Pharmacodynamic Study of CK-2017357 in Patients With Generalized Myasthenia Gravis

This study is a Phase II, double-blind, randomized, three-way crossover, placebo-controlled,
PD study of CK-2017357 in patients with generalized MG on standard therapy. 36 to 78 patients
will be randomized at approximately 15 study centers to one of six different treatment
sequences. Each treatment sequence consists of three dosing periods in which patients receive
single oral doses of placebo, 250 mg, and 500 mg of CK-2017357. All six treatment sequences
will enroll 6 patients. A wash out period of at least 7 days (to a maximum of 10 days) will
be employed between the individual doses for each patient. This study is designed to assess
the effects of CK-2017357 on measures of muscle strength, muscle fatigue and pulmonary
function utilizing the standardized Quantitative MG (QMG) score and Manual Muscle Test (MMT).
The pharmacokinetic (PK) and pharmacodynamic (PD) relationship of CK-2017357 after two single
doses will be assessed versus placebo, and the CK-2017357 concentration versus time data
obtained in this study may be used to develop a population PK model to estimate intra- and
inter-patient variability of PK parameters in patients with MG.

Patients who meet the following criteria may be included in the study:

1. Ability to comprehend and willing to sign an Informed Consent Form (ICF)

2. Ability to understand written and oral English language

3. Males and females between 18 and 80 years of age, inclusive

4. Patient's signs and symptoms not better explained by another disease process

5. Established diagnosis of MG defined as clinical evidence of muscle weakness and
positive AChR-binding antibody titer (>0.02 nmol/L)

6. Myasthenia Gravis Foundation of America (MGFA) clinical classification II or III

7. Stable MG disease for 4 weeks prior to randomization

8. Ability to refrain from IVIg treatments during the course of the study

9. Ability to refrain from cholinesterase-inhibitors (e.g. pyridostigmine) for 12 hours
before each dose

10. Ability to perform all elements of the QMG

11. Grade of 2 or 3 in two or more of the following muscle groups as measured by QMG:
right or left arm flexion, head lift, and right or left leg raise at 45° Note:
Patients may re-screen if they fail due to inadequate weakness from taking
pyridostigmine within 12 hours of screening

12. Body mass index (BMI) of 18.0 to 36.0 kg/m2, inclusive

13. Pre-study clinical laboratory findings (including troponin I [TnI] and creatine
phosphokinase [CPK]) within the normal range, or if outside of the normal range,
deemed not clinically significant by the Investigator

14. For female patients only: Agreement

- to use a double barrier during sexual intercourse (1 hormonal, plus 1 barrier
method, or 2 simultaneous barrier methods) birth control (birth control pills,
male condom, female condom, intrauterine device, Norplant, tubal ligation, or
other sterilization procedures)

15. For male patients only: Agreement either

- to use a condom during sexual intercourse with female partners who are of
reproductive potential and to have female partners use an additional effective
means of contraception (e.g., diaphragm plus spermicide, or oral contraceptives)
for the duration of the study and 10 weeks after the end of the study or b. to
abstain from sexual intercourse for the duration of the study and 10 weeks after
the end of the study

The following criteria exclude potential patients from the study:

1. History of chronic degenerative, psychiatric, or neurologic disorder other than MG
that can produce weakness or fatigue

2. Other major chronic or debilitating illnesses within six months prior to study entry

3. Hepatic insufficiency (defined as ALT or AST > 3x ULN, or total bilirubin > 3 mg/dL)

4. Renal insufficiency (defined as serum creatinine > 2.5 mg/dL or receiving dialysis)

5. Other myasthenic syndromes (e.g. Lambert Eaton syndrome; inherited myasthenic
syndrome)

6. Female patients who are premenopausal and are: (a) pregnant on the basis of a serum
pregnancy test, (b) breast-feeding, or (c) not using an effective method of double
barrier (1 hormonal plus 1 barrier method or 2 simultaneous barrier methods) birth
control (birth control pills, male condom, female condom, intrauterine device,
Norplant, tubal ligation, or other sterilization procedures)

7. Receipt of IVIg or plasmapheresis treatment within 6 weeks prior to the first dose of
study drug

8. Changes to immunosuppressive treatments (i.e., prednisone) within 6 weeks prior to the
first dose of study drug

9. Rituxan treatment within 3 months prior to study entry

10. Participation in any other investigational study drug or device trial in which receipt
of an investigational study drug or device occurred within 30 days prior to dosing

11. Any prior treatment with CK-2017357

12. Recent history of alcoholism or drug abuse, or significant behavioral or psychiatric
problems, or other conditions which in the Investigator's opinion may impair ability
to adequately comply with the requirements of the study