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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

2007; American Medical Association; Volume: 64; Issue: 10 Linguagem: Inglês

10.1001/archneur.64.10.nct70002

1538-3687

Amit Bar‐Or, Timothy R. Vollmer, Jack P. Antel, Douglas L. Arnold, Caroline Bodner, Denise I. Campagnolo, Jill Gianettoni, Farzaneh Jalili, Norman J. Kachuck, Yves Lapierre, Masaaki Niino, Joël Oger, Mary Ann Price, Susan N. Rhodes, William H. Robinson, Fu‐Dong Shi, Paul J. Utz, Frank H. Valone, Leslie P. Weiner, Lawrence Steinman, Hideki Garren,

Viral Infections and Immunology Research

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).The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding.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.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).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.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-gamma-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.In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI.