A promising combination of GlaxoSmithKline’s Volibris and Lilly’s Adcirca has met its primary endpoint in a phase IIIb/IV study in pulmonary arterial hypertension (PAH).

Both drugs are already approved separately for PAH, but preclinical data has suggested that they may have synergistic effects – and the combination was a source of excitement at the European Respiratory Society last year when initial results were announced.

The AMBITION study’s primary endpoint was reduction in clinical-failure events, defined as time from randomisation to the first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response.

The trial met this endpoint by finding that the combination therapy resulted in a significantly lower risk of clinical failure events compared to monotherapy in patients who had not received previous treatment. A primary endpoint event occurred in 18% of the combination participants, 34% of the Volibris (ambrisentan) participants, and 28% of the Adcirca (tadalafil) participants.

Compared to the pooled monotherapy group, the combination group also had greater reductions in pro-brain peptide levels (-67.2% versus -50.4%), greater improvement in 6-minute walk distance (48.98 metres verses 23.80 metres), and a higher percentage of patients with a satisfactory clinical response (39% versus 29%).

Dr Murray Stewart, GSK’s chief medical officer, says: “Combination therapy is commonly used by physicians to treat patients with pulmonary arterial hypertension, but prospective trials of combination therapy have been few in number and limited to sequential add-on therapy, resulting in a lack of evidence about when and how combination treatment could and should be used.

“Despite existing treatments, the median survival for a PAH patient is just 5-6 years after diagnosis, so the AMBITION study was designed to answer the important question of whether the upfront initiation of treatments with different modes of action could improve patient outcomes in this rare condition.”

The study was co-funded by GSK and Gilead, who market ambrisentan in the US as Letairis. Lilly also provided funding and Adcirca drug supply.

Currently the biggest player in the PAH market is Actelion with it’s Tracleer  (bosentan). The medicine will be going off-patent in the next couple of years, but the Swiss biotech has already launched its follow-up, Opsumit (macitentan).