Coactivation of TRPA1/TRPV1 and its Potential Impact on Cramps, Spasms, Spasticity and Pain in Amyotrophic Lateral Sclerosis (P4.442)

Objective: Previous findings demonstrate that coactivation of TRPA1/TRPV1 ion channels by FLX-787 significantly inhibit electrically-induced muscle cramps and nocturnal leg cramps in healthy adults. In the exploratory proof-of-concept study Flex-202, we have sought to understand the efficacy, tolerability and safety of FLX-787 and its impact on decreasing neuromuscular symptoms in ALS patients. Background: Chemical neurostimulation is the topical activation of ion channels in the oropharynx and esophagus which is believed to stimulate descending spinal pathways and increase spinal inhibitory interneuron inhibition to decrease hyperexcitability of motoneurons. Given that muscle cramps, spasms and spasticity are a consequence of α-motor neuron hyperexcitability, chemical neurostimulation may be a useful strategy when treating these symptoms. Design/Methods: We have conducted Flex-202, a multicenter, randomized, blinded, cross-over study, to investigate the effects of FLX-787 in ALS. This exploratory study assessed the clinical effects of FLX-787 in a small cohort of ALS patients (n=11). This cross-over study had a run-in period to establish a baseline followed by two randomized 14-day treatments, separated by a wash-out period. Endpoints included change from baseline assessments including cramp frequency, spasticity, sleep quality, pain and global impression of change. Results: FLX-787 was assessed on the initial parallel portion of the study as well as the overall crossover results. Overall results demonstrated both strong trends and statistically significant differences relative to control despite the small cohort size. Treatment with FLX-787 increased the number of cramp-free days and reduced the frequency of cramping, as well as self-reported NRS spasticity and pain scores. Improvements were observed in both patient and clinician global impression of change. Conclusions: Initial results from this study suggest that FLX-787 mediated activation of TRPA1/TRPV1 ion channels may be an effective approach to decrease muscle cramp frequency, cramp-associated pain and self-reported stiffness which improve patient and clinical global impression. Disclosure: Dr. Short has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Flex Pharma. Dr. Short holds stock and/or stock options in Flex Pharma, which sponsored research in which Dr. Short was involved as an investigator. Dr. Hegarty has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Flex Pharma. Dr. Hegarty holds stock and/or stock options in Flex Pharma, which sponsored research in which Dr. Hegarty was involved as an investigator. Dr. Szegda has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Flex Pharma. Dr. Szegda holds stock and/or stock options in Flex Pharma, which sponsored research in which Dr. Szegda was involved as an investigator. Dr. Golod has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Flex Pharma. Dr. Golod holds stock and/or stock options in Flex Pharma, which sponsored research in which Dr. Golod was involved as an investigator. Dr. McVicar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Flex Pharma. Dr. McVicar holds stock and/or stock options in Flex Pharma, which sponsored research in which Dr. McVicar was involved as an investigator. Dr. Wessel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Flex Pharma. Dr. Wessel holds stock and/or stock options in Flex Pharma, which sponsored research in which Dr. Wessel was involved as an investigator.