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Researchers Report Promising Results from Studies of 3 Therapeutic HCV Vaccines

Current standard therapy for chronic hepatitis C virus (HCV) infection consists of pegylated interferon plus ribavirin, and several directly targeted oral anti-HCV agents are in advanced stages of development. But another approach -- therapeutic vaccines -- is also under study, as reported in 3 presentations at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen.

Therapeutic vaccines are administered to people who are already infected in an attempt to reduce viral replication and slow or halt disease progression. This strategy is distinct from preventive or prophylactic vaccination -- also under study -- which is intended to prevent initial infection.

ChronVac-C

M. Matti Sallberg from the Karolinska Institute in Sweden presented findings from the first clinical trial of a "naked" DNA vaccine delivered via electroporation, a procedure in which cell permeability is increased by applying electricity.

This ongoing Phase 1/2a trial analyzed the safety and efficacy of ChronVac-C (being developed by Tripep AB), a T-cell vaccine based on a codon-optimized HCV non-structural (NS) 3/4A DNA gene expressed under the control of the cytomegalovirus (CMV) immediate-early promoter.

The study included 12 participants with hard-to-treat HCV genotype 1, HCV viral load < 800,000 IU/mL, and no previous hepatitis C treatment. Participants received 0.5 mL subcutaneous injections of saline containing ChronVac-C DNA, followed by 2 electrical pulses administered via an electrode array. Patients were divided into groups receiving 167 mcg, 500 mcg, and 1500 mcg of vaccine, given in 4 monthly doses.


Results

  • No severe side effects were observed in any of the 3 vaccine dose groups.
  • In the 167 mcg group, 2 patients mounted transient T-cell responses, but none had reduced HCV viral load.
  • In the 500 mcg group, 2 participants mounted stronger and more sustained HCV-specific T-cell responses, and both experienced HCV RNA reductions of up to 0.89 and 1.5 log10.
  • The third patient in the 500 mcg group had no immune response and no clear reduction in HCV viral load.
  • In the 1500 mcg group, 1 patient developed an HCV-specific T-cell response, and 2 experienced viral load reductions of up to 1.2 and 2.4 log10.
  • Overall, 4 out of 6 patients (67%) in the 2 highest dose groups experienced viral load reductions exceeding 0.5 log10 and lasting for 2 to > 10 weeks.
  • Of these participants, 3 exhibited activation of HCV-specific T-cell responses at the time of the viral load reductions.

"These data provide the first proof-of-concept for DNA-based therapeutic vaccination against chronic hepatitis C in humans using in vivo electroporation and encourage further clinical development," the researchers concluded. "The data also provides further evidence for the antiviral role of the HCV-specific T-cell response."

Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Ludvig-Maximilian University; ImmuSystems GmbH, Munich, Germany; Inovio Biomedical, Oslo, Norway; Inovio Biomedical, San Diego, CA.


TG4040

In the second study, F. Habersetzer from Civil Hospital in Strasbourg, France, and colleagues evaluated Transgene's TG4040 (MVA-HCV), a novel T-cell inducing therapeutic vaccine based on modified virus Ankara (MVA), a highly attenuated vaccinia poxvirus strain. This vaccine candidate expresses 3 HCV antigens -- NS3, NS4, and NS5B -- that are targets of immune responses in individuals who naturally control HCV.

This Phase 1 open-label dose-escalation study evaluated the safety and biological activity of TG4040 in 15 treatment-naive patients with genotype 1 chronic HCV infection. Patients in successive cohorts received 3 weekly subcutaneous injections at escalating doses of 10E6, 10E7, and 10E8 pfu of TG4040 on days 1, 8, and 15. Participants treated with the highest dose also received a booster shot of the same dose 6 months after the first injection.


Results

  • All studied doses of TG4040 were safe and generally well-tolerated.
  • The most frequent adverse drug reactions were mild-to-moderate injection site reactions and flu-like illness.
  • No grade 3/4 or serious drug reactions or adverse events leading to discontinuation or treatment modification were reported.
  • 6 out of 15 patients experienced decreases in HCV viral load ranging from 0.5 to 1.4 log10 IU/mL from baseline (5 of these participants were enrolled in the first and second cohorts).
  • In the first 2 cohorts, vaccine-specific interferon-gamma production was detected in half the participants.
  • The 2 patients who experienced the largest decreases in HCV RNA (0.8 and 1.4 log10) also exhibited the greatest increases in HCV-specific interferon-gamma-producing T-cells targeting NS3 and NS4.
  • 1 of these patients experienced a peak in interferon-gamma-producing cells 1-2 weeks after the third injection, with continued low HCV viral load.
  • Most patients in the third cohort had undetectable or low immune responses to the vaccine and little or no change in HCV RNA levels.

These results "demonstrate that TG4040 is well-tolerated" and provide preliminary evidence that vaccine-specific immune responses can be mounted in the face of ongoing viral replication, the investigators concluded, adding, "Such response can be associated with control of viral load."

In March 2008, the study was extended to include 27 patients in 3 additional cohorts, in an effort to fine-tune the timing of the booster dose and evaluate safety in patients with more advanced liver disease, according to a press release issued by Transgene. Results from the study extension are expected in the third quarter of 2009, and the company plans to initiate a Phase 2 trial of TG4040 in combination with pegylated interferon plus ribavirin starting in early 2010. Another study in Montreal is evaluating TG4040 in chronic HCV patients who relapsed after prior treatment with pegylated interferon/ribavirin.

Hepatology and Gastroenterology Department, Civil Hospital, Strasbourg; Hepatology and Gastroenterology Department, A. Michallon Hospital, Grenoble; Hepatology and Gastroenterology Department, Hotel-Dieu Hospital, Lyon; Hepatology and Gastroenterology Department, Brabois Hospital, Nancy; Hepatology and Gastroenterology Department, Hotel Dieu Hospital, Nantes; Department of Hepatology and Gastroenterology, Henri Mondor Hospital, Créteil; Transgene, Strasbourg, France


GI-5005

Finally, E.J. Lawitz from Alamo Medical Research and colleagues presented findings from a Phase 2 study of GlobeImmune's GI-5005 or Tarmogen, a vaccine using whole heat-killed S. cerevisiae expressing HCV NS3 and core antigens.

This open-label randomized study included 140 genotype 1 chronic hepatitis C patients; 74% were treatment-naive and the rest were prior non-responders to pegylated interferon/ribavirin.

Participants were randomized on a 1:1 basis and stratified according to prior virological response. Arm 1 received a "run-in" of 5 weekly subcutaneous doses of 40 YU (1 YU = 10,000,000 yeast) GI-5005 monotherapy, followed by 2 monthly doses of the vaccine, followed by triple therapy consisting of monthly 40YU GI-5005 injections plus pegylated interferon/ribavirin for 48 weeks. Arm 2 received the standard-of-care regimen without GI-5005.

In an earlier interim analysis of rapid virological response (RVR) at week 4, the response rate was more than 2-fold greater in the GI-5005 triple therapy arm compared with the standard-of-care arm. The EASL poster presented 12 week data.


Results

  • GI-5005 was generally well-tolerated, with no vaccine-related serious adverse events or dose limiting toxicities.
  • Among participants who could be evaluated for early virological response (EVR; ? 2 log10 drop in HCV RNA at week 12), treatment-naive patients receiving GI-5005 showed a trend toward a higher EVR rate compared with those receiving standard therapy (94% vs 87%; P = 0.23).
  • Among treatment-naive patients with high baseline viral load (> 600,000 IU/mL), patients receiving GI-5005 triple therapy were also more likely to achieve EVR than those receiving standard therapy, though the difference again did not reach statistical significance (93% vs 85%; P = 0.26).
  • In the small subset of prior non-responders, EVR rates were comparable in the GI-5005 and standard-of-care arms.

"Triple therapy with GI-5005 plus [pegylated interferon/ribavirin] was well tolerated and preliminary data indicate improved EVR rates, despite an unusually high EVR rate in the [standard-of-care] group," the researchers concluded.

An additional exploratory analysis at 24 weeks showed a 2-fold improvement in the proportion of patients with improved serum fibrosis markers (Fibrotest) and a 50% reduction in the number of patients with worsening fibrosis markers in the GI-5005 triple therapy group. Treatment-naive high viral load patients receiving triple therapy also had 14% greater likelihood of ALT normalization, according to a press release issued by GlobeImmune.

Alamo Medical Research, San Antonio, TX; University of Arizona, Tucson, AZ; University of Colorado Denver, Aurora, CO; Weill Cornell Medical College, New York, NY; University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; Scripps Clinical Research Center, La Jolla, CA; Virginia Commonwealth University Medical Center, Richmond, VA; Baylor College of Medicine, Houston, TX; Cruickshank and Associates, Santa Barbara, CA; GlobeImmune, Inc., Louisville, CO.

5/19/09

References

M Matti Sallberg, L Frelin, H Diepolder, and others. A First Clinical Trial of Therapeutic Vaccination Using Naked DNA Delivered by In Vivo Electroporation Shows Antiviral Effects in Patients with Chronic Hepatitis C. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

F Habersetzer, J.-P Zarski, V Leroy, and others. A Novel Vectorized HCV Therapeutic Vaccine (Tg4040): Results of a Phase I Study in Naive Patients Chronically Infected by HCV. EASL 2009. Copenhagen, Denmark. April 22-26, 2009.

EJ Lawitz, TD Boyer, GT Everson, and others. GI-5005 Immunotherapy plus Peg-IFN/Ribavirin versus Peg-Ifn/Ribavirin in Genotype 1 Chronic HCV Subjects; Preliminary Phase 2 EVR Analyses. EASL 2009. Copenhagen, Denmark. April 22-26, 2009.

Other Sources

European Association for the Study of the Liver. First Evidence for DNA-Based Vaccination against Chronic Hepatitis C. Press release. April 24, 2009.

Transgene. Transgene presents additional Phase I data for TG4040 in hepatitis C chronically infected patients at EASL and is now preparing for Phase II trial. Press release. April 23, 2009.

GlobImmune. GlobeImmune, Inc.'s Hepatitis C Therapeutic Vaccine, GI-5005, Improves EVR Rates to 94 Percent in Phase 2 Clinical Trial. Press release. April 24, 2009.