Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis.
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.
Garren
Hideki
H
Bayhill Therapeutics, Palo Alto, CA 94303, USA. hgarren@bayhilltx.com
Robinson
William H
WH
Krasulová
Eva
E
Havrdová
Eva
E
Nadj
Congor
C
Selmaj
Krzysztof
K
Losy
Jacek
J
Nadj
Ilinka
I
Radue
Ernst-Wilhelm
EW
Kidd
Brian A
BA
Gianettoni
Jill
J
Tersini
Karen
K
Utz
Paul J
PJ
Valone
Frank
F
Steinman
Lawrence
L
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*
D004676:Myelin Basic Protein; D019444:Vaccines, DNA