Conference: 2012 International PHA Conference and Scientific Sessions
Release Date: 06.22.2012
Presentation Type: Abstracts
Farber HW1; Gillies H2; Allard M2; Blair C2
1. Boston University School of Medicine, Boston, MA, USA
2. Gilead Sciences Inc., Foster City, CA, USA
BACKGROUND: Ambrisentan (ABS) is an oral, once-daily ETA-selective endothelin receptor antagonist approved for treatment of Group 1 pulmonary arterial hypertension (PAH). Presented here is an exploratory post-hoc meta-analysis examining for the first time long-term (48 weeks) efficacy and safety of ABS in patients with PAH associated with HIV infection.
METHODS: Seventeen patients with PAH associated with HIV infection were enrolled in ABS clinical studies and received ABS therapy: AMB-220 then AMB220/E (n=2/54 patients), ARIES-1 and ARIES-2 then ARIES-E (n=11/383 patients), and ARIES-3 (n=4/224 patients). AMB-220/E was the open label long term extension of AMB-220, a phase 2, 12-week double-blind, dose-ranging study. ARIES-E was the open label long term extension of two Phase 3, 12-week, placebo-controlled studies (ARIES-1 and ARIES-2). ARIES-3 was an open-label study that evaluated efficacy and safety of ABS in Group 1, 3, 4, and 5 pulmonary hypertension. Patients received ABS doses of 1mg (n=1), 2.5 mg (n=3), 5 mg (n=11), or 10 mg (n=2). Most patients (94%) were receiving antiretroviral therapy. The 48-week endpoints from AMB-220/E, ARIES-E and ARIES-3 include: change in 6-minute walk distance (6MWD), Borg Dyspnea Index (BDI), and WHO functional class (FC); survival; and time to clinical worsening. Change at week 48 from baseline is represented by descriptive statistics and last observation carried forward imputation for missing data.
RESULTS: Included are 10 males and 7 females: mean age of 459 years; WHO FC II (65%) and FC III (35%). Pulmonary vascular resistance (PVR) was 759±365 dyne.sec/cm5, mean pulmonary arterial pressure (mPAP) was 49±11 mmHg, cardiac index was 2.9±0.9 L/min/m2, mean right atrial pressure (mRAP) was 8.5±4.3 mmHg. At baseline, 6MWD was 364±6m and BDI was 3.1±2.4. At week 48, improvements were observed in 6MWD (+63m, 95% CI: +34 to +93) and BDI (-1.5, 95% CI: -2.94 to -0.02). All patients remaining on ABS improved or maintained their WHO FC and no patient died or experienced clinical worsening events. The most frequent adverse events were peripheral edema (29%), arthralgias (18%), and sinusitis (18%). Two subjects discontinued ABS due to adverse events: One patient due to headache and nasal congestion and 1 patient with a history of hepatitis C discontinued due to moderate transient elevations in serum aminotransferase.
CONCLUSIONS: Long term ABS therapy in patients with PAH associated with HIV infection was well tolerated and provided clinically relevant improvements in exercise ability, dyspnea, and WHO functional class.