Selexipag for the treatment of pulmonary arterial hypertension

Abstract

The endothelin (ET), nitric oxide (NO) and prostacyclin (PGI₂) pathways are involved in pulmonary arterial hypertension (PAH) pathogenesis. While ET and NO are targeted early in the disease process, limitations of current pharmacotherapies that target the PGI₂ pathway (PGI₂ or PGI₂ analogues) result in them not being used or delayed. Selexipag is a novel oral, selective agonist of the PGI₂ (IP) receptor. Activation of the IP receptor induces vasodilation in the pulmonary circulation and inhibits the proliferation of vascular smooth muscle cells, key factors in PAH pathogenesis. By combining oral dosing with improved receptor selectivity, selexipag may enable earlier combination therapy targeting the three-molecular pathways of PAH with anticipated improvements in daily- and long-term clinical function and outcome in PAH.

Keywords:

• Selexipag
• pulmonary arterial hypertension
• GRIPHON study

Disease incidence and prevalence

Pulmonary arterial hypertension (PAH) is a life-threatening disorder with symptoms including breathlessness, fatigue with normal physical activity, symptoms of right heart failure and severe constraints on exercise capacity that can ultimately cause a reduction in life expectancy. PAH is classified as idiopathic, heritable, drug or toxin-induced, or is associated with a number of other disease states.[1] Although PAH is a rare disease (estimated prevalence of only 15–50 cases per million), the incidence is underestimated due to diagnostic underutilization.[2,3]

Unmet medical need

There has been considerable development in the understanding of the pathophysiology of PAH in the past two decades. Three molecular pathways are known to be involved in PAH pathogenesis, namely, the endothelin (ET), nitric oxide (NO) and prostacyclin (PGI) pathways. These pathways represent key targets for PAH drugs, and drug innovations have significantly improved the prognosis for PAH patients.[4]

Ten years ago, individuals could expect PAH treatment to result in symptomatic improvements as assessed by the 6-minute walk test (6MWT) that was used as a surrogate measure for clinical outcomes. The direct effect of change in 6MWT on long-term outcomes had never been studied and more recent evidence has shown that the change in 6MWT is not a validated surrogate marker for long-term outcomes in PAH.[4] Newer treatments have been shown to delay PAH progression. In spite of these recent advances, the survival rates in PAH remain unacceptably low and the long-term prognosis for patients with PAH remains poor.

One possible reason for poor survival and long-term prognosis is that while there are effective therapeutic options that target the ET (ET receptor antagonists; ERAs) and the NO pathways (phosphodiesterase-5 inhibitors, PDE-5i, soluble guanylate cyclase stimulators), options to target the PGI₂ pathway are more limited. These limitations include the inconvenience and risks associated with IV or subcutaneous administration and the side-effect profile.[5,6] Due to these limitations, PAH therapy is generally focused on the ET and NO pathways and therapy targeting the PGI₂ pathway is underused and a substantial proportion of individuals with PAH die without having received parenteral PGI₂ therapy.[7]

Selexipag: a novel oral therapy targeting the PGI₂ pathway

Selexipag (ACT-293987, NS-304, 2-{4-[(5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino] butoxy}-N-(methanesulfonyl) acetamide) and its active metabolite (ACT-333679) are selective agonists of the (IP) receptor. Activation of the IP receptor leads to vasodilation in the pulmonary circulation and inhibition of the proliferation of vascular smooth muscle cells.[8] Selexipag is structurally distinct from the other drugs targeting the PGI₂ pathway as it is a non-prostanoid IP receptor agonist rather than PGI₂ or a PGI₂ analogue.[9]

Selexipag: clinical efficacy

Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where participants were randomized in a 3:1 ratio to selexipag or placebo.[10] The study demonstrated a 30.3% improvement in pulmonary vascular resistance (p = 0.0045) and a numerical increase in 6MWT of 24.2 m in participants already receiving a PDE-5i (27.2%), ERA (36.4%) or PDE-5i/ERA combination treatment (36.4%).

In June 2014, Actelion announced the top-line results of their pivotal multicenter, double-blind, placebo-controlled, event-driven, Phase III GRIPHON trial, which evaluated the long-term effect of selexipag on a composite morbidity/mortality (M/M) end point, tolerability and safety in 1156 participants (18–75 years) with PAH.[11] The first major presentation of the data was at the 2015 American College of Cardiology (ACC) Congress.[12] GRIPHON is the largest outcome trial ever conducted in PAH, and enrolled patients in 181 centers from 39 countries in North, South and Latin America, Europe and Asia-Pacific. Participants received selexipag twice daily (b.i.d.) or placebo either alone or in addition to stable background therapy of an ERA, a PDE-5i or an ERA and a PDE-5i. Participants in the GRIPHON study were eligible to be included in an open label extension study (GRIPHON-OLE), which is ongoing.

Selexipag dosing in GRIPHON was initiated at 200 µg b.i.d. and was increased weekly in increments of 200 µg b.i.d. up to a maximum dose of 1600 µg b.i.d. or the maximum tolerated dose. Uptitration of selexipag allowed each patient’s maintenance dose to be individualized based on tolerability.

The primary end point was the time from randomization to the first composite M/M event up to the end of treatment. The first event was defined as (a) disease progression based on a 15% decrease in 6-minute walk distance, and either worsening of functional class [FC] (for patients in FC II/III), or the need for additional PAH therapy (for patients in FC III/IV), or (b) PAH worsening resulting in the need for hospitalization, or atrial septostomy or lung transplant, or the initiation of parenteral prostanoids or chronic oxygen therapy, or (c) all-cause death. A similar composite end point was successfully used in the SERAPHIN trial examining the treatment of PAH with the ERA macitentan.[13] A composite end point is recommended by the World Symposium on Pulmonary Hypertension (WSPH) as being more predictive of long-term outcomes in PAH than single parameters such as 6MWT.[4]

In the GRIPHON study, of the 1156 patients randomized to placebo (n = 582) or selexipag (n = 574), 20% were PAH-therapy naive, 47% were on monotherapy (ERA or PDE-5i) and 33% were on combination therapy (ERA and PDE-5i) at baseline. Selexipag reduced the risk of M/M events versus placebo (log-rank p < 0.0001) by 40% (HR: 0.60; 99% CI: 0.46, 0.78). The treatment effect was consistent across age, gender, geographical region, etiology, baseline FC and background PAH therapy subgroups. Selexipag demonstrated a significant effect on the time to first composite M/M event in PAH patients and had a safety profile consistent with other therapies targeting the PGI₂ pathway. The treatment effect of selexipag was observed irrespective of background treatment with an ERA, a PDE-5i or both. The most frequent adverse events (selexipag >3% over placebo) were headache, diarrhea, nausea, jaw pain, myalgia, pain in extremity, flushing and arthralgia, consistent with prostacyclin effects.[11,12,14–17] The overall tolerability profile of selexipag in GRIPHON was consistent with other prostacyclin therapies.[11,12,14–17]

In December 2014, Actelion submitted the registration dossier for selexipag to both the European Medicines Agency and the US Food and Drug Administration for the treatment of individuals with PAH. In March 2015 the FDA announced formal acceptance of the New Drug Application (NDA) and the results from the NDA review process are expected in the last quarter of 2015.

Conclusion

Selexipag is a promising treatment option for PAH and as an oral non-prostanoid IP receptor agonist it offers a novel, more selective and convenient way to target the PGI₂ pathway compared with currently available treatment options.

Expert commentary

Increasing treatment options and combination therapy have improved outcomes in PAH, but prognosis and long-term outcomes are still poor. Current PAH treatments target the ET, NO and PGI₂ pathways. However, limitations with drugs targeting the PGI₂ pathway have resulted in these treatments often being reserved for use in the later stages of disease, or not used at all. This failure to target all three molecular pathways from the initial diagnosis of PAH may contribute to poor long-term outcomes in patients with the disease.

Five-year view

With the introduction of oral IP receptor-specific drugs, such as selexipag into the treatment armamentarium for PAH, the next 5 years will no doubt see a rapid expansion in the evidence base for triple combination therapy in PAH. If proven to be beneficial then this triple mode of attack may hold the key to individuals with PAH achieving improved physical function in their daily lives, and potentially better long-term prognosis for PAH. In the current environment, the impact of such a treatment regimen on limited health-care resources will also need to be better understood.

Key issues

• PGI₂ or PGI₂ analogues that are administered parenterally are associated with a number of complications related to the mode of delivery meaning that they are often reserved for later disease stages.

• Selexipag is a novel, oral, selective IP receptor agonist that has been shown to improve a composite M/M end point on top of the “standard PAH care” of an ERA, a PDE-5i or in addition to an ERA and a PDE-5i.

• Selexipag offers the potential for the earlier introduction of a triple combination therapy targeting the three molecular pathways (ET, NO and PGI₂) of PAH pathogenesis, which may improve daily clinical function and possibly long-term outcomes in PAH.

Financial & competing interests disclosure

Dr K Sharma was an investigator on the GRIPHON and SERAPHIN studies. M Edmondson at Syntropy Medica Ltd., funded by Actelion Pharmaceuticals, provided writing and editorial services. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Notes on contributors

Kamal Sharma