DMC determined that ambrisentan, an endothelin receptor agonist, did not show treatment benefit.

Gilead Sciences is halting its Phase III trial of ambrisentan in patients with idiopathic pulmonary fibrosis (IPF) due to lack of efficacy. During an interim analysis of unblinded data, the study’s Data Monitoring Committee (DMC) found no evidence that the treatment would benefit the patients randomized to receive ambrisentan.

Ambrisentan is an endothelin receptor antagonist. It is approved under the tradename Letairis® as a once-daily treatment to improve exercise capacity and delay clinical worsening of pulmonary arterial hypertension (PAH) in patients with WHO functional class II or III symptoms. In May 2009, Gilead reported results from an open-label, single-arm, Phase III study evaluating ambrisentan in PAH patients with class II and III symptoms as well as other etiologies. The trial demonstrated a mean 21-meter improvement from baseline in six-minute walk distance at 24 weeks.

This year’s third-quarter sales of Letairis increased 26% to $60.4 million, up from $48.1 million for the third quarter of 2009. Gilead says that sales were primarily driven by volume growth in the U.S. In 2009, Letairis sales increased 63% to $183.9 million from $112.9 million in 2008.

Commenting on Gilead’s decision to stop ambrisentan development in IPF, Avik Roy, healthcare analyst at Monness, Hardt, points out, “This comes on the heels of last March’s failure of Actelion’s Tracleer in IPF and reiterates the high barriers to entry for competitors to conduct successful clinical trials in IPF.

“IPF is a graveyard for clinical trials. Endothelin antagonists such as Letairis and Tracleer have long thought to have potential in IPF, but large clinical trials of these compounds in the disease have consistently failed,” says Roy. “Actelion invested in three expensive Phase III studies for Tracleer in IPF and ended up with nothing.

“Actelion is also studying a second-generation endothelin antagonist, macitentan, whose Phase II study in IPF is due to report out in the second half of 2011,” Roy continues. “Our expectations for this compound are low, given the experience of Letairis and Tracleer. However, even if macitentan manages to succeed, in Europe it would almost certainly be used in addition to, rather than instead of, InterMune’s Esbriet.”

Earlier this month InterMune received a positive opinion for marketing Esbriet in the EU from EMA’s Committee for Medicinal Products for Human Use. Their recommendation was to approve the drug in adults for the treatment of mild-to-moderate IPF. InterMune expects a final decision in the first quarter of 2011 and to launch Esbriet starting with Germany and France.

In May FDA asked InterMune to run an additional clinical trial despite a positive recommendation from its advisory panels. “There is significant potential for Esbriet to gain approval in countries outside the European Union—Canada and Australia are two examples—and the company’s optimism about extending Esbriet’s exclusivity past 2021 appears well-grounded,” Roy adds.

“Add Gilead to the list of potential ITMN acquirers,” he remarks. “InterMune faces no competition in IPF. InterMune owns the rights to Esbriet everywhere except Japan, Taiwan, and South Korea, making it an ideal bolt-on acquisition for a larger pharmaceutical concern with strong European marketing and distribution infrastructure. GlaxoSmithKline, AstraZeneca, sanofi-aventis, Teva, and Novartis spring immediately to mind.”

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