After six years, the FREEDOM-EV clinical trial has finished and preliminary results have been released. This study included patients with PAH who were already on a single oral therapy (either a PDE 5 inhibitor or an ERA). They were then randomized to have either a placebo or Orenitram added to their regimen. Although we don’t have all of the final results, United Therapeutics released the “Top Line” data. Patients who received Orenitram had a 26% reduction in clinical worsening over the course of the study. I expect the reduction in worsening to be driven by fewer hospitalizations and less need to add additional medications.
These results are a breakthrough for Orenitram as two prior studies showed no benefit when Orenitram was combined with other oral medications. However, the study is a decade behind the times and has some major limitations.
- The current best care for newly diagnosed PAH patients is the combination of an ERA and a PDE 5 inhibitor (Adcirca/Tadalafil and Letairis/Ambrisentan or Opsumit/Macitentan). The current study added Orenitram to a single oral agent. Thus the study has limited applicability to the current standard of care.
- The magnitude of the improvement seen with Orenitram was about half that seen in other positive combination studies (AMBITION and SERAPHIN studies showed about 50% reduction in worsening).
- From a cost perspective, the addition of Orenitram to a single oral agent will be a very expensive option.
- The side effects of Orenitram are in general much worse than PDE5 inhibitors or ERAs.
- Orenitram is taken three times daily which makes the medication much harder to take on a regular basis. Compared to once daily regimens such as Adcirca plus Letairis or Adcirca plus Opsumit, many patients will struggle to remember to take their Orenitram.
- The cutting edge of PAH care has moved past whether one drug is better than two.Ongoing studies are now looking at three drug regimens such as the TRITON study that is looking at the initial combination of Adcirca, Opsumit and Uptravi. Soon we will have studies investigating four drug regimens.
We await release of the full results from the study to help us understand how Orenitram can serve patients with PAH.
PDE 5 inhibitors: Adcirca/Tadalafil, Revatio/Sildenafil
ERA: Letairis/Ambrisentan, Opsumit/Macitentan, Tracleer/Bosentan