WASHINGTON -- In a suite of early-stage clinical studies, orally active ion channel modulators relieved muscle cramps in healthy volunteers, potentially leading to treatments for multiple sclerosis spasticity, cervical dystonia, and a host of other conditions.
With a total of 37 volunteers in three separate placebo-controlled crossover trials, the ion channel agents -- activating the TRPV1 and TRPA1 channels -- inhibited development of electrically induced foot cramps, according to researchers from in Boston, including the firm's co-founder, 2003 Nobel Prize laureate .
Action Points
- Note that these studies were presented as an abstract at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
- A series of small early-stage, placebo-controlled crossover trials investigated the potential of TRP ion channels activators to improve electrically induced foot cramps in healthy volunteers, demonstrating a statistically significant improvement in symptoms.
According to the study abstract, to be presented at the American Academy of Neurology's annual meeting here in April and released Wednesday, the treatment "significantly reduc[ed] cramp intensity by three-fold (P<0.001) and demonstrat[ed] an effect within minutes lasting up to 6-8 hours when compared to untreated subjects."
The researchers explained that cramping appears to result from repetitive firing of so-called alpha neurons with resulting hyperexcitability in motor circuits. The physiology of these neuronal connections involves ion movement into and out of cells, suggesting that ion channel modulators may provide opportunities to intervene in these processes.
Specifically, activation of TRP channels in the gastrointestinal tract "might increase inhibitory tone in the spinal cord and dampen motor neuron hyperexcitability," MacKinnon and colleagues wrote.
MacKinnon won the 2003 Nobel Prize in chemistry for his structural and mechanistic studies of ion channels (shared with , credited with the discovery of water channels).
The clinical studies used "a proprietary product containing TRP activators," according to the abstract. Flex Pharma elsewhere describes the product as containing ginger and cinnamon extracts and capsicum. These plant-based agents are FDA-listed as "generally recognized as safe," according to Flex. Preclinical tests had shown that the compounds, singly and in combination, increased intracellular calcium levels in human dorsal root ganglia tissue.
The hypothesized mechanism of action in cramping, according to the firm, is that activating TRP channels in sensory neurons in the GI tract will, in turn, send signals to the spinal cord that then create "an inhibitory effect ... on alpha motor neurons throughout the body, thereby reducing neuron excitation and muscle cramps."
Flex, which became a public company a few weeks ago in an $86-million offering, is targeting numerous conditions for the treatment. Besides MS spasticity and cervical dystonia, these also include nocturnal cramps afflicting older adults and cramping resulting from muscle exertion.
In , Flex estimated that some 4 million people older than 65 suffer from cramps every night.
The firm intends to conduct a proof-of-concept clinical study later this year in that indication.
Its plans also call for the TRP activators to be formulated as a dietary supplement -- and thus beyond the FDA's drug regulation -- for preventing exercise-induced cramps. A commercial launch could come in the first half of 2016, the firm said.
For treatment of medical conditions such as spasticity and dystonia, Flex will pursue formal FDA approvals. The firm estimates that at least 200,000 Americans with MS experience spasticity. Another 150,000 suffer spasticity from spinal cord injury, and some 90,000 have cervical dystonia.
Disclosures
The studies were funded by Flex Pharma and study authors were Flex employees and/or stockholders.