Flex Pharma (NASDAQ:FLKS) expects to report clinical readouts in 2018 from three Phase 2 studies of its anti-cramping drug candidate, FLX-787, in amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT) and multiple sclerosis (MS).
“Muscle cramps cause significant morbidity in these severe neurological diseases and there is no FDA-approved treatment,” William McVicar, president and CEO, says in an interview with BioTuesdays.
“Our innovative treatments for painful and debilitating muscle cramps and spasticity are based on novel insights in neuromuscular physiology from our co-founder, Dr. Rod MacKinnon, who shared the 2003 Nobel Prize in chemistry for his structural and mechanistic studies of ion channels,” he adds.
Mr. McVicar explains that FLX-787 acts by activating two proteins, the TRPA1 and TRPV1 ion channels, which are expressed in mouth and pharynx sensory nerves.
“Activation of these nerves is believed to trigger a signal that travels up to the brain, where it is processed, sending a signal through descending spinal cord pathways and slowing down the firing of lower motor neurons,” he suggests.
Until recently, it was believed that cramps were caused by dehydration, lactic acid build-up or electrolyte imbalances affecting the muscle.
According to Mr. McVicar, new research indicates that muscle cramps and spasms are caused by a neural mechanism: excessive firing of motor neurons in the spinal cord that control muscle contraction.
“Neurodegenerative disease induce this hyperexcitability through diminished inhibition, causing them to fire excessively and trigger cramping,” he adds.
Roth analyst Michael Higgins, who reinitiated coverage of Flex last month, said Flex has developed a novel but validated approach to cramp therapy.
Mr. Higgins noted that this entirely novel mechanism of action has been evaluated by Flex in proof-of-concept trials using the mixture or FLX-787 in both healthy volunteers and nocturnal leg cramp patients. “Results include reduced cramp intensity and duration lasting up to eight hours and reduced cramp frequency and pain over a two-week daily dosing period,” he added.
Mr. Higgins rates the stock at “buy” with a price target of $14. The shares closed at $3.34 on Friday.
There are up to 20,000 patients in the U.S. with ALS/motor neuron disease and 55% of ALS patients with pain attributed that pain to muscle cramps. Cramps are of sufficient severity to cause 57% of ALS patients to seek treatments directed at limiting cramps.
In addition, increased pain and decreased mobility negatively impact quality of life in ALS patients and are typically associated with increased depression.
CMT is a hereditary neurological disease that affects the peripheral motor and sensory nerves motor of the body. Motor nerves control muscle contractions, movement and other activities involving muscles, such as speaking, breathing and swallowing. Symptoms include muscle weakness, abnormal gait and foot deformities. CMT affects about one in 2,500 people in the U.S., approximately 150,000 patients.
In CMT, about 70% of patients report cramping. As in ALS, the presence of muscle cramps in CMT patients is consistent with the hypothesis that motor neuron dysfunction and hyperexcitability underlie muscle cramps, which are a function of the underlying disorder.
Mr. McVicar says FLX-787 is an orally disintegrating tablet designed to stimulate nerves in the mouth and throat. “Selective chemical stimulation of the vagal, glossopharyngeal, and facial nerves, resets descending inhibition via the spinal cord.”
In addition, he points out that electrical stimulation of the vagal nerve is FDA approved for treatment-resistant epilepsy, treatment-resistant depression and, earlier in 2017, for cluster headaches.
The company’s early human testing of FLX-787 demonstrated that co-activation of the TRPA1 and TRPV1 ion channels reduced the intensity of muscle cramping, with an onset of action in 15 minutes and a duration of action of up to eight hours.
More than 200 individuals have been tested with FLX-787 and/or its natural extracts for safety and anti-cramping activity. Initial pharmacokinetic data detected no drug in the blood stream. In addition, there have been no drug-related severe adverse events with the drug.
In 2016, Flex initiated a Phase 2 efficacy study in MS patients in Australia. The crossover study is designed to evaluate the safety and efficacy of FLX-787 in approximately 60 patients who suffer from cramps, spasms and/or spasticity as a consequence of MS. Data should be available in the first quarter of 2018.
In the third quarter next year, Flex expects to report data from ongoing parallel Phase 2 studies in ALS and CMT. Some 100 subjects in each study are receiving either 30mg of FLX-787 three times daily or a control.
ALS and CMT patients are being evaluated for changes in cramp frequency as the primary endpoint, with a number of secondary endpoints, such as pain and quality of life. FLX-787 has received fast track designation from the FDA for the treatment of severe muscle cramps associated with ALS.
In addition to its clinical programs, Flex Pharma has developed a consumer product for exercise-associated muscle cramps based on the same mechanism of action as FLX-787. The beverage, called HOTSHOT, is a proprietary blend of capsicum, cinnamon and ginger extracts dissolved in a lime juice-flavored base.