Date: 2012-11-20
Type of information: Results
phase: 2
Announcement: final results
Company: Neovacs (France)
Product: TNF-Kinoid®
Action
mechanism: kinoid/immunotherapy product. A Kinoid is obtained by chemically linking the cytokine of interest to a foreign carrier protein, KLH ( Keyhole Limpet Hemocyanin), and then treating the resultant compound to inactivate the cytokine. These active immunotherapies have been designed to induce an antibody response by the patient’s immune system that targets a particular over-expressed cytokine responsible for the pathogenesis and development of a given disease. The Kinoid technology can be applied in principle to any cytokine target. Three targets (Tumor Necrosis Factor (TNF), Interferon alpha (IFN alpha) and Vascular Endothelial Growth Factor (VEGF) are considered as playing a key role in the pathogenesis of certain diseases.
Disease: Crohn’s disease
Therapeutic area: Autoimmune diseases - Inflammatory diseases - Digestive diseases
Country: 7 European countries
Trial
details: Neovacs’ TNF-K 005 Phase II clinical trial is a double-blind, placebo controlled international study conducted in 60 patients with moderate to severe Crohn’s Disease (a disease activity by CDAI 1 of between 220 and 450) having failed at least one anti-TNF therapy. Patients were enrolled in 7 European countries. The schedule of administration was 3 doses of 180 mcg of TNF-Kinoid on days 0, 7, 28 with a "cross-over" from day 84, with the placebo group from the first phase of the study receiving the Kinoid (3 injections) and the Kinoid group from the first phase getting a fourth dose of the Kinoid followed by placebo injections. The study blind was maintained during this second phase.
Latest
news: * On November 20, 2012, Neovacs, a leader in active immunotherapies for the treatment of autoimmune diseases, has announced the final results of the Phase II study of its TNF–Kinoid active immunotherapy in Crohn’s Disease (TNF–K–005), in patients who had lost response to a monoclonal antibody TNF inhibitor. Final results show an association between antibodies titers induced by active immunization and clinical remission.
The interim results of the study reported in June 2012 revealed two important findings:
1) The presence of residual monoclonal antibody to TNF from a prior course of treatment interfered with the production of natural antibodies to TNF following Kinoid administration, and
2) the 180 mcg dose is too low to produce the best immune response.
The results presented here relate to the final phase of the study, after the "cross-over ".
Safety: The excellent tolerability and safety profile of the TNF–Kinoid is again confirmed. More than 100 patients have now been treated with a Neovacs immunotherapy.
Immune response results: The final phase of the study demonstrated the good immunogenicity of the Kinoid. Over the study as a whole, an immune response was achieved in 65% of patients with active disease (CDAI >150) and no residual monoclonal antibody at the time of Kinoid administration. This finding is consistent with the data presented at the ACR meeting on 11 November in rheumatoid arthritis patients who have lost response to a biologic TNF inhibitor.Further, the study presented at ACR clearly demonstrated that the 360 mcg dose produces both a higher rate of response to the Kinoid and higher levels of antibodies to TNF than the 180 mcg dose.The administration of the fourth dose at Day 84 caused a rebound in antibody titers with the peak higher than that seen after the three priming doses.
Clinical results: There is a clear association between antibodies induced by the TNF–Kinoid and clinical remission. In patients that received the placebo and with active disease (CDAI > 150) at day 84, 33% of those having an immune response to the Kinoid and clear of residual monoclonal antibody were in clinical remission three months later, as opposed to none of the patients not having an immune response. Including the Kinoid patients who developed anti–TNF antibody and clear of residual monoclonal antibody, 27% of patients were in clinical remission versus 12.5% of the patients not having an immune response
* On June 5, 2012, Neovacs has announced the interim results of its Phase II clinical study TNF-Kinoid in patients with Crohn’s disease who have failed therapy with at least one anti-TNF monoclonal antibody.
The interim analysis of the cohort of the first 60 patients did not show any statistically significant difference in terms of clinical remission between the Kinoid-treated group and the placebo group.
The interim analysis did however demonstrate 3 important points that support further clinical development:
• A statistically significant correlation between clinical remission and the level of antibodies induced by the Kinoid, which confirms the biological activity of the Kinoid. Specifically, in the Kinoid group, the patients achieving remission are those with the highest level of anti-TNF antibodies induced by the Kinoid.
• A major factor explaining non-response to the Kinoid is the ongoing presence of monoclonal antibodies at the time of entry into the study.
• The excellent safety profile of the TNF-Kinoid, consistent with the two previous studies.
The presence of residual monoclonal antibody levels in a high proportion of patients was unexpected, given a "wash-out" period of several weeks. The residual antibody seems to have had a negative effect on the immune response and thus the clinical effect of the Kinoid, and so may have had a strong influence on the results of the trial. Neovacs has therefore decided:
1. Not to recruit the second cohort into the study, but rather to wait for the additional data that will be generated by the patients already enrolled : per the study protocol, patients who received three doses of the Kinoid have now received a fourth maintenance dose, while patients in the placebo arm have received three doses of the Kinoid The results of the second phase will be available in Q4 2012.
2. To design a new study which will exclude patients with residual anti-TNF monoclonal antibody levels.
"The relationship between clinical remission and anti-TNF antibody titer induced by the Kinoid has been confirmed. The negative impact of residual anti-TNF antibodies on Kinoid immunization is an interesting scientific result, which will assist in the design of future studies. Moreover, taking into account the results seen in January in the study of the TNF-Kinoid in rheumatoid arthritis using the 360 mcg dose, we think we could improve both the response rate and the level of antibodies induced if we used this dose rather than the 180 mcg dose used in this study." commented Guy Charles Fanneau de La Horie, Neovacs’ CEO.
The 3 studies that have been conducted with the TNF-Kinoid indicate that
1. The TNF-K is safe and well tolerated
2. The TNF-K is immunogenic and 360mcg is the more immunogenic dose
3. A clear relationship exists between TNF antibody titer and clinical remission
4. There is a negative impact of residual anti-TNF antibodies on Kinoid immunization, a factor that will be taken into account.
* On December 15, 2011, Neovacs announced that it had completed patient recruitment in the first phase of its international TNF-Kinoid Phase II clinical trial. The trial’s results are expected in the second quarter 2012. The study’s objective is to evaluate the therapeutic efficacy of TNF-Kinoid versus placebo in Crohn’s disease patients having become resistant to anti-TNF drugs.
