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Selexipag: The Next Major Advance in PAH Pharmacotherapy?

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Jim Coons, PharmD, BCPS (AQ Cardiology)
University of Pittsburgh
Pittsburgh, PA, USA

Selexipag is a first-in-class, orally available, selective agonist of the prostacyclin IP receptor [1]. The IP receptor is one of 4 different types of prostanoid receptors found in the lungs and regulates vascular tone, platelet activation, and immunologic cell responses. The IP receptor is principally expressed in vascular smooth muscle cells (SMCs) and platelets. Activation of the IP receptor triggers SMC vasodilation and inhibition of SMC proliferation and platelet aggregation. These effects are regulated through stimulation of adenylate cyclase and increases in plasma cyclic adenosine monophosphate (cAMP) [1,2]. Despite its similar mode of action to endogenous prostacyclin, selexipag is chemically and pharmacologically considered a non-prostanoid. A summary of its pharmacology and relevant pharmacokinetic properties are highlighted in Table 1 below.

Table 1. Key Pharmacologic and Pharmacokinetic Features of Selexipag [1]
Selectivity for IP Receptor Orally Active Tmax Metabolism Active metabolite Half-life (parent/active metabolite) Dosing Frequency
Yes Yes 1.5 hrs Rapid hydrolysis in liver Yes; ACT - 333679 1-2 hrs/8 hrs Twice daily

The clinical efficacy and safety of selexipag have been evaluated in both phase II and phase III trials [2,3]. A multicenter, double-blind, placebo-controlled, proof-of-concept study was conducted in 43 patients with symptomatic pulmonary arterial hypertension (PAH) on stable background therapy (endothelin receptor antagonists [ERAs] or phosphodiesterase type-5 inhibitors [PDE-5i]. All patients were required to have a baseline pulmonary vascular resistance (PVR) of > 400 dynes-s/cm5. Eligible patients were initiated at 200 mcg PO BID and up-titrated to a maximum of 800 mcg PO BID [2]. The primary endpoint was change from baseline in PVR after 17 weeks. In the selexipag group, the PVR decreased significantly by 30.3% (p = 0.0045) coupled with an increase in cardiac index and reduction in systemic vascular resistance, without apparent hypotension. The most prevalent adverse events with selexipag were: headache, jaw pain, pain in extremity, nausea, and nasopharyngitis [2].

The landmark phase III trial, GRIPHON (PGI2 Receptor agonist In Pulmonary arterial HypertensiON) was completed in May 2013 and final results were presented at the ACC.15 meeting in March 2015 [3]. The trial was particularly compelling because it represents the largest randomized, double-blind, controlled study among PAH patients to date. The trial enrolled patients from 181 centers in 39 countries and was an event-driven trial which evaluated morbidity/mortality versus placebo [3]. Approximately 80% of patients received stable background PAH therapy at baseline (ERA, PDE-5i, or both). Dosing was initiated at 200 mcg PO BID and up-titrated based on patient tolerability to a maximum of 1,600 mcg PO BID. A summary of the key findings is shown in Table 2 below. The mean duration of treatment for selexipag and placebo was 76.4 ± 50.45 and 71.2 ± 48.32 weeks, respectively. The overall treatment effect of selexipag was seen regardless of age, sex, PAH etiology, baseline functional class, and background PAH therapy. In terms of safety, 14% of participants that received selexipag discontinued therapy due to an adverse event compared to 7% of those in the placebo arm. The most frequent adverse events (> 3%) were: headache, diarrhea, nausea, jaw pain, pain in extremity, myalgia, arthralgia, and flushing [3].

Table 2. Summary of Key Findings from the GRIPHON Trial [3]
Study Design Patient Population Number of Patients Primary Endpoint Results
MC, DB, PC, phase III PAH, age 18-75 yrs; 20% treatment naïve; 47% monotherapy; 33% combination therapy 1,156 Time to first morbidity/mortality (M/M) event‡ Selexipag decreased time to M/M by 40% (HR 0.60; 99% CI: 0.46, 0.78) vs. placebo (log-rank p < 0.0001)

MC = multicenter; DB= double-blind; PC = placebo-controlled
‡ M/M defined as either disease progression (based on 15% decrease in 6-minute walk distance, and either worsening functional class or need for additional PAH therapy), hospitalization for PAH worsening, PAH worsening (need for atrial septostomy or lung transplant; initiation of parenteral prostanoids or chronic oxygen therapy), or all-cause death

Relative to most prostacyclin (PGI2) analogues, selexipag exhibits a higher affinity and selectivity for the IP receptor [1]. Consequently, potential pharmacologic advantages of selexipag relative to current prostacyclin-based therapy may be realized with regard to safety and efficacy. The high selectivity of selexipag and its active metabolite for the IP receptor may minimize the frequent gastrointestinal (GI) effects seen with prostacyclin therapy by way of less stimulation of gastric smooth muscle and slowing of gastrointestinal (GI) transport leading to nausea and vomiting. However, it should be noted that similar types of adverse events to prostacyclins have still been observed in both the landmark phase II and III trials of selexipag [2,3]. The most obvious advantage to selexipag may come in the form of dosing convenience by way of oral, twice-daily administration. As an alternative to parenteral prostacyclins, this would negate complications such as catheter-related infections and injection-site pain [4]. Inhaled prostacyclins obviate these complications, but still require more frequent administration and specific delivery systems. Oral treprostinil is also now approved, but is limited by GI adverse effects and lack of clear benefit as part of combination therapy [4]. Beraprost is another oral prostacyclin that has been studied, but it remains unavailable in most countries due to lack of sustained efficacy [4]. Ultimately, the safety and efficacy of selexipag relative to prostacyclin-based therapy remain uncertain at this time and require further study.

In summary, selexipag is a promising treatment which may soon add to the rapidly growing therapeutic advancements seen in PAH management over the past decade. Its novel pharmacologic effects, dosing formulation, and phase III trial results provide optimism for the next major advance in PAH pharmacotherapy. However, key questions remain including the relative effects compared to current prostacyclin formulations. Selexipag (Uptravi®) was submitted for regulatory approval to both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) in December 2014. Regulatory review is also underway in other countries, including New Zealand, Canada, and Switzerland. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


  1. Skoro-Sajer N, Lang IM. Selexipag for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother 2014;15(3):429-36.
  2. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 2012;40:874-80.
  3. McLaughlin VV. Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: results of the GRIPHON study. Paper presented at: ACC.15; March 15, 2015; San Diego, CA.
  4. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013;62:D60-72.

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