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American Thoracic Society: Indacaterol

In another study conducted by Dr. Donahue, supratherapeu-tic doses of indacaterol (QAB 149, Novartis) among patients with mild-to-moderate COPD were associated with changes of only minimal concern. Indacaterol is entering into large-scale, 2,000-patient pivotal phase 3 trials in 300 sites, 200 of them in the U.S.

“Indacaterol is an interesting compound,” he stated. “It’s a new agent, not a formoterol derivative, and it’s an ultra-long-acting beta agonist with very fine efficacy for 24 hours. It’s similar to tiotropium [Spiriva, Boehringer Ingelheim/Pfizer], in that it’s long-acting and has comparable, if not better, efficacy in the short-duration, head-to-head studies conducted so far.”

Eighteen patients received single doses of indacaterol within the therapeutic range (400 mcg) via a dry-powder inhaler; after this, they received supratherapeutic doses at 1,000 mcg, 2,000 mcg, and 3,000 mcg. At the highest dose, the maximum mean decrease in fasting potassium (0.26 mmol/L), mean increase in fasting serum glucose (1.12 mmol/L), mean increase in heart rate (12 beats/minute), and mean decrease in the corrected QT interval (QTc) (7 milliseconds) were all considered to be within safe limits for a single dose. There were no clinically significant electrocardiographic abnormalities. Even in multiples of the therapeutic dose, Dr. Donahue said, indacaterol produced only mild-to-moderate changes in markers of systemic adrenergic stimulation in patients with COPD.

Ambrisentan (Letairis) for Pulmonary Arterial Hypertension

Presenter: Michael D. McGoon, MD, Professor of Medicine and Consultant in Cardiology, Mayo Clinic College of Medicine, Rochester, Minnesota

On June 15, 2007, after a priority review, the U.S. Food and Drug Administration (FDA) approved ambrisentan 5-mg and 10-mg tablets (Letairis, Gilead). This endothelin selective receptor antagonist is indicated for the once-daily treatment of pulmonary arterial hypertension (World Health Organization Group 1) in patients with WHO functional class 2 or 3 symptoms to improve exercise capacity and delay clinical worsening.

Because of the risks of liver injury and birth defects, the FDA required monthly monitoring of aminotransferases and urged that ambrisentan be discontinued under these circumstances: (1) if levels exceed more than five times the upper limit of normal (ULN), (2) if elevations are accompanied by bilirubin levels exceeding more than twice the ULN, or (3) if the patient had signs or symptoms of liver dysfunction.

The older endothelin receptor antagonists, bosentan (Tra-cleer, Actelion) and sitaxsentan (Thelin, Encysive), must also be monitored. On June 15th, 2007, the FDA concluded that the clinical development program for sitaxsentan did not demonstrate significant evidence of efficacy needed for approval; however, improvements in the six-minute walk test were noted. Encysive expects to file a request for formal dispute resolution with the FDA in the near term.

In a study of ambrisentan among patients who had discontinued bosentan or sitaxsentan because of abnormal serum aminotransferase levels, none of the patients discontinued ambrisentan therapy because of this abnormality.
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The median duration of endothelin receptor antagonist therapy with bosentan or sitaxsentan before a first therapy failure caused by liver function test abnormalities had been 16 weeks. With ambrisentan at doses of 2.5, 5, or 10 mg/day, he said, only one of 31 evaluable patients required a temporary reduction in the ambrisentan dose because of elevated alanine amino­transferase (ALT) levels at 3.2 times the ULN at week 12. Furthermore, liver abnormalities did not show a trend toward increasing over time; one-year rates were similar to 12-week rates.

Dr. McGoon concluded that patients who had not responded to bosentan or sitaxsentan because of liver function abnormalities could be successfully treated with ambrisentan.

Presenter: Ronald J. Oudiz, MD, Professor of Medicine, University of California, Los Angeles, School of Medicine, Torranc e, California

Dr. Oudiz presented the long-term results of an extension study (ARIES-E), a 12-week trial of ambrisentan 2.5-10 mg among 383 patients with pulmonary arterial hypertension who had been exposed to ambrisentan for a mean of 1.4 years. In that trial, aspartate transaminase (AST) and ALT levels were between three and five times the ULN in 2.1% of the patients, and no discontinuations of ambrisentan were required. In one patient (0.3% of the total) with AST/ALT elevations above eight times the ULN, multiple drug therapy had to be discontinued. Dr. Oudiz pointed out that 2.3% of placebo patients in ARIES 1 and 2 had AST and ALT values exceeding three times the ULN.

In the ARIES-E trial, patients receiving ambrisentan improved their six-minute walking distance; the time to clinical worsening; WHO functional class symptoms; Borg dyspnea scores; Self-Help Health Survey (SF-36) status; and B-type natriuretic peptide levels, which correlate significantly with mean pulmonary arterial pressure and pulmonary vascular resistan ce. tadalis sx

Ambrisentan is being made available through the Letairis Education and Access Program (LEAP), a restricted distribution system designed to help patients learn about the risks of the drug.

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