FDA Approves Combination Therapy of Gilead’s Letairis® Plus Eli Lilly’s Adcirca for patients with Pulmonary Arterial Hypertension

FDA Approves Combination Therapy of Gilead’s Letairis® Plus Eli Lilly’s Adcirca for patients with Pulmonary Arterial Hypertension

Gilead Sciences, recently announced that the FDA has approved of the use of Letairis® (ambrisentan) combined with tadalafil (marketed for PAH under the brand name Adcirca by Eli Lilly) to treat patients with pulmonary arterial hypertension (PAH) with the aim of reducing the risks of PAH progression and hospitalization for worsening of symptoms as well as to improve patients’ ability to conduct exercise.

Developed in the US in 2007, Letairis is an endothelin receptor antagonist used as a monotherapy in patients with PAH to delay clinical progression of the disease as well as to improve exercise ability.

Tadalafil was approved in the US in 2009 and is a PDE5 inhibitor use to improve exercise tolerance.

“The evidence to support the use of ambrisentan and tadalafil in PAH is well-established, however an outstanding question has been whether combining these two medications up front may further delay the progression of this disease over the long term for patients who are newly starting PAH therapy,” said Ronald J. Oudiz, MD, Professor of Medicine, David Geffen School of Medicine at UCLA and Director, Liu Center for Pulmonary Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. “Based on the data supporting today’s approval, we now know that patients receiving ambrisentan and tadalafil up front are less likely to experience disease progression or be hospitalized, and have more improvement in exercise ability than patients receiving either effective therapy alone. As such, this combination represents a new treatment strategy for patients living with this debilitating and life-threatening disease.”

Data from the double-blind, randomized, multicenter AMBITION clinical study support the new labeling. The study examined the use of first-line combination therapy with Tadalafil and AMBrIsentan as a treatment for PAH.

A total of 605 PAH patients were randomly assigned to receive treatment with Letairis and tadalafil once per day (n=302) or to receive treatment either with Letairis alone (n=152) or with tadalafil (n=151) alone.

In the beginning of the study, patients initiated the treatment with a dose of Letairis 5 mg and tadalafil at 20 mg. If these doses were found to be well tolerated, the dose for tadalafil was increased to 40 mg at four weeks of treatment and the dose of Letairis was increased to 10 mg at eight weeks of treatment.

AMBITION’s primary outcome was hospitalization for worsening of PAH, time to first occurrence of death, a decrease of 15% or more from baseline in six-minute walk distance in combination with WHO Functional Class III or IV symptoms sustained over a period of 14 days (short-term clinical worsening) or reduction in six-minute walk distance sustained for a period of time of over 14 days in combination with WHO Functional Class III or IV symptoms sustained over a period of 6 months.

Results from the study showed that the combined treatment was able to reduce the risk of the composite primary outcome by 49% and 45%, respectively, versus Letairis or tadalafil alone. The results revealed that 20% of PAH patients under the combined treatment achieved the study’s primary outcome compared to 35% and 30%, respectively, in PAH patients who received either Letairis or tadalafil alone.

There was also a reduction in the risk of hospitalization for worsening PAH of 67% of the patients under the combination treatment and 56% compared to Letairis or tadalafil alone. The results also showed that 8% of the PAH patients under the combined treatment were hospitalized for worsening of PAH in comparison to 22% and 15%, respectively, in patients who were treated with Letairis or tadalafil alone.

PAH patients who were treated with the combination therapy had significant improvements from baseline in six-minute walking distance in comparison to individual monotherapy.

Results from the AMBITION study were recently published in The New England Journal of Medicine entitled “Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension.” The combination therapy was recently recommended as a first-line treatment of patients with PAH at the “2015 European Society of Cardiology / European Respiratory Society Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension,” published in the European Heart Journal in August 2015.

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