October 28, 2008
Gilead Announces Two-Year Clinical Data for Letairis(R) (Ambrisentan) for the Treatment of Pulmonary Arterial Hypertension (WHO Group 1)
Gilead Sciences, Inc. (Nasdaq:GILD) today announced results of a two-year (104-week), open-label, uncontrolled, extension study (ARIES-E) of Letairis(R) in patients with pulmonary arterial hypertension (PAH) (WHO Group 1). Data from this study were presented today at CHEST 2008, the annual meeting of the American College of Chest Physicians, taking place in Philadelphia, October 25-30. Letairis (ambrisentan 5 mg and 10 mg tablets) is indicated 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.
This pre-specified analysis was designed to evaluate long-term safety and efficacy in patients with PAH who received ambrisentan (2.5, 5 or 10 mg once-daily) in one of the 12-week Phase III placebo-controlled studies (ARIES-1 or ARIES-2) or during the subsequent open-label extension study (ARIES-E). In an oral session, safety and efficacy data were presented for patients taking ambrisentan for up to two years, including results describing improvements from baseline in six-minute walk distance (6MWD) at two years.
The ARIES-E study included 383 patients with idiopathic PAH (IPAH) or PAH associated with connective tissue disease (PAH-CTD), HIV infection or anorexigen use. Long-term safety was the primary endpoint of ARIES-E and safety and efficacy assessments were analyzed from the time of first dose of ambrisentan. Patients who received ambrisentan in ARIES-1 or ARIES-2 were enrolled into ARIES-E at their originally randomized dose. Patients who received placebo during previous studies were randomized to ambrisentan (ARIES-1: 5 or 10 mg; ARIES-2: 2.5 or 5 mg) in ARIES-E. Patients entered into ARIES-E and at two years, 261 randomized patients remained on ambrisentan, 22 had transitioned to commercial Letairis therapy (ambrisentan exposure prior to transition ranged from 75-102 weeks), and 100 discontinued due to death, adverse events or other reasons. At two years, 82 percent (n=215) of the 261 patients were on ambrisentan monotherapy.
At baseline, approximately 89 percent of patients were classified as having WHO functional class II or III symptoms and the mean baseline 6MWD for patients was 347+/-85 m. The mean baseline Borg dyspnea index score (BDI), a measure of breathing ability, was 3.9+/-2.4. Patients receiving the FDA-approved 5 and 10 mg ambrisentan doses experienced mean improvements from baseline in 6MWD of 34.6 m (95 percent CI: 23.6 m to 45.7 m) and 37.5 m (95 percent CI: 25.4 m to 49.6 m), respectively, at 12 weeks and mean improvements of 23.2 m (95 percent CI: 8.7 m to 37.8 m) and 28.0 m (95 percent CI: 10.9 m to 45.1 m), respectively, at two years. The 95 percent confidence intervals for mean change from baseline in 6MWD remained above zero for both the 5 and 10 mg doses at all points during the study period, indicating that a mean improvement from baseline in 6MWD was observed through two years of treatment.
The probability of no clinical worsening at two years was 72 percent (95 percent CI: 67-76 percent). Clinical worsening was defined as death, lung transplantation, PAH hospitalization, atrial septostomy, addition of prostanoid therapy or study withdrawal due to addition of other PAH drugs. In addition, 88 percent of patients receiving ambrisentan were still alive at two years, as assessed by Kaplan-Meier estimates (95 percent CI: 83-91 percent). As study ARIES-E is uncontrolled, these findings do not allow for comparison with a group not given ambrisentan and cannot be used to definitively determine the long-term effect of ambrisentan on survival.
During the initial 12-week ARIES-1 and ARIES-2 studies, none of the 261 patients on ambrisentan experienced liver enzyme (aminotransferase) elevations greater than three times the upper limit of normal (ULN) compared to 2.3 percent of patients on placebo. 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. At two years in ARIES-E, Kaplan-Meier analyses estimated the probability of experiencing aminotransferase elevations greater than three times ULN to be 4.2 percent. A total of three patients taking ambrisentan had aminotransferase elevations greater than five times ULN during the two-year treatment period, two of whom discontinued treatment. One patient discontinued ambrisentan due to aminotransferase elevations greater than three times ULN.
The two-year safety profile of ambrisentan was similar in nature to that reported in the previous 12-week placebo-controlled studies. The most frequent adverse events in patients receiving ambrisentan were peripheral edema, headache, upper respiratory tract infection and dizziness. Most reports of peripheral edema were reported to be mild or moderate, with one case leading to study discontinuation.
Additional Data Presented at CHEST
Three additional ambrisentan data sets are being presented for the first time at CHEST. These include data presented during an oral session today from a post-hoc analysis evaluating clinical outcomes of patients who experienced edema during the ARIES-1 and ARIES-2 studies. On Wednesday, October 29, two additional abstracts will be presented during a poster session, including an analysis from the ARIES-3 study evaluating ambrisentan use in a subpopulation of patients with pulmonary hypertension who had previously discontinued bosentan or sitaxsentan due to liver function abnormalities. A study evaluating pharmacokinetic interactions between ambrisentan and tadalafil also will be presented.
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.
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.
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 the safety and efficacy data obtained through 104 weeks of the ARIES-E study will not be observed in other studies or in clinical practice. 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, 2007 and its Quarterly Report on Form 10-Q for the second quarter of 2008, 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.