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.
MBP8298 is a synthetic peptide with a sequence corresponding to amino acid residues 82-98 of human myelin basic protein (DENPVVHFFKNIVTPRT). It represents the immunodominant target for both B cells and T cells in multiple sclerosis (MS) patients with HLA haplotype DR2. Its administration in accordance with the principle of high dose tolerance results in long-term suppression of anti-myelin basic protein (MBP) autoantibody levels in the cerebrospinal fluid (CSF) of a large fraction of progressive MS patients. MBP8298 was evaluated in a 24-month placebo-controlled double-blinded Phase II clinical trial in 32 patients with progressive MS. The objective was to assess the clinical efficacy of 500 mg of MBP8298 administered intravenously every 6 months, as measured by changes in Expanded Disability Status Scale (EDSS) scores. Contingency analysis for all patients at 24 months showed no significant difference between MBP8298 and placebo-treatments (n = 32, P = 0.29). Contingency analysis in an HLA Class II defined subgroup showed a statistically significant benefit of MBP8298 treatment compared with placebo in patients with HLA haplotypes DR2 and/or DR4 (n = 20, P = 0.01). Long-term follow-up treatment and assessment of patients in this responder group showed a median time to progression of 78 months for MBP8298 treated patients compared with 18 months for placebo-treatment (Kaplan-Meier analysis, P = 0.004; relative rate of progression = 0.23). Anti-MBP autoantibody levels in the CSF of most MBP8298 treated patients were suppressed, but antibody suppression was not predictive of clinical benefit. Anti-MBP autoantibodies that reappeared in the CSF of one patient at 36 months, whilst under treatment with MBP8298, were not reactive with the MBP8298 peptide in vitro. The identification of a responder subgroup (62.5% of the patients in this study) enables a more efficient design of a large confirmatory clinical trial of MBP8298. The probability that patients with other less common HLA-DR haplotypes will respond to this treatment should not be ignored.
Warren
K G
KG
Multiple Sclerosis Patient Care and Research Clinic, Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Catz
I
I
Ferenczi
L Z
LZ
Krantz
M J
MJ
D000328:Adult; D000906:Antibodies / Q000134:cerebrospinal fluid; D004185:Disability Evaluation; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D015802:HLA-DR2 Antigen; D006801:Humans; D066298:In Vitro Techniques; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology; D011597:Psychomotor Performance / Q000502:physiology; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
D000906:Antibodies; D015802:HLA-DR2 Antigen; D004676:Myelin Basic Protein; D010446:Peptide Fragments