Gilead Sciences Announces Plans for Phase IV Clinical Trial Evaluating First-Line Combination Therapy Versus Monotherapy in Pulmonary Arterial Hypertension

FOSTER CITY, Calif.--(BUSINESS WIRE)--Nov. 2, 2009-- Gilead Sciences, Inc. (Nasdaq:GILD), in collaboration with GlaxoSmithKline (GSK), today announced plans for an international, event-driven (morbidity and mortality) clinical trial to study combination therapy versus monotherapy in a first-line treatment setting for pulmonary arterial hypertension (PAH). The study, AMBITION (a randomized, double-blind, multicenter study of first-line combination therapy with AMBrIsentan and Tadalafil in subjects with pulmonary arterial hypertensION), will evaluate first-line combination use with ambrisentan, an endothelin receptor antagonist (ERA) and tadalafil, a PDE5 inhibitor, in patients with PAH. Ambrisentan is approved under the tradename LetairisĀ® (ambrisentan 5 mg and 10 mg tablets) as a once-daily treatment for PAH (WHO Group 1) in patients with WHO functional class II or III symptoms to improve exercise capacity and delay clinical worsening.

“The question of first-line combination therapy versus monotherapy is one of the most important outstanding clinical questions in PAH,” said Lewis J. Rubin, MD, Professor of Medicine, University of California, San Diego. “As the first large, randomized clinical trial to address the efficacy of initial combination therapy in PAH, AMBITION has the potential to be a landmark study.”

AMBITION will be a double-blind, multicenter study, in which more than 300 treatment-naive PAH patients will be randomized to receive either the combination of ambrisentan and tadalafil or monotherapy (ambrisentan or tadalafil). Gilead and GSK are working with regulatory agencies and the PAH research community to finalize details of the study and plan to begin enrollment in 2010.

Full prescribing information for Letairis is available at www.gilead.com and at http://www.letairis.com/downloads/LETAIRIS_prescribing_information.pdf.

WARNING: POTENTIAL LIVER INJURY

Letairis can cause elevation of liver aminotransferases (ALT and AST) to at least three times the upper limit of normal (ULN). Letairis treatment was associated with aminotransferase elevations greater than three times ULN in 0.8 percent of patients in 12-week trials and 2.8 percent of patients including long-term open-label trials out to one year. One case of aminotransferase elevations greater than three times ULN has been accompanied by bilirubin elevations greater than two times ULN. Because these changes are a marker for potentially serious liver injury, serum aminotransferase levels (and bilirubin if aminotransferase levels are elevated) must be measured prior to initiation of treatment and then monthly.

Elevations in aminotransferases require close attention. Letairis should generally be avoided in patients with elevated aminotransferases greater than three times ULN at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin greater than two times ULN, treatment should be stopped. There is no experience with the re-introduction of Letairis in these circumstances.

CONTRAINDICATION: PREGNANCY

Letairis is very likely to produce serious birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals. Pregnancy must therefore be excluded before the initiation of treatment with Letairis and prevented thereafter and for one month after stopping treatment by the use of two acceptable methods of contraception unless the patient has had a tubal sterilization or chooses to use a Copper T 380A IUD or LNg 20 IUS, in which case no additional contraception is needed. Obtain monthly pregnancy tests.

About the Letairis Education and Access Program (LEAP)

Because of the risks of liver injury and birth defects, Letairis is available only through a special restricted distribution program called the Letairis Education and Access Program (LEAP) by calling 1-866-664-LEAP (1-866-664-5327). Only prescribers and pharmacies registered with LEAP are able to prescribe and distribute Letairis. In addition, Letairis may be dispensed only to patients who are enrolled in and meet all conditions of LEAP.

Important Safety Information

Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Letairis. These decreases were observed within the first few weeks of treatment with Letairis, and stabilized thereafter. Physicians should measure hemoglobin prior to initiation of Letairis, at one month, and periodically thereafter. Initiation of Letairis therapy is not recommended for patients with clinically significant anemia.

Peripheral edema is a known class effect of endothelin receptor antagonists and is also a clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with doses of 5 or 10 mg of Letairis compared to placebo. Most edema was mild to moderate in severity. Peripheral edema was similar in younger patients (age less than 65 years) receiving Letairis (14 percent; 29/205) or placebo (13 percent; 13/104), and was greater in elderly patients (age greater than or equal to 65 years) receiving Letairis (29 percent; 16/56) compared to placebo (4 percent, 1/28). The results of such subgroup analyses must be interpreted cautiously.

In addition, there have been post-marketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting Letairis. Patients required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure. Because the post-marketing experience was reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the relative frequency or establish a causal relationship to Letairis drug exposure.

Decreases in sperm count have been observed in patients taking endothelin receptor antagonists.

The most common adverse events that occurred at a higher frequency among Letairis-treated patients compared to placebo included (placebo-adjusted frequency): peripheral edema (6 percent), nasal congestion (4 percent), sinusitis (3 percent), flushing (3 percent), palpitations (3 percent), nasal pharyngitis (2 percent), abdominal pain (2 percent), constipation (2 percent), dyspnea (1 percent) and headache (1 percent).

No clinically relevant interactions of Letairis with warfarin, sildenafil, tadalafil, omeprazole (CYP2C19 inhibitor), ketoconazole (strong CYP3A-inhibitor), digoxin, ethinylestradiol or norethindrone have been observed.

Other potential interactions are not well characterized, but, based on in vitro data, interactions with P-glycoprotein (P-gp), the Organic Anion Transport Protein (OATP), and uridine 5′-diphosphate glucuronosyltransferases (UGTs) would be expected.

Letairis is not recommended in patients with moderate to severe hepatic impairment.

About Letairis

Letairis (ambrisentan) is an endothelin receptor antagonist that has a high affinity for the endothelin type-A (ETA) receptor. Activation of the ETA receptor by endothelin-1 (ET-1), a small peptide hormone, leads to vasoconstriction (narrowing of blood vessels) and cell proliferation. The clinical impact of high selectivity for ETA is not known. Endothelin concentrations are higher in the lung tissue of PAH patients, thus suggesting that ET-1 may play a critical role in the pathogenesis or progression of PAH.

About Pulmonary Arterial Hypertension (WHO Group 1)

PAH is a debilitating disease characterized by constriction of the blood vessels in the lungs leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from shortness of breath as the heart struggles to pump against these high pressures, causing such patients to ultimately die of heart failure. PAH can occur with no known underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection. PAH afflicts approximately 200,000 patients worldwide.

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 Australia.

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 the risks that Gilead and GSK may face challenges in the clinical trial protocol design and may be unable to enroll patients in the trial in 2010 as currently anticipated. In addition, the results from the clinical trial may be unfavorable, including showing no advantages from combination therapy resulting from use of ambrisentan with tadalafil. 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 Quarterly Report on Form 10-Q for the second quarter of 2009, 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.

Letairis is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Susan Hubbard, Investors, 650-522-5715
Nathan Kaiser, Media, 650-522-1853