Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy

This study is designed as a proof of concept of MEK162 in NS HCM patients. The purpose of
the present study is to determine whether the ability of MEK162 to antagonize MEK activation
in NS HCM patients, who usually have upstream mutations in the Ras-Raf-Mek-Erk pathway that
lead to MEK activation, would be beneficial over a 6 month treatment period by causing
hypertrophy regression. Such regression might result in cardiovascular clinical benefits
with longer term treatment.

The information gained from this study will be three fold:

1. the safety/tolerability of treatment with MEK162 over 6 month in the NS HCM patient
population

2. the pharmacokinetics and pharmacodynamics of MEK162 in the target patient population

3. proof of the therapeutic concept that MEK inhibition will reduce cardiac hypertrophy in
the target NS HCM patient population

Inclusion:

- Male and female Noonan syndrome patients with confirmed cardiac hypertrophy, age 18
to 65 years of age included, and in general good health as determined by past medical
history, physical examination, vital signs, electrocardiogram, and laboratory tests
at screening.

- Cardiac hypertrophy is defined by left ventricular wall thickness greater than or
equal to 12 mm by echocardiography or MRI, or the change in wall thickness is
accompanied by an associated increase in left ventricular mass which is defined by
echo or MRI as greater than 134 g/m2 and 110 g/m2 in men and women, respectively.

- Subjects must weigh at least 45 kg to participate in the study, and must have a body
mass index (BMI) within the range of 18 - 34 kg/m2.

Exclusion criteria:

- Primary Long QT syndrome or a history of significant ECG abnormalities judged by the
investigators to be inappropriate for participation in the current study.

- History of malignancy of any organ system (other than localized basal cell carcinoma
of the skin), treated or untreated, within the past 5 years, regardless of whether
there is evidence of local recurrence or metastases.

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant.

- Sexually active males must use a condom during intercourse while taking the drug
during treatment, for 5 half lives after stopping treatment and should not father a
child in this period.

- Use of any prescription drugs other than beta-blockers, diuretics, CCB, amiodarone,
disopyramide, herbal supplements, within four (4) weeks prior to initial dosing,
and/or over-the-counter (OTC) medication, dietary supplements (vitamins included)
within two (2) weeks prior to initial dosing. If needed, (i.e. an incidental and
limited need) paracetamol or acetaminophen is acceptable, but must be documented in
the Concomitant medications/Significant non-drug therapies page of the eCRF.

Other protocol-defined inclusion/exclusion criteria may apply.