PAH is a leading cause of death and late disease morbidity in CTD and is generally regarded as less responsive to therapy than other forms of PAH particularly in the setting of systemic sclerosis (SSc). Endothelin levels are increased in SSc-PAH and have vasoconstrictive effects mediated predominantly via the endothelin-A receptor (ETA). Sitaxsentan is a once daily, orally bioavailable, highly selective (6500:1 - A:B) antagonist of the ETA receptor. We investigated its clinical efficacy in PAH-CTD via analysis of all currently completed sitaxsentan placebo-controlled clinical trials in PAH.
Three multicenter, randomized, double-blind, placebo controlled trials of PAH including WHO Class II, III and IV have been completed (STRIDE -1, 2 & 4). Studies were of 12-18 weeks duration and six minute walk distance (6MWD) was the primary or secondary outcome in all. Studies included sitaxsentan at 50 mg, 100 mg and 300 mg qd. 110 of 512 patients had PAH-CTD including 63 with SSc, 22 with overlap/MCTD and 25 with SLE. All studies excluded patients with total lung capacity < 80% predicted or baseline 6MWD > 450 m (two of three studies). These trials also included IPAH and PAH associated with congenital heart defects.
Sitaxsentan 100 mg improves 6MWD in patients with PAH-CTD with a low incidence of abnormal liver function tests.
Selective ETA receptor antagonism with sitaxsentan appears to be an effective and well tolerated therapy for PAH associated with CTD.
Six Minute Walk Distance (m)Placebo (PBO) N=28Sitax 50mg N=26Sitax 100mg N=39Sitax 300mg N=17▵ from Baseline (mean ± se)−16 ± 15.0−2 ± 13.421 ± 10.42 ± 14.1PBO-subtracted treatment effect14.737.718.3P-value vs PBONSP=0.042NSN (%) Abnormal LFT >3x ULN1 (3.6%)0 (0%)0 (0%)0 (0%)
James Seibold, Grant monies (from industry related sources) Encysive Pharmaceuticals, Actelion; Consultant fee, speaker bureau, advisory committee, etc. Encysive Pharmaceuticals, Actelion; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Sitaxsentan.