Ranolazine Mediated PVC Reduction in Ischemic Heart Disease

Ischemic heart disease is a heterogeneous condition with multiple etiologies that may
contribute to an imbalance in myocardial oxygen supply and demand, resulting in depletion of
myocardial cellular energy stores. Management of this disease state is aimed primarily at
improving myocardial oxygen supply through revascularization of underlying obstructive
atherosclerosis, in conjunction with interventions to reduce myocardial oxygen demand.
Chronic treatment is directed at reducing recurrent ischemic symptoms. Despite advances in
anti-thrombotic therapy, coronary revascularization, and other preventive therapies, the
risk of recurrent events in this population remains substantial, in particular among those
patients with indicators of higher risk (e.g. ST-segment depression, or arrhythmias).

Ranolazine is a piperazine derivative that exerts anti-ischemic actions without a clinically
significant effect on heart rate or blood pressure. At clinically relevant concentrations,
ranolazine is an inhibitor of the slowly inactivating component of the cardiac sodium
current (late INa), which may reduce the deleterious effects associated with the
intracellular sodium and calcium overload that accompany and may promote myocardial
ischemia. Ranolazine is available as an anti-anginal agent for patients with chronic angina.
The Metabolic Efficiency With Ranolazine for Less Ischemia in Non−ST-Elevation Acute
Coronary Syndromes (MERLIN)-TIMI 36 trial demonstrated the safety of ranolazine in patients
after ACS and also showed it's anti-arrhythmic properties. In addition to the safety
properties of ranolazine, the study showed that ranolazine had a significant anti-ischemic
effect and patient's on therapeutic dosing.

In an analysis of the 6560 patients in MERLIN-TIMI 36, using a digital continuous
electrocardiographic Holter monitor for ischemia (Lifecard CF, Delmar Reynolds was applied
to patients at the time of randomization and remained in place for 7 days, including after
hospital discharge). Findings showed that patients treated with ranolazine had significantly
lower incidences of arrhythmias. Specifically, fewer patients had an episode of ventricular
tachycardia lasting ≥8 beats, supraventricular tachycardia or new-onset atrial fibrillation.
In addition, pauses ≥3 seconds were less frequent with ranolazine. Based on this report,
further studies of the antiarrhythmic effects of ranolazine were warranted.

Premature ventricular complexes (PVCs) are a frequent occurrence in the presence of ischemic
heart disease. A very high PVC burden can be symptomatic or occasionally result in a
cardiomyopathy. The mechanism by which PVCs cause cardiomyopathies or symptoms is not well
understood, but may be related to an increase in myocardial strain or demand. Reduction in
PVC burden has been associated with both improvement in ejection fraction and symptoms.
Ranolazine has also been shown to reduce PVC burden in patients already on optimal medical
therapy. The estimate of the minimal number of PVCs required to be associated with a
cardiomyopathy is around 10%. In fact, subjects that had evidence for PVCs on baseline 12
lead electrocardiogram were found to have a significantly higher risk of cardiovascular
events.

Current strategies for managing complex cardiomyopathies driven by arrhythmias have been
complicated by intolerance to medical therapy as well as the requirement for frequent
titration and the development of tolerance. Patients with ischemic heart disease have
limited options for antiarrhythmic medical therapy. Prior trials of flecainide and eicainide
in patients with ischemic heart disease for control of ventricular arrhythmias resulted in a
significant and deleterious proarrhythmic effect current options for management line on
amiodarone which has significant liver, thyroid, and lung toxicities or sotalol which can
have significant bronchospastic effects as well as QT prolongation or tedious and which has
to be carefully dose in the setting of renal insufficiency to avoid significant QT
prolongation and the risk for proarrhythmia.

While ICD therapy has been appropriate for patients with reduced ejection fraction and
evidence for unstable ventricular arrhythmias/sudden cardiac death, frequent or low level
ventricular arrhythmias such as nonsustained VT or frequent PVCs would not be treated by ICD
therapy. Escalation of traditional nodal therapies such as beta blockers or calcium channel
blockers is his often limited by marginal systolic blood pressures and/or symptoms.

With the increasing prevalence of ischemic heart disease, it is critically important to
identify therapies that have a neutral response to heart rate and blood pressure, good
safety profile, and can reduce ischemia and the burden ventricular arrhythmias. Ultimately,
the hope is that they will reduce strain induced ischemic heart changes. To that end,
investigation of the effects of ranolazine in patients with ischemic heart disease and an
elevated burden of PVCs is of great interest.

Inclusion Criteria:

- Males and females aged 18 years and older

- Have the ability to understand and sign a written informed consent form, which must
be obtained prior to initiation of study procedures

- History of ischemic heart disease (prior bypass or coronary stenting, documentation
on cardiac catheterization, nuclear SPECT imaging, cardiac MR, stress
echocardiography, or exercise stress testing). Subjects are not required to have
chronic angina to be enrolled in the study

- Elevated PVC burden (1%) on prior Holter/event monitor in previous 12 months or
evidence for PVC(s) on baseline ECG within prior 12 months.

- Sexually active females of childbearing potential must agree to utilize effective
methods of contraception during heterosexual intercourse throughout the treatment
period and for 14 days following discontinuation of the study medication

Exclusion Criteria:

- Hospitalization for hyperthyroidism, pericarditis, myocarditis, or pulmonary embolism
within 4 weeks prior to screening

- Implantation of ICD or permanent pacemaker within 1 month of screening

- New York Heart Association (NYHA) Class III and IV heart failure or NYHA Class II
heart failure with a recent decompensation requiring hospitalization or referral to a
specialized heart failure clinic within 4 weeks prior to Screening.

- Myocardial infarction, unstable angina, or coronary artery bypass graft (CABG)
surgery within three months prior to Screening or percutaneous coronary intervention
(PCI) within 4 weeks prior to Screening

- Clinically significant valvular disease in the opinion of the Investigator

- Stroke within 1 months prior to Screening

- History of serious ventricular arrhythmias (eg, sustained ventricular tachycardia,
ventricular fibrillation) within 4 weeks prior to Screening

- Family history of long QT syndrome

- QTc ≥ 500 msec (Bazett) at Screening ECG if in sinus rhythm (SR). If in AF, evidence
of QTc ≥ 500 msec (Bazett) within 4 weeks prior to Screening

- Prior heart transplant

- Cardiac ablation within 3 months prior to Screening, or planned ablation during the
course of the study

- Need for concomitant treatment during the trial, with drugs or products that are
strong inhibitors of CYP3A, or inducers of CYP3A. Such medications should be
discontinued 5-half- lives prior to the Run-in period

- Use of grapefruit juice or Seville orange juice during the study

- Use of drugs that prolong the QT interval

- Previous use of ranolazine within 2 months prior to screening

- Prior use of ranolazine which was discontinued for safety or tolerability

- Use of dabigatran during the study

- Use of a greater than 1000 mg total daily dose of metformin during the study

- Hypokalemia (serum potassium < 3.5 mEq/L) at Screening that cannot be corrected to a
level of potassium ≥ 3.5 mEq/L prior to randomization

- Moderate and severe hepatic impairment (ie, Child-Pugh Class B and C), abnormal liver
function test defined as ALT, AST, or bilirubin > 2 x ULN at Screening

- Severe renal impairment defined as creatinine clearance ≤ 30 mL/min at Screening

- Females who are pregnant or are breastfeeding

- Exclusion of patients with Contraindications to use of RANEXA, including patients on
CYP3A4 inducers/potent inhibitors, and patients with liver cirrhosis

- Exclusion of Patients with CrCl < 30 mL/min

- Limit dose of RANEXA to 500mg BID in patients on concurrent diltiazem/verapamil

- Limit concurrent simvastatin to 20 mg/day

- In the judgment of the Investigator, any clinically-significant ongoing medical
condition that might jeopardize the subject's safety or interfere with the study,
including participation in another clinical trial within the previous 30 days using a
therapeutic modality which could have potential residual effects that might confound
the results of this study

- Any technical issue (device related) which in the judgment of the investigator would
disrupt adequate data collection or interpretation