Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment
Warren KG, Catz I, Ferenczi LZ, Krantz MJ;
Commented by , 24 Nov 2006
Background
Induction of tolerance is an effective treatment in animal models of MS, but results in humans have so far been disappointing. An immunodominant disease-associated T-cell epitope in MS patients with HLA-DR2 haplotype has been recognized in the central region of the myelin basic protein (MBP) and the same domain is a dominant target of MS autoantibodies.
The MBP residues 85-96 defines the identity of the B- and T-cell epitope and has therefore been considered to be the prime candidate for restoration of immunological tolerance. MBP autoantibodies remain high in the CSF of patients with progressive MS, and may therefore be used to monitor treatment efficacy.
Aim
To determine if i.v. MBP8298 has an effect on the rate of disease progression in MS compared with placebo, to determine if suppression of CSF anti-MBP levels in response to i.v. MBP8298 is associated with disease stabilization and to confirm safety of MBP8298.
Methods
The study was a 24-months, double-blinded, placebo-controlled Phase II clinical trial in 32 patients with primary or secondary progressive MS (EDSS 3.0-7.5). MBP8298 was administered i.v. as a dose of 500 mg every 6 months. Quantitative neurological assessment and EDSS were collected two times pre entry and every 6 months. MRI (with and without Gd) was conducted before entry and every year, CSF analysis every 2 months and extensive blood analyses every 6 months.
Results
There was no significant difference between the EDSS of the MBP8298 and placebo group (p=0.29) after 24 months. Subgroup analysis of HLA haplotypes DR2 and/or DR4 showed benefit of treatment compared with placebo (n=20, p=0.01). Long term follow up in this group showed a median time to progression of 78 months for the MBP8298 group, compared with 18 months for the placebo group (Kaplan-Meier analysis p=0.004).
CSF anti-MBP autoantibodies were suppressed in most MBP8298 treated patients, but were not predictive of clinical benefit. There were no serious adverse events during the study.
Dr Blinkenberg's comments
The study shows that MBP8298 delay progressive MS significantly in a subgroup of patients characterized by the HLA haplotype DR2 and/or DR4. Although this effect is sustained in the long-term data, the disease process does continue despite tolerance induction, presumably due to epitope spreading.
Although the CSF analysis is not predictive of outcome, the autoanitbodies were generally suppressed and the study provides substantial documentation for the therapeutic potential of MBP8298. Regarding safety, the immunotolerance principle is feasible since it does not affect essential immunological activities unrelated to the disease, which is usually a problem for several MS immunomodulatory or immunosuppressive treatments.
In the current study the authors did not record any significant side effects during treatment, and especially no signs of encephalitogenic potential, previously described in a tolerance induction study. The safety profile is therefore considered to be benign.
MBP8298 seem to be a very promising treatment approach in HLA DR2 and/or DR4 primary or secondary progressive MS patients.
It is encouraging to see significant treatment effect on disability measures in this group of patients where treatment options are sparse. An ongoing phase III study will show if the efficacy of MBP8298 can be reproduced and if there are other subgroups that may respond to treatment.