The US Food and Drug Administration (FDA) has approved the use of Gilead Sciences' Letairis (ambrisentan) in combination with tadalafil for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to reduce the risks of disease progression and hospitalization 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. Tadalafil is a PDE5 inhibitor that was initially approved for PAH in the US in 2009 to improve exercise ability.

"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."

The new labeling is supported by data from the AMBITION study (a randomized, double-blind, multicenter study of first-line combination therapy with ambrisentan and Tadalafil in patients with pulmonary arterial hypertensION). In AMBITION, 605 patients with WHO Functional Class II or III PAH were randomized (2:1:1) to receive once-daily Letairis plus tadalafil (n=302) or to Letairis (n=152) or tadalafil (n=151) alone.

Treatment was initiated with Letairis 5 mg and tadalafil at 20 mg. If tolerated, tadalafil was increased to 40 mg at four weeks and Letairis was increased to 10 mg at eight weeks. The primary endpoint was time to first occurrence of death, hospitalization for worsening PAH, greater than 15 per cent 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 Letairis and tadalafil demonstrated superiority in reducing the risk of the composite primary endpoint by 49 per cent and 45 per cent, respectively, versus monotherapy with Letairis (hazard ratio = 0.51; 95 per cent CI: 0.35, 0.73; p=0.0002) or tadalafil (hazard ratio = 0.55; 95 percent CI: 0.37, 0.81; p=0.002). Overall, 20 per cent of patients receiving combination therapy experienced a primary endpoint event compared to 35 per cent and 30 per cent, respectively, in patients receiving Letairis or tadalafil.

Combination therapy also demonstrated a reduced risk of hospitalization for worsening PAH of 67 per cent and 56 per cent, respectively, compared to Letairis (hazard ratio = 0.33; 95 percent CI: 0.19, 0.55) or tadalafil (hazard ratio = 0.44; 95 per cent CI: 0.25, 0.79). Overall, 8 per cent of patients receiving combination therapy were hospitalized for worsening PAH compared to 22 per cent and 15 per cent, respectively, in patients receiving Letairis or tadalafil.

Patients receiving Letairis plus tadalafil also experienced statistically significant improvements from baseline in 6MWD versus individual monotherapy, with a median difference of 24 meters and 20 meters, respectively, from Letairis (95 per cent CI: 11, 37; p=0.0004) or tadalafil (95 per cent CI: 8, 32; p=0.0016) at Week 24.

When Letairis is used in combination with tadalafil, the common adverse reactions (>5 per cent than on either monotherapy) were peripheral edema (Combination: 45 per cent; Letairis: 38 per cent; tadalafil: 28 per cent), headache (Combination: 41 per cent; Letairis: 34 per cent; tadalafil: 35 per cent), nasal congestion (Combination: 19 per cent; Letairis: 16 per cent; tadalafil: 11 per cent), cough (Combination: 18 per cent; Letairis: 13 per cent; tadalafil: 16 per cent), anemia (Combination: 15 per cent; Letairis: 7 per cent; tadalafil: 11 per cent), dyspepsia (Combination: 11 per cent; Letairis: 3 per cent; tadalafil: 12 per cent) and bronchitis (Combination: 10 per cent; Letairis: 4 per cent; tadalafil: 9 per cent). Letairis has a labeled boxed warning and an associated Risk Evaluation and Mitigation Strategy (REMS) programme regarding the risk of embryo-fetal toxicity.

Data from AMBITION were published in The New England Journal of Medicine and Letairis plus tadalafil was the only recommended initial combination therapy option for PAH in 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.

AMBITION was cosponsored by Gilead and GlaxoSmithKline (GSK). Eli Lilly and Company also provided funding and tadalafil drug supply for the trial. Gilead commercialises ambrisentan under the tradename Letairis in the US and GSK commercialises ambrisentan under the tradename Volibris in territories outside of the US.

PAH is a debilitating disease characterized by constriction of the blood vessels in the lungs leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from shortness of breath as the heart struggles to pump against these high pressures, causing such patients to ultimately die of heart failure. PAH can occur with no known underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection.