Rajbeer Singh Sangha, MD

Urfer R, Moebius HJ, Skoloudik D, Santamarina E, Sato W, Mita S, and Muir KW. Phase II Trial of the Sigma-1 Receptor Agonist Cutamesine (SA4503) for Recovery Enhancement After Acute Ischemic Stroke. Stroke. 2014

While therapy for acute ischemic stroke has made many advances in the past two decades, enhancement of functional recovery during the sub-acute and chronic phases of stroke represents a major therapeutic goal and one that remains elusive thus far. Current theory based on pre-clinical in vivo models suggests that a time-limited window of neuroplasticity exists following neuronal injury. One of the mechanisms is via the sigma-1 receptor chaperone protein (Sig-1R) mediated functional recovery in a model of neuronal plasticity.  Cutamesine (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride, SA4503), is an orally available, central nervous system active, selective agonist of the Sig-1R. During previous studies, it has shown that use of this compound had enhanced functional recovery in rat models when treatment commenced 48 hours after stroke and continued for one month, without affecting infarct size. The authors of this study conducted a phase II clinical trial of cutamesine in which they examined the safety and preliminary efficacy of this compound in ischemic stroke patients.

60 patients were randomized between 48 and 72 hours post-stroke to receive cutamesine at 1 mg/day, 3 mg/day, or placebo for 28 days. Effects on safety and function were assessed at baseline, at end of treatment (Day 28) and at end of follow-up (Day 56). No significant effect was observed on the primary efficacy measure (change in NIHSS from baseline to day 56), or modified Rankin Scale and Barthel Index scores. Further Post-hoc analysis of moderately and severely affected patients (baseline NIHSS ≥7 and ≥10) showed greater NIHSS improvements in the 3 mg/day cutamesine group compared to placebo (p=0.034 and p=0.038, respectively). A trend also was noted towards a higher proportion of the cutesamine group being able to complete a 10m timed walk when compared to the placebo group. The nature and frequency of adverse events were as expected from the medical history of enrolled subjects and mostly reflect sequelae of the recent stroke.

Clinical trials thus far investigating the effects of compounds that may enhance functional recovery following stroke have had disappointing results. Cerebrolysin is a compound that comes to mind that also did not show significant improvements in functional recovery.  While the power is limited with only 60 subjects enrolled in the study, Cutesamine does show encouraging results in the post hoc analysis that moderately and severely affected patients did better than their placebo counterparts and this is an avenue for hope. The authors also allude to this in their article and one of the limitations in the study was the controlling of the rehab therapies for the patients going forward. While they do mention that further studies need to investigate cutesamine’s effect on the moderate to severely affected stroke group of patients, it should also be recommended that patient self-reported functional outcomes be utilized as a tool to assess the effects of this compound going forward. Use of the Neuro-QOL may provide a more sensitive and specific analysis of cognitive improvements in these patients.