EASL 2012: Promising Findings for Therapeutic Hepatitis C Vaccine TG4040

An investigational hepatitis C virus (HCV) therapeutic vaccine significantly improved the likelihood of sustained response to interferon-based therapy, according to a proof-of-concept study reported at the 47th International Liver Congress (EASL 2012) this week in Barcelona.

Interferon-based therapy and new direct-acting antiviral agents are not able to cure all patients with chronic hepatitis C. But the fact that some people respond very well to therapy -- and that some are able to spontaneously clear HCV without treatment -- suggests it may be possible to further boost the natural immune response to the virus.

Heiner Wedemeyer from Hannover Medical School in Germany and colleagues conducted a Phase 2 study of TG4040, a therapeutic vaccine being developed by the French company Transgene that is designed to stimulate immunity against HCV when combined with interferon. TG4040 is a recombinant vaccinia poxvirus (MVA) vaccine containing sequences encoding the NS3, NS4, and NS5B proteins from genotype 1b HCV.

The open-label HCVac trial included 153 treatment-naive genotype 1 chronic hepatitis C patients; about 80% had subtype 1b. Most were white men and the average age was about 43 years. Approximately 25% had the favorable IL28B CC gene pattern associated with good interferon response. About 10% of people who received TG404 had advanced fibrosis (stage F3), compared with only 1 person in the standard therapy control group.

Participants were randomly allocated (2:2:1) into 3 treatment arms. All received standard-of-care (SOC) pegylated interferon alfa-2a (Pegasys) plus ribavirin for 48 weeks. In addition, the first group received 6 injections of TG4040 beginning 4 weeks after treatment initiation (SOC lead-in), the second group started TG4040 12 weeks before beginning pegylated interferon/ribavirin (TG4040 lead-in), and the control arm did not receive TG4040.

The primary endpoint was complete early virological response (cEVR) 12 weeks after starting pegylated interferon/ribavirin.

Results

• TG4040 alone reduced HCV RNA by > 0.5 log IU/mL in 43% of patients during the TG4040 lead-in (range 0.5-5.1 log decline).
• In an intent-to-treat analysis, complete EVR rates in were 44% in the SOC lead-in arm and 62% in the TG4040 lead-in arm, compared with 29% in the control arm, a statistically significant difference.
• In an analysis of evaluable patients, corresponding cEVR rates were 46%, 64%, and 30%, respectively.
• In a week 24 intent-to-treat analysis, 67%, 76%, and 65%, respectively, maintained undetectable viral load.
• End-to-treatment response (ETR) rates were 56% in the SOC lead-in arm and 62% in the TG4040 lead-in arm; evaluation of the TG4040 lead-in group was ongoing, but all 19 patients evaluated so far were undetectable.
• Discontinuation rates were relatively high, 40% in the SOC lead-in arm, 34% in the TG4040 lead-in arm, and 35% in the control arm, with the most common reason being virological failure (futility) at week 12 or 24.
• Most patients experienced some adverse events, but these were typical of those seen with interferon.
• 33% in the SOC lead-in arm and 59% in the TG4040 lead-in arm had adverse events attributed to the vaccine, mainly injection site swelling or itching.
• 7 people (11%) in the SOC lead-in arm, 6 (10%) in the TG4040 lead-in arm, and 2 (6%) in the control arm stopped due to adverse events.
• 3 vaccine recipients developed severe thrombocytopenia and 1 developed aplastic anemia.

"[The] primary objective of the study, improvement of cEVR, [was] reached in TG4040 lead-in arm," the investigators summarized. "TG4040 pre-vaccination impacts significantly the slope of viral load decrease after [pegylated interferon/ribavirin] initiation."

TG404 demonstrated a "good safety profile," but blood toxicity events are being further studied.

"TG404 as an active immunotherapy should be evaluated in combination with interferon-free direct-acting antiviral treatment regimens," they recommended.

"These data are important for TG4040 as they confirm the efficacy profile of our therapeutic vaccine," Transgene CEO Philippe Archinardin said a company press release. "As far as we know, they are unheard of for an immunotherapy in HCV."

5/2/12

Reference

H Wedemeyer, E Janczewska, M Wlodzimierz, et al. Significant Improvement of Complete EVR in HCVac Phase II Clinical Trial When Adding TG4040 Therapeutic Vaccine to PegIFNa2a and Ribavirin. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 1403.

Other Source

Transgene SA. Transgene Reports Positive Follow Up Phase 2 Data on its HCV Therapeutic Vaccine TG4040. Press release. April 23, 2012.