Sitaxentan as an effective treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) exists in a rare idiopathic or unexplained form (which occurs in familial and sporadic forms) called idiopathic pulmonary arterial hypertension (IPAH, previously referred to as primary pulmonary hypertension, PPH)) and a relatively common form of secondary pulmonary hypertension, as occurs in patients with connective tissue disease, (PAH related to CTD), congenital heart defects (PAH related to CHD) and other related conditions (such as sleep apnea).

Up until recently there were very few choices of pharmacotherapy in the treatment of IPAH, but despite the rarity of this condition, affecting only 100,000 sufferers across the US and EU, this market has attracted R&D investment. This activity is driven by the high unmet need and high value per patient of treatment. Physicians have historically prescribed a number of different treatments in order to dilate blood vessels, the most common being calcium channel blockers. GlaxoSmithKline’s prostanoid Flolan, is a potent vasodilator which must be administered by continuous intravenous infusion. The need for a permanent catheter inserted into a vein in the neck to administer Flolan with a portable infusion pump presents disadvantages to its use. In 2002 the FDA approved a second prostacyclin, Remodulin, a synthetic form of prostacyclin, for the treatment of PAH. While less invasive than Flolan, Remodulin drug delivery is sub-optimal, requiring a small microinfusion device for continuous subcutaneous infusion. Furthermore, injection site pain limits the use of subcutaneous Remodulin. Both Remodulin and Flolan are also very expensive.

A key advance in the treatment of PAH was however recently made with the launch of Actelion's twice-daily Tracleer (bosentan) as the first orally active treatment of PAH. In a recent press release  Actelion announced first quarter sales of Tracleer for 2004 amounting to CHF 97.1 million (USD 76 million). With increasing awareness of the condition and the success of Tracleer, treatment for PAH is set to enter a new era.

Tracleer is the first generation of a class of drugs known as endothelin receptor antagonists. Released from the endothelial cells, endothelin-1 (ET-1) is an endogenous peptide with potent vasoconstrictor, mitogenic, and profibrotic effects and appears to play a significant role in the pathophysiology of PAH. Patients with PAH have increased plasma ET-1 levels correlating with elevated mean pulmonary arterial pressure (PAPm) and increased pulmonary vascular resistance (PVR), as well as reduced exercise capacity.

The actions of ET-1 are mediated through two distinct ET-1 receptor isoforms: ETA and ETB. Activation of ETA receptors, located predominately on the smooth muscle cells, results in sustained vasoconstriction and proliferation of vascular smooth muscle cells. In contrast, ETB receptors are located predominately on the endothelial cells. Endothelial cell ETB receptors are believed to be principally involved in the clearance of ET-1, particularly in the vascular beds of the lung and kidney. Additionally, activation of the endothelial cell ETB receptors by ET-1 leads to the release of nitric oxide (NO) and prostacyclin. Both of these vasoactive peptides result in sustained vasodilation and anti-proliferative effects on vascular smooth muscle cells, in essence serving to offset the effects of smooth muscle cell ETA receptor activation. To date, bosentan, a nonselective ET receptor antagonist, is the only approved ET receptor antagonist for the treatment of PAH. Selective antagonism of ETA receptors may be more beneficial than antagonism of both ETA and ETB receptors for the treatment of PAH by blocking the vasoconstrictor effects of ETA while maintaining the vasodilator and clearance functions of endothelial cell ETB receptors.

Encysive's sitaxsentan sodium (Thelin TM) is a potent ET-1 receptor antagonist that has high oral bioavailability (>90%) and a long duration of action (t1/2 of 10-11 hours in PAH patients). Sitaxsentan is approximately 6,500-fold more selective as an antagonist for the ETA receptors compared with the ETB receptors. The Sitaxsentan To Relieve Impaired Exercise (STRIDE-1) Trial was designed to evaluate the safety and efficacy of sitaxsentan in patients with symptomatic PAH.

Results from this trial have recently been reported by Barst et al. in the American Journal of Respiratory & Critical Care Medicine. This multi-center, randomized, double-blind, placebo-controlled trial evaluated the effects of sitaxsentan (100mg and 300mg orally once daily) in 178 patients with symptomatic and idiopathic PAH, despite treatment with anticoagulants, vasodilators, diuretics, cardiac glycosides, and/or supplemental oxygen.

Compared to previous placebo-controlled studies, the STRIDE-1 trial design was unique in that it included a broad population of PAH patients, including patients with mild disease, i.e. NYHA functional class II; as well as patients with PAH related to congenital heart defects. In addition, the study did not employ a ceiling cut-off for the six minute walk test. In view of this expanded study population and since PAH is characterized by a reduction in peak oxygen uptake (VO2) compared to predicted values, an improvement in VO2 as a % of predicted values was used as a primary end-point in this study. Traditional PAH study endpoints, such as six (6) minute walk test (6MW), NYHA functional class, and hemodynamics were also evaluated. As it relates to % of predicted peak VO2, the 300mg dose met the study endpoint with a 3% increase at 12 weeks compared to the placebo group. The 100mg dose did not. In contrast to this study endpoint, at both the 100mg and 300mg once daily dose, sitaxsentan increased 6MW relative to placebo and baseline as well as NYHA functional class improvements. Specifically, the 100mg and 300mg dose increased 6MW by 22m and 20m, respectively, versus a deterioration of 13m in the placebo group over the same 12 week time period. Other secondary end-points including pulmonary vascular resistance and cardiac index were also improved compared with placebo. From a regulatory perspective, the FDA had previously indicated that an improvement in six-minute walk distance is important to regulatory approval.

No clinically meaningful differences were seen between the sitaxsentan and placebo groups in the total number of adverse events reported or in the incidence of patient with adverse events. The incidence of serious adverse events was infrequent with no differences between the treatment groups (placebo 15%; sitaxsentan 100mg 5%; sitaxsentan 300mg 16%). Headache, peripheral edema, nausea, nasal congestion, and dizziness, adverse effects previously noted with ET receptor antagonists, were observed more frequently in the treatment groups. No patients discontinued the study in the 100mg sitaxsentan group versus 5 patients in the placebo group and 7 patients in the 300mg sitaxsentan group discontinued during the 12 week study. Dose-dependent liver enzyme abnormalities were observed (placebo 3%; sitaxsentan 100mg 0%; sitaxsentan 300mg 10%).

This study is the first placebo-controlled multicenter study to evaluate a selective ETA receptor antagonist in PAH. Although the 300mg group met the primary endpoint, both this dose and the lower 100mg dose improved six minute walking distance, NYHA functional class, and hemodynamics vs. placebo. While the optimal dose of sitaxsentan requires further investigation, the data from this STRIDE-1 trial suggests that sitaxsentan represents an effective treatment of PAH. Patients with PAH are currently being enrolled in five separate sitaxsentan protocols including the randomized, placebo-controlled, double-blind phase III STRIDE-2 study, which has an open-label bosentan arm in addition to the other 3 arms, i.e. placebo, 50 mg and 100 mg sitaxsentan orally once daily, as well as the STRIDE-6 study evaluating the efficacy of sitaxsentan in patients with PAH who have failed bosentan therapy.

Entry date Friday, June 04, 2004

Adapted from Barst et al, Am J Respir Cell Mol Biol. 2004 Feb 15 [Epub ahead of print].