The Griphon Study

The GRIPHON trial, which was presented at ACC 2015, studies selexipag, a first-in-class orally available selective non-prostanoid IP receptor agonist, in patients with PAH. Dr. Bradley Maron and Dr. John Ryan discuss the results of the GRIPHON trial with lead investigator Dr. Vallerie McLaughlin.

  1. Why did you choose the composite primary endpoint and how did you decide on the outcomes chosen?
    • There was continuous dialog between the PH experts of the GRIPHON Steering Committee and the study sponsor to ensure that a robust and clinically meaningful primary endpoint was in place for this pivotal trial in PAH.
    • The composite endpoint was designed to be clinically meaningful and is indicative of how the patients' disease is progressing and whether the treatment under investigation impacted this.
    • The primary endpoint was based on the recommendations for Phase 3 PAH trials from the World Symposia on PH:
      • The recommendation to use a composite primary endpoint that measures morbidity and mortality was outlined after the Dana Point meeting in 2008 and confirmed after the Nice meeting in 2013. This recommendation reflects the established gold standard for large heart failure trials, which use composite endpoints that assess morbidity and mortality.
      • Many of the Steering Committee members are task force members at the PH World Symposia; we are committed to the evolution of the design of pivotal studies in PAH.
  2. Your study is impressively large – how did you orchestrate such a large study in this rare condition?
    • It is remarkable that in a rare disease like PAH we have been able to progress from small short-term trials to long-term outcome studies, like the SERAPHIN trial with macitentan, and the GRIPHON trial with selexipag.
    • This success is a testament to the commitment of the PAH medical community and the sponsor:
      • In addition to this commitment, factors such as allowing enrolment of patients who were already receiving PAH medication (albeit drugs that do not target the same pathway as the investigational drug) were essential, given the PAH landscape today.
      • In the GRIPHON study, 80% of the patients were already receiving PAH therapy at baseline, and 33% of the enrolled patients were receiving two PAH therapies at baseline.
    • The ability to enroll large numbers of patients, in this case over 1,000 patients from 181 sites in 39 countries, is a breakthrough in PAH. It allows us to conduct long-term, event-driven studies that teach us about long-term outcomes in PAH. In this respect, the GRIPHON study is more similar to the trials that are performed in other cardiovascular conditions, like left heart failure.
  3. Where do you feel selexipag fits in your treatment algorithm for PAH- first line or an additive agent, such as it was in this study?
    • The population enrolled in GRIPHON is a true representation of the patients we usually see in our clinical practice:
      • The vast majority of patients were in WHO functional class (FC) II and III.
      • In addition, the study enrolled patients already receiving treatment for PAH (with an endothelin receptor antagonist [ERA], a PDE-5 inhibitor [PDE-5i] or both), as well as treatment-naïve patients.
      • The benefit of selexipag was evident in these subgroups (as well as in the other subgroups assessed), and consistent with the benefit seen in the overall population.
    • Looking at the treatment algorithm, selexipag has the potential to be used in combination with a single oral agent (an ERA or a PDE-5i) or in combination with both an ERA and a PDE-5i.

The potential to have a treatment algorithm for PAH that includes a therapy which targets the prostacyclin pathway, has a convenient oral route of administration and, most importantly, has a robust level of long-term evidence is a tantalizing prospect.


  1. McLaughlin VV, Channick R, Chin K, et al. Effect of Selexipag on Morbidity/Mortality in Pulmonary Arterial Hypertension: Results of the GRIPHON Study. J Am Coll Cardiol 2015;65;

Keywords: Acetamides, Algorithms, Committee Membership, Drugs, Investigational, Endothelin Receptor Antagonists, Epoprostenol, Heart Failure, Humans, Longitudinal Studies, Outcome Assessment, Health Care, Pharmaceutical Preparations, Phosphodiesterase 5 Inhibitors, Pyrazines, Pyrimidines, Rare Diseases, Research Personnel, Sulfonamides, Hypertension, Pulmonary

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