Mexiletine in Sporadic Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily motor
neurons, for which treatment designed to slow or arrest progression remains lacking.
Mexiletine is a use-dependent sodium channel blocker that has been FDA-approved for decades
for the treatment of cardiac arrhythmias and more recently to treat neuropathic pain in
diabetic polyneuropathy. Mexiletine has been shown also to be protective of neurons following
spinal cord, head injury, and cerebral ischemia, largely by blocking excitotoxicity. Based on
previous studies, mexiletine appears to penetrate into the central nervous system at
concentrations sufficient to confer significant protection. Recent unpublished studies in the
laboratory of Dr. Robert Brown at the University of Massachusetts have also demonstrated that
mexiletine ingestion in mice genetically engineered to express high levels of mutant
cytosolic copper-zinc superoxide dismutase-1 (SOD1) transgene prolongs survival in these
animals. As mexiletine already has FDA-approval as an anti-arrhythmic agent, much is known
about the pharmacology and safety of this drug in non-ALS patients. We anticipate that by
excluding subjects with a known history of cardiac disease and with the known neuroprotectant
properties of this medication, mexiletine is a good choice for further study in an ALS
clinical trial.

Inclusion Criteria:

1. Sporadic ALS diagnosed as possible, laboratory-supported probable, probable, or
definite ALS as defined by revised El Escorial criteria.

2. Age 18 years or older.

3. Symptom onset of weakness or spasticity due to ALS ≤ 60 months prior to Screening
Visit.

4. Slow vital capacity (SVC) measure ≥50% of predicted for gender, height, and age at the
screening visit.

5. Must be able to swallow capsules throughout the course of the study, according to Site
Investigator judgment.

6. Capable of providing informed consent and following trial procedures.

7. For TMS: a resting motor threshold defined as 50% of pulses eliciting a motor evoked
potential (MEP) of amplitude ≥ 50 µV.

8. For TTNCS: median Compound Muscle Action Potential (CMAP) ≥ 1.5 mV.

9. Subjects must not have taken riluzole for at least 30 days or be on a stable dose of
riluzole for at least 30 days prior to the Screening Visit and continue on the stable
dose throughout the course of the study (riluzole-naïve subjects are permitted in the
study).

10. Subjects must not have taken medication for muscle cramping such as cyclobenzaprine,
baclofen, carisoprodol, or methocarbamol, for at least 30 days prior to screening or
be on a stable dose for at least 60 days prior to screening.

11. Geographic accessibility to the site.

12. Women must not become pregnant for the duration of the study and must be willing to
use two contraceptive therapies and have a negative pregnancy test throughout the
course of the study.

13. Use of medications known to affect the neurophysiology measures in the study must be
scheduled, not as needed (pro re nata, PRN). A subject must have been on a fixed dose
for 30 days prior to the Screening Visit, and there must be no reason to believe that
a subsequent change would be necessary during the course of the study. These
medications include: benzodiazepines, muscle relaxants, tricyclic antidepressants,
selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors,
hypnotics (including anti-histamines) and anti-cholinergics.

Exclusion Criteria:

1. Invasive ventilator dependence, such as tracheostomy.

2. Creatinine level greater than 1.5 mg/dL at screening.

3. Serum Glutamic-Oxaloacetic (SGOT/AST) / Serum Glutamic-Pyruvic (SGPT/ALT) greater than
3 times the upper limit of normal at screening.

4. History of known sensitivity or intolerability to mexiletine or lidocaine.

5. Any history of either substance abuse within the past year, unstable psychiatric
disease, cognitive impairment, or dementia.

6. Clinically significant conduction abnormalities on electrocardiogram or a known
history of cardiac arrhythmia.

7. Known history of epilepsy.

8. Known history of congestive heart failure (CHF) or history of myocardial infarction
within the past 24 months.

9. Use of mexiletine for 30 days prior to Screening Visit.

10. Exposure to any other experimental agent (off-label use or investigational) including
high dose creatine (>10 grams a day) within 30 days prior to Screening Visit.

11. Metal in the head and neck region, cardiac pacemaker or brain stimulator, cochlear
implants, implanted infusion device or personal history of epilepsy.

12. Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine.

13. Pregnant women or women currently breastfeeding.

14. Placement of Diaphragm Pacing System (DPS) device < 60 days prior to Screening Visit.

15. Planned DPS device implantation during study participation