Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy

• Published in: Annals of neurology 2009-02, Vol.65 (2), p.140-150
• Main Authors: Banno, Haruhiko, Katsuno, Masahisa, Suzuki, Keisuke, Takeuchi, Yu, Kawashima, Motoshi, Suga, Noriaki, Takamori, Motoko, Ito, Mizuki, Nakamura, Tomohiko, Matsuo, Koji, Yamada, Shinichi, Oki, Yumiko, Adachi, Hiroaki, Minamiyama, Makoto, Waza, Masahiro, Atsuta, Naoki, Watanabe, Hirohisa, Fujimoto, Yasushi, Nakashima, Tsutomu, Tanaka, Fumiaki, Doyu, Manabu, Sobue, Gen
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Androgen Antagonists - therapeutic use; Biological and medical sciences; Cineradiography - methods; Double-Blind Method; Follow-Up Studies; Humans; Injections, Subcutaneous - methods; Injuries of the nervous system and the skull. Diseases due to physical agents; Japan; Leuprolide - therapeutic use; Male; Medical sciences; Microscopy, Video - methods; Middle Aged; Muscular Atrophy, Spinal - drug therapy; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - pathology; Muscular Atrophy, Spinal - physiopathology; Mutation; Neurology; Peptides - genetics; Prospective Studies; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Severity of Illness Index; Skin - metabolism; Skin - pathology; Traumas. Diseases due to physical agents
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21540

Objective 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. Methods 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). Results 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. Interpretation 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