Gilead’s Ranexa® Reduces Angina Frequency in Study of Chronic Angina Patients With Type 2 Diabetes

  Gilead’s Ranexa® Reduces Angina Frequency in Study of Chronic Angina
  Patients With Type 2 Diabetes

   - Data Presented at Late-Breaking Clinical Trial Session at the American
             College of Cardiology’s Annual Scientific Session -

Business Wire

SAN FRANCISCO -- March 10, 2013

Gilead Sciences, Inc. (Nasdaq: GILD) today announced data from the Phase 4
TERISA (Type 2 Diabetes Evaluation of Ranolazine In Subjects With Chronic
Stable Angina) study, which demonstrated that the addition of ranolazine to
background antianginal therapy in chronic angina patients with type 2 diabetes
significantly reduced the frequency of weekly angina episodes compared to
placebo and background antianginal therapy. Results were presented today
during a Late-Breaking Clinical Trial session at the American College of
Cardiology’s 62^nd Annual Scientific Session (ACC.13) in San Francisco and
were published online ahead of print in the Journal of the American College of
Cardiology.

Ranexa^® (ranolazine) is indicated for the treatment of chronic angina. Ranexa
is not indicated for the treatment of diabetes and should not be considered a
treatment for diabetes.

Chronic angina, the most common symptom of coronary artery disease, can be a
debilitating heart condition. Angina typically manifests as recurrent pain or
tightness in the chest upon exertion or emotional stress. Patients with
diabetes have more extensive coronary artery disease and a propensity for
greater angina burden compared to patients without diabetes.

“Given the high prevalence of angina in patients with diabetes, there is a
need for effective therapeutic strategies in this difficult-to-treat
population,” said Mikhail Kosiborod, MD, Associate Professor of Medicine at
the University of Missouri, Kansas City, cardiologist at St. Luke’s Mid
America Heart Institute and lead author of the TERISA study. “Although the
safety and efficacy profile of ranolazine is well established, this is the
first study to prospectively evaluate the antianginal effectiveness of
ranolazine in patients with chronic angina and concurrent type 2 diabetes.”

Following a single-blind, four-week placebo run-in phase, 927 randomized
patients received ranolazine (twice-daily 500 mg up-titrated to twice-daily
1,000 mg on Day 8) (n=462) or matching placebo (n=465) in addition to
background antianginal therapy for eight weeks. Patients were asked to
document the number of angina episodes and sublingual (under the tongue)
nitroglycerin doses taken on a daily basis using an electronic diary.

During weeks 2-8, average weekly angina frequency was significantly lower with
ranolazine versus placebo (3.8 [3.6-4.1] versus 4.3 [4.0-4.5] episodes,
P=0.008), as was weekly sublingual nitroglycerin use (1.7 [1.6-1.9] versus 2.1
[1.9-2.3] doses, P=0.003).

The rate of serious adverse events and the rate of discontinuations due to
adverse events were similar between the ranolazine and placebo groups. Notable
non-serious adverse events included nausea, reported in 17 ranolazine and two
placebo patients; dizziness, reported in 17 ranolazine and six placebo
patients; and constipation, reported in eight ranolazine and two placebo
patients; see below for important safety information.

About the TERISA Study

TERISA was a randomized, double-blind, placebo-controlled, parallel study
designed to evaluate the efficacy of ranolazine in chronic stable angina
patients with concurrent type 2 diabetes who remain symptomatic for angina
despite receiving a stable dose of one or two concomitant antianginal agents,
including beta-blockers, calcium channel blockers or long-acting nitrates.

A total of 949 patients were randomized (1:1, 473 and 476 in the ranolazine
and placebo arms, respectively), 22 of whom either never initiated or
discontinued treatment during the first two weeks (11 in each treatment arm),
leaving 927 evaluable patients (462 and 465 in the ranolazine and placebo
arms, respectively). Their mean age was 64 and 61 percent were male. The
patients had a mean diabetes duration of 7.5 years and a mean baseline
hemoglobin A1c (HbA1c, a laboratory measure of blood glucose) level of 7.3
percent. At randomization, 56 percent of patients were receiving one
antianginal agent and 44 percent were receiving two antianginal agents.

The primary efficacy endpoint was average angina frequency during weeks 2-8,
with the effect of ranolazine treatment estimated as a ratio of ranolazine to
placebo frequency. During the four-week, single-blind, placebo run-in phase,
average weekly angina frequency was similar between the ranolazine and placebo
groups (6.6 [6.3-7.0] versus 6.8 [6.4-7.2]; ratio 0.98 [0.91-1.05]). During
weeks 2-8, weekly angina frequency was significantly lower in the ranolazine
group than in the placebo group (3.8 [3.6-4.1] versus 4.3 [4.0-4.5] episodes;
ratio 0.89 [0.82-0.97] P=0.008).

Similarly, at baseline, average weekly sublingual nitroglycerin use was
similar between treatment arms (4.1 [3.7-4.6] versus 4.5 [4.1-5.0]; ratio 0.92
[0.80-1.06]). During weeks 2-8, the average weekly number of sublingual
nitroglycerin doses was significantly lower in patients receiving ranolazine
compared to placebo (1.7 [1.6-1.9] versus 2.1 [1.9-2.3] doses; ratio 0.83
[0.73-0.94] P=0.003).

In prespecified subgroup analyses, the efficacy of ranolazine was consistent
irrespective of baseline average weekly angina episodes (<3 versus ≥3), number
of concomitant antianginal medications (one versus two), age (<65 versus ≥65)
and sex. There was, however, a significant difference in the effect of
ranolazine versus placebo on the primary endpoint by the geographic region of
enrollment (Russia, Ukraine and Belarus versus other countries;
P[interaction]=0.016): The average number of weekly angina episodes between
the ranolazine and placebo arms among patients enrolled in Russia, Ukraine and
Belarus was not statistically significantly different (4.1 [3.9-4.4] versus
4.3 [4.1-4.6]; ratio 0.95 [0.87-1.05] P=0.31). Among patients enrolled in
other countries, there was a significant reduction in average weekly angina
episodes in the ranolazine group versus placebo (3.1 [2.8-3.5] versus 4.1
[3.7-4.6]; ratio 0.77 [0.65-0.90] P=0.002).

Serious adverse events with onset during the treatment phase were reported in
16 of the 470 ranolazine patients and 20 of the 474 placebo patients who took
at least one dose. Five patients died during the treatment phase, including
three patients in the ranolazine group (two myocardial infarctions and one
sudden cardiac death) and two patients in the placebo group (one patient with
acute cardiac failure and one with pulmonary embolism). The discontinuation
rate due to adverse events was also comparable between both treatment groups
(nine and 11 in the ranolazine and placebo groups, respectively). Notable
non-serious adverse events included nausea, reported in 17 ranolazine and two
placebo patients; dizziness, reported in 17 ranolazine and six placebo
patients; and constipation, reported in eight ranolazine and two placebo
patients.

About Gilead’s Ranolazine Diabetes Program

TERISA is one of several Gilead studies evaluating the role of ranolazine in
patients with chronic angina and/or type 2 diabetes. Results of a Phase 2
study and post-hoc analyses of previous clinical trials with ranolazine
suggest that ranolazine may reduce HbA1c when added to antidiabetic therapy.
Gilead is now conducting three Phase 3 clinical trials in patients with type 2
diabetes, which will determine the effects of ranolazine on glycemic control
as monotherapy and in combination with other antidiabetic therapies. Top-line
results from these three trials are expected in late 2013.

Ranolazine is an investigational medication for type 2 diabetes and has not
been proven safe and efficacious for this indication.

About Ranexa

Ranexa is an extended-release tablet approved as a treatment for chronic
angina. Ranexa may be used in combination with beta-blockers, nitrates,
calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE
inhibitors and angiotensin receptor blockers. Ranexa was approved in the
United States in January 2006. In 2008, the U.S. Ranexa indication was updated
to include first-line treatment for chronic angina.

Ranexa at therapeutic levels can inhibit the cardiac late sodium current.
However, the mechanism of Ranexa’s antianginal effects has not been
determined. The relationship between the inhibition of the late sodium current
and angina symptoms is uncertain.

Important Safety Information

Contraindications

  *Ranexa is contraindicated in patients:

  *Taking strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole,
    clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and
    saquinavir)
  *Taking inducers of CYP3A (e.g., rifampin, rifabutin, rifapentin,
    phenobarbital, phenytoin, carbamazepine, and St John’s wort)
  *With liver cirrhosis

Warnings and precautions

  *Ranexa blocks lKr and prolongs the QTc interval in a dose-related manner.
  *Clinical experience did not show an increased risk of proarrhythmia or
    sudden death.
  *There is little experience with high doses (> 1000 mg twice daily) or
    exposure, with other QT-prolonging drugs, with potassium channel variants
    resulting in a long QT interval, in patients with a family history of (or
    congenital) long QT syndrome, or in patients with known acquired QT
    interval prolongation.

Adverse reactions

  *The most common adverse reactions (> 4% and more common than with placebo)
    during treatment with Ranexa were dizziness, headache, constipation, and
    nausea.

Dosage and administration

  *Begin treatment with 500 mg twice daily and increase to the maximum
    recommended dose of 1000 mg twice daily, based on clinical symptoms.
    Swallow tablets whole; do not crush, break, or chew.
  *Limit the dose of Ranexa to 500 mg twice daily in patients on moderate
    CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin, fluconazole,
    and grapefruit juice or grapefruit-containing products).

Drug interactions

  *Inducers and strong inhibitors of CYP3A: Do not use Ranexa (see
    Contraindications).
  *Moderate CYP3A inhibitors: Limit Ranexa to 500 mg twice daily (see Dosage
    and Administration).
  *P-gp inhibitors (e.g., cyclosporine): Ranexa exposure increased; titrate
    Ranexa based on clinical response.
  *CYP3A substrates: Limit simvastatin to 20 mg when used with Ranexa. Doses
    of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A
    substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus,
    sirolimus) may need to be reduced with Ranexa.
  *Drugs transported by P-gp (e.g., digoxin) or metabolized by CYP2D6 (e.g.,
    tricyclic antidepressants and antipsychotics): Doses of these drugs may
    need to be reduced.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and
commercializes innovative therapeutics in areas of unmet medical need. The
company’s mission is to advance the care of patients suffering from
life-threatening diseases worldwide. Headquartered in Foster City, California,
Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements, within the meaning of
the Private Securities Litigation Reform Act of 1995, that are subject to
risks, uncertainties and other factors, including risks related to the
possibility of unfavorable results from other clinical trials involving
ranolazine for the treatment of type 2 diabetes. In addition, Gilead may also
be unable to obtain Phase 3 clinical trial results from the studies in the
timelines currently anticipated and may need to modify or delay the clinical
trials or to perform additional trials. In addition, Gilead may make a
strategic decision to discontinue development of ranolazine for type 2
diabetes if, for example, Gilead believes commercialization will be difficult
relative to other opportunities in its pipeline. These risks, uncertainties
and other factors could cause actual results to differ materially from those
referred to in the forward-looking statements. The reader is cautioned not to
rely on these forward-looking statements. These and other risks are described
in detail in Gilead’s Annual Report on Form 10-K for the year ended December
31, 2012, as filed with the U.S. Securities and Exchange Commission. All
forward-looking statements are based on information currently available to
Gilead, and Gilead assumes no obligation to update any such forward-looking
statements.

U.S. full prescribing information for Ranexa^® is available at www.gilead.com.

For more information on Gilead Sciences, please visit the company’s website at
  www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead
             Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Contact:

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Nathan Kaiser, 650-522-1853 (Media)
 
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