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Oral Prostanoids for the Mgmt of PH: The Holy Grail or Beraprost Revisited?
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In this presentation reviewing data from recent clinical trials, Dr. Vallerie McLaughlin describes the evolution in the approach to targeting the prostacyclin pathway in the treatment of PAH. Filmed at the 2016 CHEST Annual Meeting.

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Hello, I'm Dr. Vallerie McLaughlin, and today we're going to talk about oral prostanoids for the management of pulmonary hypertension. The Holy Grail or Beraprost revisited?
We've been using prostacyclins and their analogs for pulmonary arterial hypertension for two decades now, starting out in the 1990s with parenteral prostacyclins, IV epoprostenol, progressing on to subcutaneous treprostinil, moving on to inhaled therapies, and more recently oral prostacyclin analogs and prostacyclin receptor agonists.

We'll go back to the study of Beraprost, and there were a couple of studies on Beraprost in the early 2000s, and this one was a longer term study. It was a 12 month study, and what we learned was that at three and six months there was an improvement in exercise tolerance, but that tapered off over time, and Beraprost was never further developed for pulmonary arterial hypertension.

Oral treprostinil has more recently been evaluated in a number of trials, including the FREEDOM-M trial, when it was looked at in patients who were not on any background therapy, and it demonstrated a modest but statistically significant improvement in the primary endpoint of six minute hall walk measured at peak. This led to the FDA approval of oral treprostinil. It was also studied in two trials looking at oral treprostinil on top of other therapy, PDE5s, ERAs, or both, and there was no improvement in the primary endpoint of six minute hall walks at 16 weeks in either of those two trials.

When we think about oral treprostinil, is it the Holy Grail or Beraprost revisited? We can summarize it as saying oral treprostinil monotherapy resulted in a modest improvement in six minute hall walk at the end of 12 weeks, but there were no improvements in any of the secondary endpoints in that trial.

Oral treprostinil on top of background therapy was not effective in the FREEDOM-C or C2 trials at 16 weeks, but of course could it be effective over the longer term at higher doses? We don't know the answer to that question. It does have a potential role in patients who have not responded to parenteral therapy. There's a small case series of patients being transitioned to oral treprostinil from parenteral prostacyclins, but we can sum it up by saying it's neither the Holy Grail nor Beraprost revisited.

Let's move on to Selexipag, which is an oral prostacyclin receptor agonist, and it really highlights the evolution that we've made in clinical trials in pulmonary arterial hypertension over the past two decades. The early trials, some of which we've already discussed, were short term six minute hall walk trials, and now with the GRIPHON trial, we've studied Selexipag in a large, more than 1100 patient trial, with patients observed for months to years, looking at a more solid endpoint, time to first morbidity and mortality event. The components of that time to first morbidity mortality event are summarized on this slide, disease progression, hospitalization, which is a very important endpoint, initiation of parenteral prostacyclin, need for lung transplantation or atrial septostomy, or all cause death. Very important in these endpoint-driven trials is that all of those endpoints were adjudicated by a critical events committee. In the Selexipag trial, patients who received active drug had less of these outcomes, less of these morbidity and mortality events than patients randomized to placebo. You can see those curves separate early within months and stay separated for out the duration of the trial, resulting in a 40% risk reduction in the patients who are on active therapy.

Very impressive in the GRIPHON trial was the consistency of the effect across the subgroups. Listed on this slide are a number of the key subgroups, age, disease etiology, background therapy. The treatment effect in each of these subgroups mirrored the treatment effect in the overall trial. I want to specifically point out the treatment effect in patients who are already on two background therapies. This is very good data on triple combination therapy. About a third of the patients in the trial were on both an ERA and a PDE5, and those who were randomized to Selexipag had less events during the course of the trial. In fact, the risk reduction in this sub-population was essentially the same as the risk reduction in the overall trail.

So is it the Holy Grail or Beraprost revisited? We have a large trial demonstrating an important reduction in clinical events with consistent effect across the subgroup, and specifically consistent effect as add-on therapy even to those who are on double combination therapy. There was a modest improvement in the secondary endpoint of six minute hall walk. It's a very impressive trial. Neither the Holy Grail, it's not for everyone, not for the most ill patients, but definitely not Beraprost revisited.

To summarize, our approaches to targeting the prostacyclin pathway have evolved over the years. Oral prostacyclins and prostacyclin receptor agonists are now available, and while effective, I just want to highlight that they're not a substitute for parenteral prostacyclin therapy in that most critically ill group, that functional class four group or functional class three with a lot of high risk features, but it's an opportunity for combination therapy to be used and considered at earlier stages of the disease. 

Thank you very much for joining me today.