title: Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis.
abstract: OBJECTIVE
  To evaluate the efficacy and safety of BHT-3009 in relapsing-remitting multiple sclerosis (MS) and to confirm that BHT-3009 causes immune tolerance.
  
  
  METHODS
  BHT-3009 is a tolerizing DNA vaccine for MS, encoding full-length human myelin basic protein. Relapsing-remitting MS patients were randomized 1:1:1 into three groups: placebo, 0.5 mg BHT-3009, or 1.5 mg BHT-3009, given intramuscularly at weeks 0, 2, 4, and every 4 weeks thereafter until week 44. The primary end point was the 4-week rate of occurrence of new gadolinium-enhancing lesions on brain magnetic resonance images from weeks 28 to 48. Protein microarrays were used to measure levels of anti-myelin autoantibodies.
  
  
  RESULTS
  Compared with placebo, in the 267 patient analysis population the median 4-week rate of new enhancing lesions during weeks 28 to 48 was 50% lower with 0.5 mg BHT-3009 (p = 0.07) and during weeks 8 to 48 was 61% lower with 0.5 mg BHT-3009 (p = 0.05). The mean volume of enhancing lesions at week 48 was 51% lower on 0.5 mg BHT-3009 compared with placebo (p = 0.02). No significant improvement in magnetic resonance imaging lesion parameters was observed with 1.5 mg BHT-3009. Dramatic reductions in 23 myelin-specific autoantibodies in the 0.5 mg BHT-3009 arm were observed, but not with placebo or 1.5 mg BHT-3009.
  
  
  CONCLUSIONS
  In relapsing-remitting MS patients, treatment with the lower dose (0.5 mg) of BHT-3009 for 44 weeks nearly attained the primary end point for reduction of the rate of new enhancing magnetic resonance imaging lesions (p = 0.07) and achieved several secondary end points including a reduction of the rate of enhancing magnetic resonance imaging lesions from weeks 8 to 48 (p = 0.05). Immunological data in a preselected subgroup of patients also indicated that treatment with 0.5 mg induced antigen-specific immune tolerance. The greater dose was ineffective.
authors.affiliation: Bayhill Therapeutics, Palo Alto, CA 94303, USA. hgarren@bayhilltx.com
authors.forename: Hideki
authors.initials: H
authors.lastname: Garren
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
authors.forename: Eva
authors.initials: E
authors.lastname: Krasulová
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdová
authors.forename: Congor
authors.initials: C
authors.lastname: Nadj
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selmaj
authors.forename: Jacek
authors.initials: J
authors.lastname: Losy
authors.forename: Ilinka
authors.initials: I
authors.lastname: Nadj
authors.forename: Ernst-Wilhelm
authors.initials: EW
authors.lastname: Radue
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kidd
authors.forename: Jill
authors.initials: J
authors.lastname: Gianettoni
authors.forename: Karen
authors.initials: K
authors.lastname: Tersini
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.forename: Frank
authors.initials: F
authors.lastname: Valone
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000188:drug therapy*; D004676:Myelin Basic Protein / Q000235:genetics*; D016896:Treatment Outcome; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000009:adverse effects*
chemical_list: D004676:Myelin Basic Protein; D019444:Vaccines, DNA