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) last month 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 one person in the standard therapy control group.
Participants were randomly allocated (2:2:1) into three treatment arms. All received standard-of-care (SOC) pegylated interferon alfa-2a (Pegasys) plus ribavirin for 48 weeks. In addition, the first group received six injections of TG4040 beginning four 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.
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 early virological response rates (EVR) 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. In total, 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.
Seven 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.Three vaccine recipients developed severe thrombocytopenia and 1 developed aplastic anaemia.
"[The] primary objective of the study, improvement of cEVR, [was] reached in TG4040 lead-in arm," the investigators summarised. "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."
Wedemeyer H, Janczewska E, Wlodzimierz M, 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, abstract 1403, 2012. See the abstract here.
Transgene SA Transgene reports positive follow up phase 2 data on its HCV therapeutic vaccine TG4040. Press release, 23 April 2012.