Wednesday, July 26, 2017

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A word from the PHSANZ President.
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A word from the PHSANZ President

Effects of Selexipag on morbidity/mortality in pulmonary arterial hypertension: Results of the GRIPHON Study.

The main results of the GRIPHON study where presented by Nazzarino Galie at the recent International Society for Heart and Lung Transplantation Annual Scientific Meeting in Nice. This report is from my notes taken.
 
This was an event driven Phase III placebo controlled RCT with 1:1 randomisation of 1156 WHO group 1 patients (iPAH 62%, CTD PAH 29%, CHD 10%). Background therapy was permitted with 20% treatment naïve, 47% on monotherapy and 33% on dual therapy. The study drug selexipag is an orally active non prostanoid selective IP receptor agonist.
 
As with prostanoids, progressive uptitration was undertaken to the limit of tolerability (typical prostanoid side effects). Starting dose was 200μg BD with 30% of patients reaching a peak dose of 1600μg BD.
 
The study met the primary endpoint with a 40% reduction in morbidity and mortality events in the active treatment arm (using a similar* adjudicated composite endpoints as was used in the recently published macitentan pivotal study). Mortality was an uncommon event (<5%) and did not differ between the treatment and placebo groups. Thus the end-point was driven by need for additional therapy or clinical failure. Six minute walk distance was a secondary endpoint and improved  (placebo controlled) overall 12% with a clear effect (+34m) in the in treatment naïve patients but was not improved (+7m) in the previously treated patients.
 
As would be expected, typical prostenoid side effects were common. An interesting finding was an apparent lack of dose response in the therapeutic effect- ie those not reaching the peak dose of 1600 μg BD did just as well as those achieving the higher dosage as long as the patients reaches their maximum tolerated dosage.
 
Comment:
These are exciting findings and the efficacy of selexipag is confirmed in this study in both treatment naïve and previously treated patients. This is the first major study I can recall where efficacy is demonstrated when added to existing dual therapy. We wait with great interest for the publication of these important findings.
 
*In GRIPHON the need for chronic oxygen for disease progression, 15% deterioration in 6MWD with either worsening WHO FC or additional therapy were included in the primary disease progression endpoint. This was in addition to (in the setting of worsening of PAH)  the “usual” suspects –hospitalisation, IV prostanoids, lung transplantation, atrial septostomy as well as deaths. All events were centrally adjudicated.
 

Prof Trevor Williams | PHSANZ president
 
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