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 -
SAN FRANCISCO--(BUSINESS WIRE)--
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 62nd 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
"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
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
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
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
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; Pinteraction=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
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.
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
Ranexa is contraindicated in patients:
Taking strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole,
clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and
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
Clinical experience did not show an increased risk of proarrhythmia or
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.
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).
- Inducers and strong inhibitors of CYP3A: Do not use Ranexa (see
- 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
- 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
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.
Source: Gilead Sciences, Inc.