Data from Pivotal Phase III Studies of Gilead's Letairis (ambrisentan) for Pulmonary Arterial Hypertension (WHO Group 1) in Patients with WHO Functional Class II or III Symptoms Published in Circulation

FOSTER CITY, Calif.--(BUSINESS WIRE)--May 29, 2008--Gilead Sciences, Inc. (Nasdaq:GILD) today announced that data from the pivotal Phase III ARIES-1 and ARIES-2 studies of Letairis(R) were published in Circulation online before print. Letairis (ambrisentan 5 mg and 10 mg tablets) is indicated as a once-daily treatment for pulmonary arterial hypertension (PAH) (WHO Group 1) in patients with WHO functional class II or III symptoms to improve exercise capacity and delay clinical worsening.

"This publication highlights the efficacy and safety observed in pivotal studies of ambrisentan, a treatment option for people living with PAH," said Professor Nazzareno Galie, Professor of Cardiology and Head of the Pulmonary Hypertension Centre at the University of Bologna. "In the ARIES-1 and ARIES-2 studies, ambrisentan improved exercise capacity as measured by six-minute walk distance (6MWD)."

ARIES-1 and ARIES-2 were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients, respectively. Patients were included if they had PAH as defined according to current guidelines. This includes patients with idiopathic PAH (IPAH) or PAH associated with connective tissue disease (PAH-CTD), HIV infection or anorexigen use. The studies primarily enrolled PAH patients (WHO Group I) with WHO functional class II (38 percent) or III (55 percent) symptoms. These studies were identical in design except for the investigative sites and doses of ambrisentan evaluated (ARIES-1: 5 or 10 mg; ARIES-2: 2.5 or 5 mg). In each study, patients were randomized to placebo or ambrisentan orally once-daily for 12 weeks. The two studies were analyzed separately and a pre-specified analysis of the combined 5 mg and placebo groups was also conducted.

The primary endpoint for each study was change in 6MWD from baseline to week 12. Secondary endpoints included time to clinical worsening, change in WHO functional class, SF-36(R) Health Survey score (a patient-reported quality of life questionnaire) and Borg dyspnea score (a measure of breathlessness following exercise). Time to clinical worsening was defined as the time from randomization to the first occurrence of death, lung transplantation, hospitalization for PAH, arterial septostomy, study withdrawal due to the addition of other PAH therapeutics or study withdrawal due to two or more predefined early escape criteria. Early escape was defined as meeting two of the following criteria after a minimum of four weeks of treatment: a greater than 20 percent decrease in 6MWD, increase in WHO functional class, worsening right ventricular failure, progressing hepatic, or renal failure or systolic blood pressure less than 85 mmHg. All patients who completed the study and all placebo patients who discontinued the study due to early escape criteria were eligible to enter a long-term extension study (ARIES-E).

ARIES-1 patients were randomized to placebo (n=67), ambrisentan 5 mg (n=67) or ambrisentan 10 mg (n=68). ARIES-2 patients were randomized to placebo (n=65), ambrisentan 2.5 mg (n=64) or ambrisentan 5 mg (n=63). All of the randomized patients received at least one dose of study drug, except one patient in the 10 mg group who was not included in the analysis of safety or efficacy. Baseline characteristics were similar among all six treatment groups.

Study Results

ARIES-1 and ARIES-2 primarily studied PAH patients (WHO Group I) with WHO functional class II or III symptoms. The mean placebo-corrected increase in 6MWD at week 12 in ARIES-1 was +31 meters (95 percent CI, 3 to 59 meters; p=0.008) for ambrisentan 5 mg and +51 meters (95 percent CI, 27 to 76 meters; p less than 0.001) for ambrisentan 10 mg. The mean placebo-corrected increase in 6MWD at week 12 in ARIES-2 was +32 meters (95 percent CI, 2 to 63 meters; p=0.022) for ambrisentan 2.5 mg and +59 meters (95 percent CI, 30 to 89 meters; p less than 0.001) for ambrisentan 5 mg. There was a mean placebo-corrected improvement of +45 meters (95 percent CI, 24 to 65 meters; p less than 0.001) for the combined 5 mg group from both studies.

In ARIES-2, a statistically significant improvement in time to clinical worsening was observed for patients receiving ambrisentan compared to placebo (p less than 0.001) and similar results were observed for the 2.5 mg and 5 mg groups separately (p=0.005, p=0.008, respectively). An improvement in time to clinical worsening was also observed in ARIES-1 for patients receiving ambrisentan compared to placebo for the combined 5 and 10 mg group and for the 5 mg and 10 mg groups separately, but the difference was not statistically significant (p=0.307, p=0.292 and p=0.214, respectively). A statistically significant improvement in time to clinical worsening was observed for the combined 5 mg group compared to the combined placebo groups from both studies (p=0.005).

In ARIES-1 and ARIES-2, none of the 261 patients receiving ambrisentan developed serum aminotransferase (liver enzymes) concentrations greater than three times the upper limit of normal (ULN) compared to three patients (2.3 percent) in the placebo groups. In the Letairis full prescribing information, for all Letairis-treated patients (N=483), the 12-week incidence of aminotransferases greater than three times ULN was 0.8 percent.

In ARIES-1 and ARIES-2, mean values for alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and alkaline phosphate did not increase from baseline in the ambrisentan groups. Peripheral edema, headache and nasal congestion were more frequent in patients treated with ambrisentan compared to placebo, but only nasal congestion appeared to increase with ambrisentan dose in both studies.

Of the 361 patients who entered into ARIES-E, 43 discontinued prior to completing 48 weeks of treatment, including 14 who died. The 43 patients who discontinued had more severe disease at baseline, as evidenced by a lower 6MWD, a higher baseline Borg dyspnea score and a higher baseline WHO functional class. A total of 298 patients were treated with ambrisentan for at least 48 weeks as of November 30, 2006, including 18 patients who also received concomitant prostanoid or phosphodiesterase-5 inhibitor (PDE5i) therapy. The mean change from baseline in 6MWD for the 280 patients receiving ambrisentan monotherapy at week 48 (all doses combined) was +39 meters (95 percent CI; 29 to 49 meters).

Full prescribing information for Letairis is available at www.gilead.com and at 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 by the use of at least two reliable methods of contraception unless the patient is unable to become pregnant. 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.

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.

Caution should be used when Letairis is co-administered with cyclosporine A, as it may cause increased exposure to Letairis.

Caution should be used when Letairis is co-administered with strong CYP3A-inhibitors (e.g., ketoconazole) or CYP2C19-inhibitors (e.g., omeprazole).

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 or sildenafil have been observed.

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.

GlaxoSmithKline (GSK) holds rights to commercialize ambrisentan for PAH in territories outside of the United States. On April 25, 2008, GSK announced that the European Commission issued a marketing authorisation for ambrisentan, under the tradename Volibris(R), for the treatment of PAH in patients classified as WHO functional class II and III, to improve exercise capacity. GSK has stated that its first European launches of Volibris are planned in the summer of 2008.

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.

    Letairis is a registered trademark of Gilead Sciences, Inc.

    Volibris 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.


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

    SOURCE: Gilead Sciences, Inc.
 

Posted: May 2008

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