Very interesting ECTRIMS Abstract
Posted: Fri Sep 29, 2006 2:32 pm
After careful consideration, this abstract gets my vote for most interesting news from ECTRIMS 2006. To cut to the chase, this small study showed a reduction in annual relapse rate sustained over 5 years of 87.5% (from an average of 1.0 per year to an average of 0.125 per year)! The other good news is they say they have the funding to do a phase II trial.
Immunomodulation - Part I
Thursday, September 28, 2006, 15:30 - 17:00
Short-term blockade of CD154 potentiates long term clinical and MRI remission of RRMS: A five-year follow up
L. Kasper, C. Fadul, K. Ryan, J. Smith, H. Wishart, I. Kasper, R. Noelle (Lebanon, New Hampshire, USA)
Objective: To assess clinical and MRI progression in subjects with relapsing MS following blockade of CD154, a critical co-stimulatory ligand required for CD4+ T cell effector activation.
Background: MS is associated with a Th1 skewed immune response that requires costimulation via CD40/154 ligation. Pre-clinical studies have suggested the importance of this co-stimulatory interaction in the pathogenesis of MS. A Phase I clinical trial (Kasper LH et. al ECTRIMS 2003) was performed to assess safety and tolerability in response to anti-CD154 blockade.
Design/Methods: For the Phase I trial, four cohorts (n=3 subjects/group) with relapsing MS each received doses of 1, 5, 10, or 15 mg/kg of fully humanized anti-CD154 every other week (n=4 doses/patient). Clinical, laboratory and MRI evaluations were performed at serial time points thru week 18 to assess safety and toxicity. All patients completed treatment without serious adverse events. Thereafter, all patients were followed clinically every 6 months and by MRI with Gd enhancement every year. Patients with acute flares were treated with steroids if indicated. Nine patients elected to be on approved immune modulating drug (3-high dose IFNbeta, 6- GA) during the first year post anti-CD154 treatment. No immediate effect of therapy on either EDSS or MRI was observed at 18 weeks post treatment.
Results: No statistically significant change in EDSS for the 4 groups of subjects was observed during the five year follow-up (Baseline EDSS 2.3±0.5 and 5 years 2.5±1.6 p=0.622). A correlation between dose and EDSS was significant (r=-.51 p<.05). Higher dose of anti-CD154 is associated with lower EDSS at 5 years. The average annual relapse rate during the five years was 0.125 (compared to 1.0 without immunotherapy). At 5 years post treatment, MRI lesion volume in subjects treated with anti-CD154 is 1.4 times that of baseline study. 3/12 patients have elected to remain off current approved therapies at 5 years.
Conclusion: The 5 year follow- up data for the Phase I trial using anti-CD154 demonstrates a profound reduction in clinical relapse rate that compares favourably to all currently approved drugs. These findings suggest that blockade of CD154 is a potentially important therapy for the treatment of RRMS. These promising long-term clinical outcomes warrant further studies in a closely monitored Phase II trial. Funding for this trial is in place and awaits availability of product.
Supported by NIH AI061938
Immunomodulation - Part I
Thursday, September 28, 2006, 15:30 - 17:00
Short-term blockade of CD154 potentiates long term clinical and MRI remission of RRMS: A five-year follow up
L. Kasper, C. Fadul, K. Ryan, J. Smith, H. Wishart, I. Kasper, R. Noelle (Lebanon, New Hampshire, USA)
Objective: To assess clinical and MRI progression in subjects with relapsing MS following blockade of CD154, a critical co-stimulatory ligand required for CD4+ T cell effector activation.
Background: MS is associated with a Th1 skewed immune response that requires costimulation via CD40/154 ligation. Pre-clinical studies have suggested the importance of this co-stimulatory interaction in the pathogenesis of MS. A Phase I clinical trial (Kasper LH et. al ECTRIMS 2003) was performed to assess safety and tolerability in response to anti-CD154 blockade.
Design/Methods: For the Phase I trial, four cohorts (n=3 subjects/group) with relapsing MS each received doses of 1, 5, 10, or 15 mg/kg of fully humanized anti-CD154 every other week (n=4 doses/patient). Clinical, laboratory and MRI evaluations were performed at serial time points thru week 18 to assess safety and toxicity. All patients completed treatment without serious adverse events. Thereafter, all patients were followed clinically every 6 months and by MRI with Gd enhancement every year. Patients with acute flares were treated with steroids if indicated. Nine patients elected to be on approved immune modulating drug (3-high dose IFNbeta, 6- GA) during the first year post anti-CD154 treatment. No immediate effect of therapy on either EDSS or MRI was observed at 18 weeks post treatment.
Results: No statistically significant change in EDSS for the 4 groups of subjects was observed during the five year follow-up (Baseline EDSS 2.3±0.5 and 5 years 2.5±1.6 p=0.622). A correlation between dose and EDSS was significant (r=-.51 p<.05). Higher dose of anti-CD154 is associated with lower EDSS at 5 years. The average annual relapse rate during the five years was 0.125 (compared to 1.0 without immunotherapy). At 5 years post treatment, MRI lesion volume in subjects treated with anti-CD154 is 1.4 times that of baseline study. 3/12 patients have elected to remain off current approved therapies at 5 years.
Conclusion: The 5 year follow- up data for the Phase I trial using anti-CD154 demonstrates a profound reduction in clinical relapse rate that compares favourably to all currently approved drugs. These findings suggest that blockade of CD154 is a potentially important therapy for the treatment of RRMS. These promising long-term clinical outcomes warrant further studies in a closely monitored Phase II trial. Funding for this trial is in place and awaits availability of product.
Supported by NIH AI061938