Gilead Announces New Letairis (Ambrisentan) Data for the Treatment of Patients With Pulmonary Arterial Hypertension (WHO Group 1) With WHO Functional Class II or III SymptomsTORONTO--(BUSINESS WIRE)--May 20, 2008 - Gilead Sciences, Inc. (Nasdaq:GILD) today announced results of a post-hoc analysis of data collected during the ARIES-1, ARIES-2 and ARIES-E studies for Letairis(R) in pulmonary arterial hypertension (PAH) (WHO Group 1) patients with primarily WHO functional class II or III symptoms. This analysis compared one-year clinical outcomes for PAH (WHO Group 1) patients who initially received placebo during the 12-week, placebo-controlled ARIES-1 and ARIES-2 studies before receiving ambrisentan during a long-term, open-label extension study (ARIES-E) to patients receiving continuous ambrisentan treatment throughout the ARIES studies. Data from this analysis were presented by Vallerie McLaughlin, MD, Associate Professor of Medicine, Director, Pulmonary Hypertension Program at the University of Michigan Health System, at ATS 2008 -- Toronto, the International Conference of the American Thoracic Society, taking place May 16-21. 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.
ARIES-1 and ARIES-2 were concurrent, double-blind, placebo-controlled studies evaluating ambrisentan in PAH patients. The studies primarily enrolled PAH patients with WHO functional class II or III 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 receive placebo or ambrisentan orally once daily for 12 weeks. The primary endpoint for each study was change in six-minute walk distance (6MWD) from baseline to week 12. Following 12 weeks of treatment, patients continued treatment with ambrisentan (ABS/ABS group, n=261) or crossed over from treatment with placebo to ambrisentan (PLB/ABS group, n=132) in ARIES-E.
In this analysis, one-year (48 weeks) clinical outcomes were examined for patients in the ABS/ABS and the PLB/ABS groups.
Baseline for all patients was defined as the time of randomization in ARIES-1 or ARIES-2. Clinical efficacy measures assessed in this analysis included 6MWD and time to clinical worsening. 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 early escape criteria. A Kaplan-Meier analysis was used to evaluate time to clinical worsening and includes all patients from the time of randomization.
Baseline characteristics were comparable between the ABS/ABS and PLB/ABS groups. As previously reported, the change from baseline 6MWD at week 12 in the ambrisentan group was +42 meters (95 percent CI: 34 to 51) compared to +3 meters in the placebo group (95 percent CI: -10 to 16). At week 12 of treatment, 96 percent of patients in the ambrisentan group (95 percent CI: 93 percent to 98 percent) were event-free, compared to 86 percent of patients in the placebo group (95 percent CI: 80 percent to 92 percent).
At week 48, 6MWD in the ABS/ABS group was +47 meters (95 percent CI: 35 to 59) compared to 33 meters in the PLB/ABS group (95 percent CI: 16 to 50). Following the addition of ambrisentan to the placebo group after week 12, the rate of clinical worsening decreased for the PLB/ABS group. At one year of treatment, the probability of no clinical worsening was 84 percent in the ABS/ABS group (95 percent CI: 80 percent to 89 percent) compared to 76 percent in the PLB/ABS group (95 percent CI: 68 percent to 83 percent).
"Despite the availability of multiple therapies, PAH is often not diagnosed in a timely manner, largely because classic PAH symptoms such as shortness of breath and chest pain can be attributed to more common medical conditions," said Dr. McLaughlin. "This data analysis suggests that delay of initiation of an effective therapy like ambrisentan may result in a decreased long-term improvement in exercise capacity and an increased risk of disease progression for patients with PAH, highlighting the importance of early diagnosis and treatment."
During the first 12 weeks of treatment, three (2.3 percent) placebo patients had liver aminotransferases (ALT or AST) elevations greater than three times the upper limit of normal (ULN) compared to zero patients in the ambrisentan group. After one year of treatment, a total of four (3.0 percent) PLB/ABS patients and four (1.5 percent) ABS/ABS patients had aminotransferase abnormalities greater than three times ULN. Peripheral edema and headache occurred in greater than or equal to 10 percent of patients in both the ambrisentan and placebo groups during the first 12 weeks. By week 48, the adverse events occurring in greater than or equal to 10 percent of patients in both the ABS/ABS and PLB/ABS groups were peripheral edema, headache, dizziness, dyspnea exacerbated, upper respiratory tract infection and arthralgia. In addition, cough, nasal congestion and palpitations occurred in greater than or equal to 10 percent of patients in the ABS/ABS group. Nausea was observed in greater than or equal to 10 percent of patients in the PLB/ABS group. Right ventricular failure was observed in greater than or equal to 10 percent of patients at week 12 in the placebo group and at week 48 in the PLB/ABS group.
Data from this analysis comparing the PLB/ABS and ABS/ABS groups during open-label follow-up treatment at 48 weeks have not been reviewed by the U.S. Food and Drug Administration.
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.
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.
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.
Gilead Sciences, Inc.
Patrick Oâ??Brien, 650-522-1936 (Investors)
Nathan Kaiser, 650-522-1853 (Media)
Posted: May 2008