Regulatory Decision Summary for VOLIBRIS

The pivotal trial for supporting the proposed additional indication was a double-blind, randomized study in 500 newly diagnosed pulmonary arterial hypertension (PAH) patients treated with a combination of Volibris (ambrisentan) plus tadalafil, or with ambrisentan monotherapy or tadalafil monotherapy. The primary endpoint in a time-to-event analysis was the first event of clinical failure, defined as the first occurrence of a composite of death, hospitalization for worsening PAH, disease progression, or an unsatisfactory long-term clinical response.

The results of the pivotal trial demonstrated that the benefit, that is, decreasing clinical failure, of the combination of Volibris and tadalafil versus ambrisentan or tadalafil monotherapy in these PAH patients was statistically significant and clinically relevant. A risk reduction of 52% and 47%, respectively, was demonstrated. Secondary endpoints, such as a significantly increased 6-minute walk distance and significantly decreased plasma levels of N-terminal pro-brain natriuretic peptide, supported the superiority of the combination therapy over either monotherapy.

The safety findings in the pivotal clinical trial were consistent with the experience with ambrisentan and tadalafil administered as single agents. No new safety signals were seen with combination therapy.

The incidence of some known adverse events, such as peripheral edema, liver enzyme elevations, and anemia were higher with combination therapy, but this did not lead to higher rates of withdrawals (7-13% in all study groups). Serious adverse events occurred at similar rates in all three study arms.

In conclusion, the benefit of Volibris and tadalafil combination therapy versus both monotherapies is statistically and clinically relevant. This benefit was particularly evident in WHO functional class II patients, which is an important consideration, as combination treatment was shown to better delay progress of the disease than monotherapies, thereby prolonging the lives of these patients and with a better quality of life. There appear to be no clinically significant safety concerns with treatment combining Volibris and tadalafil. The overall benefit risk profile of the initial combination therapy with ambrisentan and tadalafil is favorable.