Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year

Inclusion Criteria:

• A diagnosis of familial or sporadic ALS (defined as meeting the possible,laboratory-supported probable, probable, or definite criteria for a diagnosis of ALSaccording to the World Federation of Neurology El Escorial criteria) ≤ 24 months priorto screening

• Upright SVC ≥ 70 % of predicted for age, height and sex

• Able to swallow tablets without crushing, and in the opinion of the Investigator, isexpected to continue to be able to do so during the trial

• A caregiver if one is needed

• Clinical laboratory findings within the normal range or, if outside the normal range,deemed not clinically significant by the Investigator

• Male patients must agree for the duration of the study and 10 weeks after the end ofthe study to use a condom during sexual intercourse with female partners who are ofchildbearing potential (i.e., following menarche until post-menopausal if notanatomically and physiologically incapable of becoming pregnant) and to have femalepartners use an additional effective means of contraception (e.g., diaphragm plusspermicide, or oral contraceptives) or the male patient must agree to abstain fromsexual intercourse during and for 10 weeks after the end of the study, unless the malepatient has had a vasectomy and confirmed sperm count is zero

• Female patients must be post-menopausal (≥ 1 year) or sterilized, or, if ofchildbearing potential, not be breastfeeding, have a negative pregnancy test, have nointention to become pregnant during the course of the study, and use effectivecontraceptive drugs or devices while requiring male partner to use a condom for theduration of the study and for 10 weeks after the end of the study

• Patients must be either on a stable dose of riluzole 50 mg twice daily for at least 30days prior to screening or have not taken riluzole for at least 30 days prior toscreening and are willing not to begin riluzole use until they complete study drugdosing

Exclusion Criteria:

• At the time of screening, any use of non-invasive positive pressure ventilation (NIPPV, e.g. continuous positive airway pressure [CPAP] or bi-level positive airwaypressure [BiPAP]) for any portion of the day, or mechanical ventilation viatracheostomy, or on any form of oxygen supplementation

• Patients with a diaphragm pacing system (DPS) at study entry or who anticipate DPSplacement during the course of the study

• BMI of 20.0 kg/m2 or lower

• Unwilling or unable to discontinue tizanidine and theophylline-containing medicationsduring study participation

• Serum chloride outside the normal reference range

• Neurological impairment due to a condition other than ALS, including history oftransient ischemic attack within the past year

• Presence at screening of any medically significant cardiac, pulmonary, GI,musculoskeletal, or psychiatric illness that might interfere with the patient'sability to comply with study procedures or that might confound the interpretation ofclinical safety or efficacy data, including, but not limited to:

1. Poorly controlled hypertension

2. NYHA Class II or greater congestive heart failure

3. Chronic obstructive pulmonary disease or asthma requiring daily usebronchodilator medications

4. GI disorder that might impair absorption of study drug

5. History of significant liver disease defined by bilirubin > 2 times the upperlimit of normal (ULN) or ALT or AST > 3 times the ULN on repeat testing

6. Poorly controlled diabetes mellitus

7. History of vertigo within three months of study entry

8. History of syncope without an explainable or treated cause

9. History of untreated intracranial aneurysm or poorly controlled seizure disorder

10. Amputation of a limb

11. Cognitive impairment, related to ALS or otherwise, sufficient to impair thepatient's ability to give informed consent and to understand and/or comply withstudy procedures

12. Cancer with metastatic potential (other than basal cell carcinoma, carcinoma insitu of the cervix, or squamous cell carcinoma of the skin excised with cleanmargins) diagnosed and treated within the last two years

13. Any other condition, impairment or social circumstance that, in the opinion ofthe Investigator, would render the patient not suitable to participate in thestudy

14. Patient judged to be actively suicidal or a suicide risk by the Investigator

• Has taken any investigational study drug within 30 days or five half-lives of theprior agent, whichever is greater, prior to dosing

• Prior participation in any form of stem cell therapy for the treatment of ALS

• Previously received tirasemtiv in any previous clinical trial