Potential conflict of interest: Nothing to report.
Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy†
Article first published online: 3 MAR 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 65, Issue 2, pages 140–150, February 2009
How to Cite
Banno, H., Katsuno, M., Suzuki, K., Takeuchi, Y., Kawashima, M., Suga, N., Takamori, M., Ito, M., Nakamura, T., Matsuo, K., Yamada, S., Oki, Y., Adachi, H., Minamiyama, M., Waza, M., Atsuta, N., Watanabe, H., Fujimoto, Y., Nakashima, T., Tanaka, F., Doyu, M. and Sobue, G. (2009), Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol., 65: 140–150. doi: 10.1002/ana.21540
- Issue published online: 3 MAR 2009
- Article first published online: 3 MAR 2009
- Manuscript Accepted: 5 SEP 2008
- Manuscript Revised: 25 AUG 2008
- Manuscript Received: 15 JUL 2008
- Ministry of Education, Culture, Sports, Science and Technology, Japan. Grant Numbers: 17025020, 19209033, 20390243
- Ministry of Health, Labor and Welfare, Japan (Health and Labor Sciences Research). Grant Numbers: H18YO022, H20YP015, CCT-B-1701, CCT-C-1810
- Program for Improvement of Research Environment for Young Researchers from Special Coordination Funds for Promoting Science and Technology (SCF) commissioned by the Ministry of Education, Culture, Sports, Science and Technology of Japan
Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA.
Fifty SBMA patients underwent subcutaneous injections of leuprorelin acetate or placebo in a randomized, placebo-controlled trial for 48 weeks, followed by an open-label trial for an additional 96 weeks, in which 19 patients of the leuprorelin group and 15 of the placebo group received leuprorelin acetate. The patients who did not participate in the open-label trial were also followed up for the 96-week period (UMIN000000474).
Leuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem.
These observations suggest that administration of leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large-scale clinical trials of androgen deprivation for SBMA. Ann Neurol 2009;65:140–150