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

CY 4031 is a multi-national, double-blind, randomized, placebo-controlled, stratified,
parallel group study in patients with ALS with the selective fast skeletal muscle troponin
activator, tirasemtiv. The study includes three phases; an open-label phase (2 weeks), a
double-blind, placebo-controlled phase (48 weeks), and a double-blind, placebo-controlled
tirasemtiv withdrawal phase (4 weeks). Patients who can complete two weeks of treatment with
open-label tirasemtiv (125 mg twice daily) will be randomized 3:2:2:2 to placebo and three
different dose levels of tirasemtiv. Approximately 600 patients will be enrolled onto
open-label treatment. Patients who enter the study on riluzole 50 mg twice daily will
continue on riluzole but at a reduced dose of 50 mg once daily.

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 ALS
according to the World Federation of Neurology El Escorial criteria) ≤ 24 months prior
to screening

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

- Able to swallow tablets without crushing, and in the opinion of the Investigator, is
expected 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 of
the study to use a condom during sexual intercourse with female partners who are of
childbearing potential (i.e., following menarche until post-menopausal if not
anatomically and physiologically incapable of becoming pregnant) and to have female
partners use an additional effective means of contraception (e.g., diaphragm plus
spermicide, or oral contraceptives) or the male patient must agree to abstain from
sexual intercourse during and for 10 weeks after the end of the study, unless the male
patient has had a vasectomy and confirmed sperm count is zero

- Female patients must be post-menopausal (≥ 1 year) or sterilized, or, if of
childbearing potential, not be breastfeeding, have a negative pregnancy test, have no
intention to become pregnant during the course of the study, and use effective
contraceptive drugs or devices while requiring male partner to use a condom for the
duration 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 30
days prior to screening or have not taken riluzole for at least 30 days prior to
screening and are willing not to begin riluzole use until they complete study drug
dosing

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 airway
pressure [BiPAP]) for any portion of the day, or mechanical ventilation via
tracheostomy, or on any form of oxygen supplementation

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

- BMI of 20.0 kg/m2 or lower

- Unwilling or unable to discontinue tizanidine and theophylline-containing medications
during study participation

- Serum chloride outside the normal reference range

- Neurological impairment due to a condition other than ALS, including history of
transient 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's
ability to comply with study procedures or that might confound the interpretation of
clinical 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 use
bronchodilator medications

4. GI disorder that might impair absorption of study drug

5. History of significant liver disease defined by bilirubin > 2 times the upper
limit 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 the
patient's ability to give informed consent and to understand and/or comply with
study procedures

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

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

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 the
prior 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