Randomized Double-Blind Placebo-Controlled Adaptive Design Trial Of Intrathecally Administered Autologous Mesenchymal Stem Cells In Multiple System Atrophy

Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurodegenerative disease for which there is no disease-modifying treatment. Recent insights into pathophysiologic mechanisms suggest a crucial role of deprivation of neurotrophic factors which have been shown to be secreted by mesenchymal stem cells (MSCs). In a recent phase I/II study adipose-derived autologous MSCs were delivered intrathecally to patients with early MSA utilizing a dose-escalation design. At a dose of 50 million MSCs, injections were generally well tolerated, but thickening of cauda equina nerve roots was observed which was either asymptomatic or associated with low back pain. The rate of disease progression assessed using the Unified MSA Rating Scale (UMSARS) was markedly slower compared to a matched control group. An even more favorable side effect profile and virtually lack of disease progression was seen in an add-on cohort receiving 25 million MSCs per injection. Neurofilament light chain, an index of central axonal degeneration, decreased in all patients receiving that dose. MSC administrations resulted in a marked, dose-dependent increase of neurotrophic factors in CSF. 2-year survival was significantly higher than observed in natural history cohorts.

Based on these findings we are now conducting a double-blind, placebo-controlled, adaptive design phase II trial of adipose-derived intrathecal autologous MSCs in MSA with the goal to establish optimal treatment frequency and simultaneously derive placebo-controlled efficacy and safety data in preparation for a multicenter phase III trial. Up to 76 adult subjects with MSA will be enrolled. To ensure a homogenous patient population with comparable rates of disease progression, we will restrict the study to early cases but still fulfilling strictest diagnostic consensus criteria. Participants will undergo a subcutaneous fat biopsy to derive autologous MSCs, which are cultured, expanded, and prepared for delivery in Mayo's Cell Therapeutics Lab. In a first phase, subjects will be randomized 1:1:1 to receive 25 million MSCs at two different injection intervals (every 6 months or every 3 months) as the two active arms or lactated Ringer's solution as the placebo arm. An interim analysis will take place after approximately 38 patients have completed the trial with assessments of the primary endpoint available at all timepoints. Additional patients enrolled after the first 38 patients and before the results of the interim analysis are available will receive the higher frequency administration utilizing 2:1 randomization. The DSMB will review efficacy and safety/tolerability data available at the time of the interim analysis and pick a "winner" based on efficacy trends and adverse events. The study will then continue utilizing 2:1 randomization ("winner" active: placebo). Patients undergo clinical assessments at baseline, 3, 6, 9, and 12 months to derive the primary endpoint, the rate of disease progression assessed using UMSARS total and a mixed effects regression model. MRI of the head and lumbar spine will be completed at baseline and 12 months to expand safety data and to assess the rate of atrophy of selected brain regions using morphometric measures as surrogate markers of disease progression. Spinal fluid before and after administrations, as well as stem cell product media will be collected to further explore biological properties and effects of MSCs and to assess selected spinal fluid markers as biomarkers of disease progression.