Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (SALS)

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unpublished studies in the laboratory of Dr.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:

- Sporadic Amyotrophic Lateral Sclerosis (SALS) diagnosed as possible,
laboratory-supported probable, probable, or definite ALS as defined by revised El
Escorial criteria.

- Age 18 years or older.

- Disease duration ≤ 36 months from ALS symptom onset.

- Capable of providing informed consent and following trial procedures.

- Subjects must not have taken riluzole for at least 30 days or be on a 50 milligrams
twice daily dose of riluzole for at least 60 days prior to randomization
(riluzole-naïve subjects are permitted in the study).

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

- Geographic accessibility to the site.

- 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.

- Slow vital capacity (SVC) measure greater than or equal to 50% of predicted for
gender, height, and age at the screening visit.

- Subjects medically able to undergo lumbar puncture (LP) as determined by the
investigator (for example, no bleeding disorder, allergy to local anesthetics, a skin
infection at or near the LP site, or evidence of high intracranial pressure).

- Must be able to swallow capsules throughout the course of the study, according to
Principal Investigator (PI) judgment.

- Must have a caregiver assist with dispensing the study drug.

Exclusion Criteria:

- Invasive ventilator dependence, such as tracheostomy.

- Creatinine level greater than 1.5 milligram/deciliter.

- Serum glutamic oxaloacetic transaminase or (aspartate transaminase) / serum glutamic
pyruvic transaminase (alanine aminotransferase) greater than 3 times the upper limit
of normal at screening.

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

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

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

- Known history of epilepsy.

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

- Use of mexiletine for 60 days prior to Baseline Visit.

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

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

- Pregnant women or women currently breastfeeding.

- Placement of Diaphragm Pacing System (DPS) device less than 60 days prior to Baseline
Visit.

- Planned DPS device implantation after Baseline Visit.