Several recent findings implicating androgens in SBMA provided the rationale for this study: (1) DHT caused neurodegeneration in a fly model of SBMA;21
(2) male transgenic mice develop progressive weakness, and females are relatively unaffected; motor function improved in the males with androgen reduction, and the females developed weakness with androgen administration;4,22
(3) two sisters homozygous for the AR repeat expansion had only mild manifestations, indicating that SBMA in humans as in mice is male-limited, presumably because of higher androgen levels in males.23
Together, these observations provided impetus for testing androgen-reducing therapy in SBMA.
The drug leuprorelin has shown benefit in mouse models of SBMA, and more recently some indications of efficacy in human subjects.5
Leuprorelin decreases testicular testosterone production. Dutasteride offers a more selective approach to decreasing androgens. Differential expression of 5-alpha-reductase in skeletal muscle and motor neurons suggests that DHT may be the primary ligand for the AR in motor neurons, while testosterone serves this role in skeletal muscle.24,25
Thus, suppression of DHT production may decrease the toxic activation of the mutant AR in motor neurons without disrupting the beneficial anabolic action of testosterone in muscle.
In this study 50 men with SBMA were randomised to receive placebo or dutasteride for 24 months. DHT levels decreased markedly in the dutasteride group, indicating an appropriate pharmacological effect. QMA, an outcome measure previously used in amyotrophic lateral sclerosis and muscular dystrophy studies,26
did not show a significant difference at 12 or 24 months between the study groups. There was no open-label extension, such as might have given an indication of a longer term effect, albeit uncontrolled. In retrospect this study was under-powered. Given the slow progression of weakness in the placebo group, more time or a larger number of patients may be needed to show a decrease in the rate of progression using QMA. Of the secondary measures, AMAT and SF-36v2 PCS may be better for use in future trials.
Analysis of the SF-36v2 PCS and MCS revealed positive and negative effects. Subjects receiving dutasteride had an increase in PCS scores at 24 months, while PCS scores for the placebo arm decreased. In contrast, MCS scores for the dutasteride study arm at 24 months showed a decrease from baseline, while placebo MCS scores increased. Other self-assessed parameters, including ADL and IIEF, did not show a significant difference.
Dysphagia is an important source of morbidity in SBMA. The six barium swallow parameters reported here represent the common areas of difficulty in this population. The average swallow score did not show a significant difference at 12 or 24 months. However, is not possible to draw a clear conclusion from this subset due to selection bias. In the phase 2 leuprorelin trial, Banno et al.
reported increased cricopharyngeal opening time with leuprorelin.5
However, a later phase 3 study did not confirm a significant effect on swallow function.6
Dutasteride was generally well tolerated in our population, with a low dropout rate and high compliance. There was a difference in the number of subjects reporting musculoskeletal AEs, with fewer dutasteride subjects reporting events in this category. Most of this difference is attributable to falls, which like the SF-36v2 PCS might indicate a benefit of dutasteride that was not detected as significant with QMA and the other secondary measures. In other studies, dutasteride’s most common adverse effects included impotence and decreased libido;27
these may have contributed to lower MCS scores in the dutasteride group.
The data collected from this trial provides an indication of the rate of decline for various measures over 24 months in a placebo group. The SF-36v2 PCS, AMAT, and swallow scores showed the greatest percent decline per year. This data can be used in future trials of other agents, such as HSP90 inhibitors,28
which have been shown to improve motor function in mouse models.
The finding that dutasteride had no significant effect on muscle strength as measured by QMA after 24 months likely reflects the complex role of androgens in SBMA as well as the sensitivity of the test. Whereas androgens contribute to the toxicity of the mutant AR in mouse models of SBMA, higher blood androgen levels correlated with increased muscle strength in a cross-sectional study of this patient population.8
Based on these results, we do not currently recommend dutasteride as treatment for SBMA. Nevertheless, there are indications of potential benefit that point to the need for further investigation of androgen-lowering therapy. The current study contributes to our understanding of SBMA and indicates that future clinical trials need to take into account the rate of decline and use clinically meaningful outcome measures that can reliably predict a therapeutic benefit.