Date: 2013-04-29
Type of information:
phase: 2
Announcement: presentation of results at the European Association for the Study of the Liver (EASL) Congress in Amsterdam
Company: Transgene (France)
Product: TG4040 (MVA-HCV)
Action
mechanism: This recombinant vector is based on the MVA virus carrying and expressing three of the major non-structural proteins (NS3, NS4 and NS5B) of the hepatitis C virus (“HCV”). The MVA vector is a highly attenuated strain of vaccinia virus, which has been tested extensively in humans as a vaccine against smallpox and is known to strongly stimulate innate and adaptive immune responses to antigens.
Disease: chronic hepatitis C
Therapeutic area: Infectious diseases
Country: Europe, USA, Israel
Trial details: 153 patients in the HCVac study were recruited in five countries in Europe, in the United States and in Israel, and were randomized in one control arm (Arm A) or one of the two experimental arms (Arms B and C). In the Arm B, the TG4040 dosage was administered 6 times and the standard of care was given 4 weeks prior to the initiation of TG4040. In the Arm C, the TG4040 dosage was administered 13 times and the standard of care was introduced 12 weeks after the initiation of treatment with TG4040. The HCVac study is investigating the efficacy and safety of two different schedules of administration of TG4040 administered in subcutaneous injections at the dose of 107 pfu in combination with Peg-IFN and RBV.
Latest
news: * On April 29th, 2013 - Transgene, a biopharmaceutical company that develops targeted immunotherapy products to treat major unmet medical needs in cancer and chronic infectious diseases, has announced final data of the Phase 2 HCVac trial of TG4040 for the treatment of genotype 1 chronic hepatitis C at an oral presentation of the European Association for the Study of the Liver (EASL) Congress in Amsterdam, the Netherlands. This open label study evaluated in 153 randomized patients two schedules of TG4040 in combination with PegIFN?2a (P) and ribavirin (R) versus P/R alone (Arm A): Arm B with six TG4040 injections initiated 4 weeks after P/R and pre-vaccination Arm C with thirteen TG4040 injections initiated 12 weeks before P/R.
The positive effect of TG4040 was seen with pre-treatment of TG4040 in Arm C. The benefit of pre-treatment was observed as early as one week after initiation of PEG-IFN?/RBV with a 40% improvement in decline of mean HCV RNA viral load. The primary endpoint was met in Arm C with a complete early viral response (cEVR) of 64% as compared to 30% in the control arm (p=0.0037). The virologic response was sustained over time with a SVR24 of 58% in Arm C, compared to 48% in the control arm.
The key immunologic findings were that induction of MVA and HCV specific T-cell responses were essentially seen in Arm C before the addition of PEG-IFN?/RBV. The viral response seen in Arm C was observed in spite of the development of anti-MVA responses. Overall, safety was similar across the three arms (percentage of adverse events and grade). The investigation of the four cases of severe blood toxicity led to the conclusion of an exacerbation of IFN-known immune side effects in patients with autoimmune predisposition.
Transgene is examining different opportunities for TG4040’s future clinical development. Given the results of this Phase 2 study, immunotherapy with TG4040 may warrant further evaluation in combination with IFN-free direct-acting antivirals treatment regimens once they are approved.
* On April 23, 2012, Transgene has announced the presentation, during the EASL (European Association for the Study of Liver) congress in Barcelona, Spain, of follow up interim data showing both a more rapid response as well as an improved long term effect on viral load decrease in a combination of TG4040 with PEG-IFN? (pegylated interferon alpha) and ribavirin (the current standard of care) in patients chronically infected with genotype 1 hepatitis C virus. These data were observed in a randomized phase 2 trial that has enrolled 153 patients (the "HCVac" study). HCVac had three treatment arms: one control arm (Arm A) with the current standard of care alone and two arms (B and C) with a combination of this standard of care and TG4040 delivered in two different administration schedules, including one schedule (Arm C) with pre-vaccination by TG4040 (i.e. TG4040 injected prior to the introduction of PEG-IFN and ribavirin).As reported in November 2011 (see below) at the AASLD meeting in San Francisco, the primary endpoint of the HCVac study was met in the pre-vaccination arm C with 64% (34/53) evaluable patients having achieved a complete early viral response1 (“cEVR”) at week-12 after initiation of treatment with the standard of care compared to 30% (9/30) in the control arm A (p=0.003). The positive effect of TG4040 pre-vaccination was observed as early as one week after initiation of treatment with the standard of care: the slope of mean viral load decrease was significantly steeper in Arm C (1.4 log10 IU/ml) compared to Arms A and B (respectively 0.9 and 1.0 log10 IU/ml) (p=0.04), meaning a faster viral response in Arm C than in other arms.
When following the viral response at week-24 after the initiation of treatment with the standard of care in the patients evaluable for cEVR (week-12), the responses continue to improve as expected in all arms: 70% in the control Arm A, 67% in the Arm B (initiation of treatment with the standard of care before introduction of TG4040) and 79% (vs. 64% at week-12) in the Arm C.
Preliminary End-of-Treatment Response measurement ("ETR", or viral response measured at the end of 48 weeks of standard of care), is respectively 64% and 56% in Arm A and B. In arm C, 19 out of 19 patients analysed so far are undetectable.
* On November 7, 2011, Transgene has announced the publication, during the AASLD congress (American Association for the Study of Liver Diseases), of interim data showing a substantial viral suppression at 12 weeks by using the combination of its therapeutic vaccine TG4040 with the commonly used treatment regimen in patients with chronic hepatitis C. These data were observed in a randomized Phase II trial that has included 153 patients (the “HCVac” study).
The study evidenced activity of the therapeutic vaccine in the two experimental arms with a substantial early viral suppression in arm C, with 64% of patients who achieved complete Early Virologic Response (“cEVR”), the primary endpoint of the study, compared to 30% in the control arm. The cEVR patients had no detectable viral load 12 weeks after the beginning of the treatment with Peg-IFN and RBV. The detection limit of the blood hepatitis C virus in the study was set at 10 IU/ml (using the Roche COBAS® HCV TaqMan® assay).
* On October 11, 2011, Transgene has reported about the Phase II study HCVac testing the therapeutic vaccine TG4040 in chronic viral hepatitis C in combination with standard of care (“SOC”). The HCVac study has met its primary efficacy endpoint based on improvement of complete early viral response (“cEVR”) rate with the combination of TG4040 and SOC. cEVR is defined as the disappearance of HCV’s viral genome in the blood 12 weeks after the start of the treatment.
Three cases of severe hematological adverse events were recently reported in the experimental arms of the study and are under investigation (two cases of thrombocytopenia, one with neutropenia, and one case of aplastic anemia). In the HCVac study these adverse events occurred only after prolonged IFN treatment, but not during the TG4040 monotherapy treatment phase and no such events were observed in Phase I in with TG4040.A possible relationship with TG4040 cannot be today formally ruled out and is under active investigation.
Although the safety profile of TG4040 was otherwise good as expected from Phase I findings, the Company has decided to submit an amendment to the study design so as to avoid further exposing patients to possible similar adverse events.The proposed amendment will enable the patients in the experimental arms to continue to receive the SOC as planned but without TG4040 (all patients treated in the experimental arms have received the majority of doses of TG4040 they were expected to receive under the protocol). It will have no impact on protocol observation of other endpoints, including long term efficacy and tolerance. Notably, long term efficacy, defined by Sustained Viral Response (“SVR”) rate, will be measured. It has been demonstrated that patients who achieve cEVR also achieve a high SVR rate. SVR, measured six months after completion of a treatment, is the reference clinical efficacy endpoint for HCV treatments. The HCVac study will also measure TG4040’s ability to elicit an immune response. An additional expected outcome of the study is to identify molecular biomarkers related to TG4040 efficacy in combination with the standard of care. Final data are expected in the fourth quarter of 2012.
* On March 31, 2011, Transgene has announced that, with 154 patients randomized and treated, the enrolment of patients in the phase II HCVac trial is now complete. This study explores the combination of TG4040 (MVA-HCV) with standard of care (Pegylated-Interferon ?2a and Ribavarin) in treatment naive patients with chronic genotype 1 hepatitis C. The patients were recruited in five countries in Europe, in the United States and in Israel, and were randomized in the three arms of the study (one control arm without TG4040 and two experimental arms). HCVac investigates the efficacy and safety of two different schedules of administration of TG4040 administered in subcutaneous injections at the dose of 107 pfu in combination with the standard of care.
HCVac will measure the proportion of patients who achieve complete Early Virologic Response (cEVR), i.e. have no detectable viral load 12 weeks after the beginning of the treatment. These data will be available during the fourth quarter of 2011.
The study will also measure the patients’ Sustained Virologic Response (SVR), i.e. the treatment’s long term effects on the viral load, up to 24 weeks after the end of the treatment, as well as TG4040’s ability to elicit an immune response. An additional expected outcome of the study is to identify molecular biomarkers related to TG4040 efficacy in combination with the standard of care. Final data are expected in the fourth quarter of 2012.
