Induction of Antigen-Specific Tolerance in Multiple Sclerosis After Immunization With DNA Encoding Myelin Basic Protein in a Randomized, Placebo-Controlled Phase 1/2 Trial

• Published in: Archives of neurology (Chicago) Vol. 64; no. 10; pp. 1407 - 1415
• Main Authors: Bar-Or, Amit, Vollmer, Timothy, Antel, Jack, Arnold, Douglas L, Bodner, Caroline Anita, Campagnolo, Denise, Gianettoni, Jill, Jalili, Farzaneh, Kachuck, Norman, Lapierre, Yves, Niino, Masaaki, Oger, Joel, Price, Mary, Rhodes, Susan, Robinson, William H, Shi, Fu-Dong, Utz, Paul J, Valone, Frank, Weiner, Leslie, Steinman, Lawrence, Garren, Hideki
• Format: Journal Article
• Language: English
• Published: United States American Medical Association 01.10.2007
• Subjects: Adult; Antigens; Atorvastatin Calcium; Clinical trials; Deoxyribonucleic acid; Disability Evaluation; DNA; Double-Blind Method; Endpoint Determination; Female; Heptanoic Acids - therapeutic use; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Immune Tolerance - immunology; Immunization; Injections, Intramuscular; Lymphocyte Count; Magnetic Resonance Imaging; Male; Middle Aged; Multiple sclerosis; Multiple Sclerosis - immunology; Multiple Sclerosis - prevention & control; Multiple Sclerosis, Relapsing-Remitting - immunology; Multiple Sclerosis, Relapsing-Remitting - prevention & control; Myelin Basic Protein - immunology; NMR; Nuclear magnetic resonance; Oligonucleotide Array Sequence Analysis; Plasmids - genetics; Plasmids - immunology; Pyrroles - therapeutic use; Recurrence; Statins; T-Lymphocytes - immunology; Vaccines, DNA - adverse effects; Vaccines, DNA - therapeutic use; North America
• ISSN: 0003-9942; 2168-6149; 1538-3687; 2168-6157
• DOI: 10.1001/archneur.64.10.nct70002

OBJECTIVE To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human myelin basic protein, in patients with multiple sclerosis (MS). DESIGN The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding. SETTING The trial was conducted at 4 academic institutions within North America. PATIENTS Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years. INTERVENTIONS BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg). MAIN OUTCOME MEASURES The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium-enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses. RESULTS BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-γ–producing, myelin-reactive CD4+ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone. CONCLUSION In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00103974.Published online August 13, 2007 (doi:10.1001/archneur.64.10.nct70002).Arch Neurol. 2007;64:(10)938-944 -->