The medical treatment of inoperable chronic thromboembolic pulmonary
hypertension (CTEPH) looks set to be confined to off-label therapy
for the foreseeable future, because the only rigorously conducted
trial of any drug in this specific indication has failed to show a
clear benefit [1].

That trial--Bosentan Effects in Inoperable Forms of Chronic
Thromboembolic Pulmonary Hypertension (BENEFIT)--conducted with the
dual endothelin antagonist bosentan (Tracleer, Actelion
Pharmaceuticals), produced mixed results, with a positive treatment
effect of bosentan on hemodynamics but no improvement in exercise
capacity. The BENEFIT results were first reported at the European
Society of Cardiology (ESC) meeting in Vienna in 2007 and appear in
the December 16, 2008 issue of the Journal of the American College
of Cardiology, by Dr Xavier Jais (Antoine Beclere Hospital, Clamart,
France) and colleagues.

Coauthor Dr Irene M Lang (Medical University of Vienna, Austria),
told heartwire that the published results do not differ from those
she presented at the ESC meeting, but she believes they could be
sufficient for bosentan to be approved for CTEPH. However, the
drug's manufacturer told heartwire it has no plans to pursue an
approval for this indication.

Inoperable CTEPH: A Chronic, Devastating Disease

CTEPH is a form of pulmonary hypertension (PH); PH affects more than
2.5 million people worldwide and is characterized by hypertension in
the pulmonary artery, vein, or capillaries, leading to shortness of
breath, dizziness, fainting, and other symptoms, all of which are
worsened by exertion and can lead to markedly decreased exercise
tolerance, heart failure, and death. The only approved therapies
currently available are for a different form of PH, pulmonary
arterial hypertension, which comprises only a small proportion of PH
cases, so the majority of patients are without approved treatment.

When the BENEFIT results were reported at the ESC meeting, the
discussant, Dr Nazzareno Galie (University of Bologna, Italy), said
this was the first time a randomized controlled study has shown
favorable hemodynamic effects of a targeted therapy in this group of
patients (inoperable CTEPH), but he noted the obvious discrepancy: a
clear decrease in pulmonary vascular resistance was demonstrated,
but there was no change in six-minute walking distance.

Lang told heartwire: "Some people think there is a signal there and
that [bosentan] should be approved for inoperable CTEPH because
there is a bad need for medical treatments for this indication. This
is a chronic, very devastating disease that hits elderly people, and
it's an important problem."

Was the Follow-Up Too Short in BENEFIT?

There are a couple of possible explanations for the discrepancies in
BENEFIT, Galie said in Vienna. First, CTEPH patients are older and
have more comorbidities than patients with PAH, in whom bosentan is
already approved. In addition, the short duration of the study--just
three months of follow-up--may have played a role, he said,
explaining that improvements in exercise capacity can sometimes take
as long as a year to manifest.

Lang takes this up, explaining to heartwire that there is to be
a "statistical look" at the open-label phase of the BENEFIT trial,
but that she does not yet know the results of this phase. She added
that she was not sure whether Actelion Pharmaceuticals would file
for approval of bosentan for inoperable CTEPH on the basis of
BENEFIT, stating that this is a matter "of some debate."

However company spokesperson Roland Haefeli, vice president for
investor relations and public affairs, told heartwire: "In terms of
[inoperable] CTEPH, we currently have no plans for regulatory
proceedings [with bosentan]."

Much Off-Label Use of Bosentan, Sildenafil

Lang told heartwire that whether or not bosentan is actually
approved for inoperable CTEPH, the drug would still be used for this
indication. "I estimate that around 60% of patients with inoperable
CTEPH are treated medically off-label, mainly with sildenafil and
bosentan, which is a very bad situation," she said.

In many countries, sildenafil is the preferred option, she added,
because it is available generically and therefore considerably
cheaper than bosentan. Sildenafil, a phosphodiesterase inhibitor
best known as the erectile-dysfunction therapy Viagra, is approved
for PAH as Revatio (Pfizer). Lang added that there has never been an
appropriately powered trial to assess sildenafil for the CTEPH
indication, "but it appears to do something."

Another new drug is also being investigated for inoperable CTEPH as
well as other forms of PH, she adds. Bayer's riociguat, a soluble
guanylate cyclase stimulator, is about to begin two phase 3 trials:
one in CTEPH and the other in PAH [2]. And phase 2 studies of
riociguat are under way in patients suffering from other forms of PH.

The BENEFIT trial was funded by Actelion Pharmaceuticals. Lang
reports receiving honoraria from Actelion, Bayer-Schering, Pfizer,
AstraZeneca, GlaxoSmithKline, AOP Orphan Pharmaceuticals, the
European Union, and the Austrian government. Disclosures for other
BENEFIT authors are listed in the paper.


Jais X, D'Armini AM, Jansa P, et al. Bosentan for treatment of
inoperable chronic thromboembolic pulmonary hypertension. BENEFIT
(bosentan effects in inoperable forms of chronic thromboembolic
pulmonary hypertension) a randomized, placebo-controlled trial. J Am
Coll Cardiol 2008; 52:2127-2134. Abstract
Bayer Schering Pharma. Bayer reports progress in clinical program
for riociguat [press release]. October 6, 2008. Available at:
http://www.press.bayer.com/baynews/baynews.nsf/id/A2F9D590C44A5879C12
574DA001A936C?Open.