, said Dr. Pockros. Patients in whom prior P/R therapy induced no notable decrease in HCV viral load, as well as those in whom prior treatment initially resulted in undetectable HCV RNA followed by a viral rebound, were excluded from the analysis.

Among the study’s treatment-naive patients, 58% of those who received the vaccine achieved SVR, compared with 48% of those who received P/R alone. Among the prior poor and partial responders, the respective SVR rates in the vaccine and control groups were 17% and 5%, Dr. Pockros reported.

"There was a slight benefit in the treatment-naive and nonresponders, [but] this was numerical only and was not statistically significant," he said. However, the overall benefit in the vaccine vs. control groups was statistically significant, with respective SVR rates of 47% and 35%, he noted.

The vaccine strategy appears to be safe. "The most common associated adverse events were mild, transient injection-site reactions," said Dr. Pockros. Additionally, he stated, "the discontinuation rates due to adverse events were comparable [13%] in both the triple-therapy and standard-of-care arms."

Of particular interest, Dr. Pockros noted, was the T-cell response in a subgroup of difficult-to-treat patients receiving the vaccine. Previous studies have suggested that patients carrying the T allele of the IL28 gene are at high risk of treatment failure with the standard interferon-based therapy. The T-cell response in vaccine-treated patients, as measured by interferon-gamma enzyme-linked ImmunoSpot assay, "mimicked what we saw with a virologic response," he said.

"Four of five T/T allele patients had a T-cell response – one did not actually get treated – but none of the patients who received standard of care had a T-cell response."

This finding is consistent with the hypothesis that the GI-5005 vaccine corrects a fundamental deficit in cellular immunity in IL28B T/T genotype patients, he said. Although the findings need to be confirmed in additional studies with larger patient populations, the vaccine will likely be genotype specific, he noted.

Because the immune response is similar to that observed in HCV-infected patients who are able to clear the virus without treatment, future studies will evaluate the efficacy of monotherapy with the vaccine in genotype-specific patients, Dr. Pockros said.

The proof-of-concept study was funded by GlobeImmune, manufacturer of the vaccine. Dr. Pockros disclosed financial relationships with GlobeImmune, Genentech, Vertex, Merck, Gilead, Abbott, Pfizer, Phenomix, Tibotec, Pharmasset, 3RT, Novartis, Johnson & Johnson, Achillon, Regulus, Debio, Zymogenetics, and Human Genome Sciences.

GlobeImmune's GI-5005 HCV Therapeutic Vaccine increases SVR by 12% in previous treatment failures

By Liz Jones Hollis (http://www.fiercebiotech.com/node/93538/print)
Created Nov 4 2010 - 6:56am

Phase 2b Study Demonstrates GlobeImmune's GI-5005 HCV Therapeutic Vaccine Increases Sustained Virologic Response by 12 Percent in Patients Who Previously Failed Therapy with Standard of Care.

Additional data suggest that cellular immunity may be a fundamental deficit in hardest-to-treat IL28B T/T genotype patients and is corrected by GI-5005
Data to be presented at annual meeting of the American Association for the Study of the Liver Diseases

LOUISVILLE, Colo., October 30, 2010 - GlobeImmune Inc. today announced additional data from the GI-5005-02 Phase 2b study demonstrating that GI-5005, the Company's investigational Tarmogen® product, improved sustained virologic response (SVR) by 12% in patients with genotype 1 chronic hepatitis C virus (HCV) infection who had failed prior treatment with standard of care (SOC, pegylated-interferon alpha 2a plus ribavirin). This study suggests that GI-5005 may have the potential to be the first successful therapeutic vaccine for patients chronically infected with HCV.
Paul J. Pockros, M.D., of Scripps Clinic will deliver the oral presentation of the results in a late-breaker session at 6 p.m. EDT Monday November 1, 2010 at the 61st Annual Meeting of the American Association for the Study of the Liver Diseases (AASLD) in Boston.

On an intent-to-treat basis (subjects who received at least one dose of combination therapy), prior non-responders receiving GI-5005 plus SOC as a triple therapy had an SVR rate of 17%, compared to an SVR rate of only 5% in patients receiving SOC alone. Prior non-responders in this study were defined as patients who did not clear virus after a minimum of 12 weeks of SOC, including null responders, poor responders, and partial responders. Relapsers and on-treatment breakthroughs were not enrolled in the study. The most common adverse events associated with GI-5005 were injection site reactions that were generally mild and transient in nature. Discontinuation rates due to adverse events in the GI-5005 triple therapy arm were comparable to the discontinuation rates in the SOC alone arm.

"Only 4-7% of patients with genotype 1 HCV who were null, poor or partial responders to their first course of pegylated interferon-based therapy would be expected to achieve a sustained virologic response with a second course of treatment," said Dr. Pockros. "In this study, GI-5005 conferred a three-fold improvement in SVR, an important treatment effect in this challenging patient population."

Additional immunology data from the study will be presented in a poster on Tuesday November 2, 2010 by John M. Vierling, M.D., of Baylor College of Medicine. These data show that GI-5005 improved HCV-specific T cell responses 10-fold over SOC alone in patients with the IL28B T/T genotype (~20% of chronically infected patients), the subgroup most likely to fail treatment with SOC alone. Patients with the IL28B T/T genotype receiving SOC alone had an HCV-specific cellular immune response that was 17-fold lower than patients in the IL28B C/C or C/T subgroups. The improved HCV-specific T cell immunity in IL28B T/T patients receiving GI-5005 plus SOC correlates with previously reported data that demonstrated GI-5005 increased SVR rates by 60 percent in interferon-naïve T/T patients compared to T/T patients receiving SOC alone.

"These data suggest that the fundamental deficit in patients carrying the T allele of the IL28B gene is a deficit in adaptive cellular immunity, the mechanism that GI-5005 was designed to address," said David Apelian, M.D., Ph.D., Chief Medical Officer at GlobeImmune. "We are confident that GI-5005 will become a cornerstone of HCV therapy, particularly for difficult to treat populations, such as IL28B T/T patients."

A 40 patient expansion of this study in patients having the IL28B T/T genotype was initiated last week to further explore the potential treatment effect of GI-5005 in this patient population.

GI-5005 is a therapeutic vaccine candidate designed to generate HCV-specific T-cell responses and improve virologic responses in patients with chronic hepatitis C virus infection.

About GlobeImmune
GlobeImmune Inc. is a private company developing therapeutic vaccines called Tarmogens for the treatment of cancer and infectious diseases. Tarmogens generate activated killer T cells that are designed to locate and eliminate virally-infected cells and/or cancer cells. The Company's lead product candidate, GI-5005, is a Tarmogen being developed for the treatment of chronic hepatitis C virus (HCV) infection. GI-5005 is designed to complement both the current standard of care and emerging novel therapies for HCV. The Company's lead oncology program, GI-4000, targets cancers caused by mutated versions of the Ras oncoprotein. GI-4000 is being investigated in clinical trials for the treatment of pancreas cancer as well as other cancers that contain mutated Ras, including non-small cell lung cancer and colorectal cancer. In May 2009, the Company announced a global partnership with Celgene focused on the discovery, development and commercialization of multiple product candidates for the treatment of cancer.
For additional information, please visit the company's website at www.globeimmune.com.