Dr. Robert Aris MD

GLG News^SM Analyses by Robert Aris(?)

Oral Treprostinil: An effective medicine hiding in a study with a challenging design?

November 18, 2008

Analysis of:Freedom-C Trial of Oral Treprostinil in Pulmonary Arterial Hypertension Fails to Meet Primary Endpoint | ir.unither.com

This phase III study was done without the benefit of conventional drug development with Phase I and Phase II studies (which would have provided more information about the effective dose) preceding it because pharmacokinetic date from IV and SC dosing studies were used to extrapolate for the oral dosing. While in hindsight, this may have not been ideal, the trial holds a lot of promise that treprostinil will be effective since there was a nice dose-response curve and the higher doses clearly appeared to be effective. Oral Treprostinil is probably very similar to subcutaneous and intravenous prostanoids (remodulin and flolan) that require a slow uptitration of dose to allow the patient to become tolerant to the side effects. Thus having smaller doses for titration, which were available later in the trial, probably would have allowed for greater success had these doses been available earlier in the study.

Mild PAH improved by early treatment with bosentan

July 18, 2008

Analysis of:Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. | www.sciencedirect.com

While functional class II (FC II) PAH patients have been included in previous clinical trials, the EARLY trial is the first study to concentrate (ie recruit exclusively) FC II PAH patients.  This is important because the definition of functional class II is that a patient has a sight limitation in physical activity. Understanding "slight" is not so easy in clinical practice and there has been some reservation in treating "slightly" ill patients with very expensive drugs without better outcome studies in this target group. Thus the results of the EARLY study (Lancet June 2008) are welcome news to the PAH community.  Analyses were done with 168 patients and showed significant improvements in pulmonary vascular resistance and a strong trend (p = 0.075) toward improvement in 6 minute walk distance in bosentan-treated patients.  These results will certainly compell clinicians to treat patients with "slight" PAH more aggressively.

Peer reviewed literature on Ambrisentan, a selective ETRA for PAH

June 10, 2008

Analysis of:Ambrisentan for the Treatment of Pulmonary Arterial Hypertension | circ.ahajournals.org

This Circulation paper is the first peer reviewed data on the 2 pivotal Phase III trials on ambrisentan that lead the FDA to approving it for the treatment of PAH in July 2007. This paper is critically important since all new research needs to withstand the rigor of peer-review for physcians to fully embrace the findings.  And the journal Circulation is a top notch publication with "rigorous" reviewers.  Thus this publication will be well received by the PAH community and can be assimilated into the overall database of knowledge on PAH.