FDA approves combination of Letairis (ambrisentan) and Adcirca (tadalafil) in pulmonary arterial hypertension- Gilead Sciences

The FDA has approved the use of Letairis (ambrisentan), from Gilead Sciences, in combination with Adcirca (tadalafil) for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to reduce the risks of disease progression and hospitalisation for worsening PAH, and to improve exercise ability. Letairis is an endothelin receptor antagonist that was first approved in 2007 in the US as monotherapy for PAH to improve exercise ability and delay clinical worsening.

The new labelling is supported by data from the AMBITION study in which 605 patients with WHO Functional Class II or III PAH were randomised (2:1:1) to receive once-daily ambrisentan plus tadalafil (n=302) or to ambrisentan (n=152) or tadalafil (n=151) alone. The primary endpoint was time to first occurrence of death, hospitalisation for worsening PAH, greater than 15% decrease from baseline in six-minute walk distance (6MWD) combined with WHO Functional Class III or IV symptoms sustained over 14 days (short-term clinical worsening), or reduction in 6MWD sustained over 14 days combined with WHO Functional Class III or IV symptoms sustained over 6 months (inadequate long-term clinical response).

In the study, combination therapy with ambrisentan and tadalafil demonstrated superiority in reducing the risk of the composite primary endpoint by 49% and 45%, respectively, versus monotherapy with ambrisentan or tadalafil. Overall, 20% of patients receiving combination therapy experienced a primary endpoint event compared to 35% and 30%, respectively, in patients receiving ambrisentan or tadalafil. Combination therapy also demonstrated a reduced risk of hospitalisation for worsening PAH of 67% and 56%, respectively, compared to ambrisentan or tadalafil. Overall, 8% of patients receiving combination therapy were hospitalised for worsening PAH compared to 22% and 15%, respectively, in patients receiving ambrisentan or tadalafil. Patients receiving ambrisentan plus tadalafil also experienced statistically significant improvements from baseline in 6MWD versus individual monotherapy, with a median difference of 24 metres and 20 metres, respectively, from ambrisentan or tadalafil at Week 24. The most common adverse reactions were peripheral oedema and headache.

Comment: Letairis is licensed as Volibris in the EU.