New drug for pulmonary arterial hypertension in connective-tissue disease

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New drug for pulmonary arterial hypertension in connective-tissue

disease

Jul 4, 2005 Zosia Chustecka

Vienna, Austria - A new drug for use in the treatment of pulmonary

arterial hypertension (PAH) is approaching the market: sitaxsentan

(developed by Encysive, formerly known as Texas Biotech). The company

submitted an application for US Food and Drug Administration approval

(as Thelin) in May and intends to apply to the European Agency for the

Evaluation of Medicinal Products (EMEA) this month, Dr Terrence Coyne,

chief medical officer at Encysive, told rheumawire. A launch is

expected in about a year.

Sitaxsentan is a highly selective endothelial-A receptor antagonist,

Coyne explained, and the company believes that it will have advantages

over nonselective endothelial antagonists (which block both endothelial

A and B receptors) such as bosentan (Tracleer, Actelion). The clinical

data to date suggest that patients with PAH taking bosentan don't

deteriorate any further, but those taking sitaxsentan show

statistically significant improvement, Coyne told rheumawire. It may

also have a safety advantage: bosentan has been associated with

liver-function abnormalities in some patients, at a rate of 11%,

Encysive notes in a press release, whereas in an 18-week phase 3 study,

the rate associated with sitaxsentan (at the 100-mg dose) was 3% and

with placebo was 6%.

Clinical trial data on sitaxsentan were featured in several poster

presentations during the recent European League Against Rheumatism

(EULAR) 2005 meeting, and one focused on the use of sitaxsentan for PAH

in patients with connective-tissue disease [1]. (All of the studies

involved the manufacturer.)

PAH is often associated with connective-tissue diseases (occurring in

12% to 50% of patients), Dr Reda E Girgis (s Hopkins University,

Baltimore, MD) and colleagues noted. PAH in these patients is

frequently more difficult to manage and is associated with greater

morbidity and mortality than idiopathic PAH, they added.

In their poster, Girgis presented data on a subgroup of patients with

PAH related to connective-tissue disease who took part in the

Sitaxsentan to Relieve Impaired Exercise (STRIDE-1) study. (The overall

results from this study were published last year [2].) STRIDE-1

involved 178 patients (of whom 42 had connective-tissue disease) and

compared sitaxsentan at 100 mg and 300 mg orally once daily with

placebo over a 12-week period. Because the treatment effects in the

total intent-to-treat population were similar, the two dose groups were

pooled together, Girgis explained.

A post hoc analysis of the intent-to-treat subgroup of patients with

connective-tissue disease (placebo n=9, sitaxsentan n=33) showed that

several measures were improved with the drugthe six-minute walk test,

NYHA functional class, and hemodynamicsGirgis et al reported. The

treatment effect on the six-minute walk test was 58 m (p=0.0274), owing

to an increase in the sitaxsentan group and a decrease in the placebo

group. At baseline, all the patients with connective-tissue disease

were NYHA class 2 or 3. During the study, eight of 33 patients (24%) on

sitaxsentan improved by one NYHA functional class and none

deteriorated; in the placebo group, one patient of the nine improved

and one patient deteriorated (11% in each case). The drug was well

tolerated, the researchers comment, and not discontinued in any

patients because of adverse effects. When these results are compared

with those reported in other trials in which other drugs were used to

treat PAH related to connective-tissue diseases (epoprostenol,

treprostinil, and bosentan), sitaxsentan " is shown to be at least as

effective as currently available therapies, " Girgis et al conclude.

Another poster presented at the same meeting featured two-year efficacy

data from a group of 11 patients who had originally participated in the

STRIDE-1 study and showed that the beneficial effects of sitaxsentan

are sustained long-term [3]. Dr Langleben (Sir Mortimer B

Jewish General Hospital, McGill University, Montreal, QC) and

colleagues treated the 11 patients with 100-mg sitaxsentan under a

compassionate-use protocol: four patients had PAH related to

connective-tissue disease, three had congenital heart disease, and four

were idiopathic. In one patient, PAH had deteriorated (related to

scleroderma) at seven months, and another patient (with congenital

heart disease) developed multiple myeloma during the second year; in

both these patients, therapy was stopped. In the remaining nine

patients, mean results on the six-minute walk test improved

significantlyfrom 378 m (+122) at baseline to 436 m (+82) at one year

(p=0.04) and to 440 m (+86) at two years (p=0.02). At baseline, nine

patients were NYHA functional class 3 and two were class 2; by the end

of the two years the remaining nine patients were NHYA functional class

2.

Works in patients who discontinue bosentan

A third poster presentation featured patients who had discontinued

treatment with bosentan but went on to be treated successfully with

sitaxsentan [4]. Dr L Benza (University of Alabama, Birmingham)

and colleagues reported a set of data that came from the phase 3 study

STRIDE-6, which included 48 patients who had previously taken but

discontinued bosentan, 35 because of inadequate clinical response and

13 because of safety issues (12 because of hepatotoxicity and one

because of rash).

In the efficacy subset, five patients discontinued bosentan because of

clinical worsening, and disease progression of more than 15% was seen

in 15% to 20% of patients. Among the patients treated with sitaxsentan

100 mg, 40% (six of 15 patients) showed a 10% improvement in the

six-minute walk test; on the lower dose of sitaxsentan (50 mg), 10% of

patients (2 of 20) showed this improvement. The majority of patients

remained in the same NYHA functional class throughout the study (75% of

those taking 50 mg, 80% of those taking 100 mg).

In the safety subset, only one of the 12 patients who had discontinued

bosentan because of liver-function-test abnormalities had a recurrence

of this problem on sitaxsentan. In that one patient, the recurrence

occurred after 12 weeks of sitaxsentan treatment, and the elevated

aminotransferases returned to baseline levels after the drug was

stopped.

Benza et al conclude that sitaxsentan at a dose of 100 mg once daily is

a viable treatment option for PAH patients who discontinue bosentan

therapy because of safety issues or inadequate clinical response, but

they caution that close monitoring is required to identify PAH patients

who continue to deteriorate so that appropriate prostacyclin therapy

can be instituted.

Sources

1. Girgis R, McLaughlin V, Hill N, et al. Sitaxsentan improves 6MW

and hemodynamics in patients with pulmonary arterial hypertension (PAH)

related to connective tissue disease (CTD). EULAR 2005; June 8-11,

2005; Vienna, Austria. Abstract FRI0086.

2. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for

pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;

169:441-447.

3. Langleben D, Hirsch AM, Shalit E, et al. Sustained efficacy with

the highly selective orally active endothelial-A receptor antagonist,

sitaxsentan, after two years of therapy in patients with pulmonary

arterial hypertension. EULAR 2005; June 8-11, 2005; Vienna, Austria.

Abstract THU0115.

4. Benza RL, Mehta S, Koegh A, et al. Sitaxsentan treatment for

patients with pulmonary arterial hypertension (PAH) failing bosentan

treatment due to lack of efficacy. EULAR 2005; June 8-11, 2005; Vienna,

Austria. Abstract FRI0160.

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