Gilead Sciences’ decision to pull the plug on Letairis/Volibris in idiopathic pulmonary fibrosis (IPF) is not as damaging as a typical phase III failure. For one, analysts had ascribed no value to the compound outside pulmonary arterial hypertension (PAH), where it is already marketed and brings in a small fraction of the HIV specialist’s sales.
For another, the company had already prepared another arrow for its quiver in IPF: the $225m purchase two days earlier of privately held Arresto Biosciences, whose lead product is an IPF treatment called AB0024. While the failure of yet another late-stage candidate will come as a great disappointment to clinicians and patients of the debilitating and fatal condition, investors shrugged off the news yesterday; Gilead shares fell less than 1%, closing at $36.26.
Known generically as ambrisentan, Letairis has been a disappointment for the California group since it acquired the compound with the $2.6bn purchase of Myogen in 2006 (Gilead has little to show for its expensive CV push, December 15, 2009). Once forecast to achieve nearly $800m in sales in 2012, current forecasts have it peaking at half that in 2014 before declining to $311m in 2016, according to EvaluatePharma data.
No analysts were forecasting sales in IPF, a sign of little faith that the expensive four-year 660-patient Artemis-IPF trial would strike gold in extending patients lives’ or time to disease progression. The failure earlier this year of another drug in the same class, Actelion's Tracleer, meant few expected Letairis to work in this setting (Actelion stopped in its tracks with negative Tracleer data, March 1, 2010).
As it was, the trial’s data monitoring committee reviewed unblinded interim data and found no evidence of treatment benefit, prompting the end of the trial.
This represents yet another bit of bad news in the IPF space, which has seen little but stumbles of late (Little left to lift spirits in IPF field, May 19, 2010).
The year dawned with symptom management as the standard of care in most of the major markets, but with high hopes for approval of InterMune’s pirfenidone in the US and Europe, and positive data from Actelion’s Tracleer, Pfizer’s Revatio and of course Letairis.
The year ends with only pirfenidone achieving half its goal, winning approval as Esbriet in Europe in the waning days of December, giving patients of the fatal disease a new option (InterMunereceives welcome European approval gift for Esbriet, December 20, 2010). Its path foward in the US remains unclear.
Research into IPF treatments so far has followed two strategies: tumour necrosis-alpha inhibition, as with Esbriet, or endothelin A receptor antagonism, as with Tracleer, Letairis and Actelion’s phase II macintentan. In phase II, Celgene is experimenting with a c-Jun N-terminal kinase (JNK) inhibitor while MorphoSys/Johnson & Johnson and Novartis are testing monoclonoal antibodies.
The antibody approach is the strategy with which Arresto has been experimenting with AB0024. Its target is the lysyl oxidase-like 2 protein, overexpression of which has been implicated in fibrotic diseases. Arresto, based in California, has begun recruiting for a phase I safety trial of the antibody in advanced solid tumours and has listed, but not begun recruitment, of phase I trials in IPF and a separate trial in polycythemia vera and myelofibrosis.
With the Arresto purchase, Gilead is signalling that there remains great interest in IPF even after the many failures of 2010. There certainly remains significant unmet need and the new treatment about to hit the European market, Esbriet, has not demonstrated overwhelming efficacy; room for improvement clearly exists.