Leuprorelin Leuprorelin, a GnRH agonist which blocks the synthesis of testosterone when given continuously, was initially shown to be effective at improving motor function in mouse models of<unk> . A small pilot study was performed in which five<unk>  patients were given subcutaneous injections of leuprorelin every four weeks for six months, with serial scrotal skin biopsies performed. Nuclear accumulation of polyglutamine androgen receptor was significantly reduced in patient scrotal biopsies. Additionally, serum CK, a marker of muscle deterioration, and testosterone levels were both reduced in patients receiving leuprorelin. Notably, in this study patients were not randomized to treatment groups or placebo controlled. A subsequent larger study consisted of fifty<unk>  patients randomized to either leuprorelin treatment or placebo. This trial spanned 48 weeks of treatment with treatment occurring every four weeks initially. Following treatment, thirty-four patients had an open-label follow-up spanning an additional ninety-six weeks with treatment continuing every twelve weeks. At the forty-eight week mark, there was no significant difference in the ALS functional rating scale, the primary outcome measure of the study, between placebo and leuprorelin treated groups. There was improvement in swallowing a barium contrast marker, a secondary endpoint of the study, at forty-eight weeks. Further, there was improvement in the ALS functional rating scale at the 96 and 144 week marks, suggesting a longer period may be needed to see effects of leuprorelin. A larger, multi-center, placebo-controlled, double blind study was then conducted which contained 199<unk>  patients who were randomized to either placebo or leuprorelin treatment. The study spanned forty-eight weeks with leuprorelin treatment every 12 weeks, with ability to swallow a barium contrast marker as the primary endpoint. In this study, there was not a significant difference in barium swallow at forty-eight weeks. There was also no difference in other videofluorography measurements, supporting the lack of improvement in swallow function in the treatment group. Other secondary measures, such as number of AR positive scrotal cells and serum CK level were significantly different in the treatment group. Though the primary endpoint of the study did not show an effect of leuprorelin on<unk>  patients, a subgroup analysis performed on patients who had symptoms for ten years or less did show improved swallowing function, and it was suggested that treatment may be more effective in patients who have shown symptoms for shorter periods of time or with less advanced disease. A recent follow-up open-label study compared thirty-six patients treated with leuprorelin to nontreated controls over eighty four months, and found that the treated group showed slower decline in motor function than the non-treated group. Significantly differing endpoints of this study included the ALS Functional Rating Scale, the Limb Norris Score, and the Norris Bulbar Score. Dutasteride Dutasteride is a 5α-reductase inhibitor which blocks the conversion of testosterone into dihydrotestosterone. Dihydrotestosterone binds to androgen receptor more avidly, and inhibiting conversion of testosterone into dihydrotestosterone reduces overall androgen receptor activation. Fifty patients were recruited to a randomized, placebo controlled trial spanning two years, with a primary endpoint of quantitative muscle assessment. No significant difference was found in quantitative muscle assessment between the placebo and dutasteride groups at the two year mark. Secondary outcomes including barium swallow and manual muscle testing also showed no significant difference between groups. Exercise A small pilot study was performed on eight<unk>  patients evaluating the effects of exercise. Patients performed thirty minute training sessions on a stationary bicycle with increasing frequency per week (two sessions per week in weeks 1-2, three sessions per week in weeks 3-4, and five sessions per week for weeks 5-12). No significant changes in the primary endpoint VO2max, the maximum oxygen uptake which is a marker of endurance and fitness, were found following the exercise regimen. A larger study was conducted in 2015 including 50<unk>  patients randomized to exercise or a stretching-only program for twelve weeks. The adult myopathy assessment tool was used as the primary endpoint of the study. Secondary endpoints included muscle strength, quality of life score, balance, and IGF-1 levels. No significant differences were found between the primary endpoint or secondary endpoints of the study. However, subgroup analysis did show benefit for low-functioning groups, suggesting there may be a role for exercise in these patients. BVS857 IGF-1, a signaling molecule downstream of growth hormone, has well established functions promoting skeletal muscle growth. In preclinical studies on mouse models of ALS, IGF-1 was shown to be protective against motor neuron death. A double blind, placebo-controlled clinical trial was performed with eighteen<unk>  patients receiving BVS857, a mimetic of IGF-1, with nine placebo controls. The study found increased thigh muscle volume improved lean body mass following 12 weeks of treatment in the BVS857 group compared to placebo. However, eleven of eighteen patients were found to have an immune response against BVS857, with five patients developing neutralizing antibodies, posing a challenge for long term treatment.
Spinal and bulbar muscular atrophy
Infantile progressive bulbar palsy
Ataxic cerebral palsy
Madras motor neuron disease
Multiple system atrophy
Spinal muscular atrophy
Spinal muscular atrophy with lower extremity predominance 1
Babinski–Nageotte syndrome