A futility trial of sirolimus in multiple system atrophy

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PROJECT SUMMARY Our ultimate goal is to develop new treatments for patients with multiple system atrophy (MSA), a rare neurodegenerative disease with no cure caused by the abnormal accumulation of the protein alpha-synuclein (αSyn) in neurons and glia. There are no treatments that can halt or slow the progression of the disease, and patient with MSA die within 8-10 years from symptom onset. Because disease progression in MSA is causally linked to accumulation, aggregation, and spreading of αSyn in the central nervous system (CNS), much effort has gone into devising strategies to combat this process, although, so far, all attempts to identify a treatment have failed. Autophagy is the major cellular digestion process that removes damaged macromolecules, organelles, and misfolded proteins, including αSyn, from cells. In patients with MSA, autophagy is impaired and misfolded αSyn accumulates in neurons and glia, causing neurodegeneration. Sirolimus, a medication that has been approved by the U.S. Food and Drug Administration for chronic treatment in humans for a variety of disorders for almost 20 years ago, is a potent activator of autophagy. Our HYPOTHESIS is that treatment with sirolimus might activate autophagy of αSyn resulting in reduced neurodegeneration and slower progression of the neurological deficits in patients with MSA. Our OBJECTIVE is to perform a single-center, randomized, placebo-controlled, phase II futility clinical trial to determine if sirolimus is of sufficient promise to slow the disease progression of patients with MSA, prior to embarking on a large-scale and costly phase-III study to assess its efficacy. A futility design under the null hypothesis assumes that sirolimus will slow the progression of the disease, whereas the alternative hypothesis assumes no benefit of sirolimus. If the null hypothesis is rejected (i.e., futility of sirolimus to slow progression of MSA), a major phase III study will be discouraged, whereas non-futility will offer strong support for a phase III trial to detect clinical efficacy. The AIMS are: ONE. To determine if sirolimus is of sufficient promise to slow the progression of disease in patients with MSA as measured by patient-reported outcome measures. TWO. To assess the potential effects of sirolimus on retinal and brain imaging biomarkers in patients with MSA. THREE. To explore the effect of sirolimus on CNS-derived blood-based αSyn extracellular vesicles. As far as we are aware, this is the first time sirolimus or analogs will be used clinically with the aim of slowing disease progression in patients with neurodegenerative disorders. Our observations may offer strong support for a phase III trial to confirm the efficacy of sirolimus in MSA. Furthermore, the outcome of our study may potentially have a broad therapeutic benefit for other, more frequent neurodegenerative disorders, such as Parkinson disease.