Included Studies

The evidence for this review came from one randomized, placebo-controlled, event-driven, group-sequential trial in patients with symptomatic PAH. Patients, treating physicians, and investigators who assessed the primary outcome were blinded to treatment. The objective of the trial was to demonstrate the effect of selexipag on time to first morbidity and/or mortality event (primary composite outcome) in patients with PAH. A total of 1,156 patients, mainly with WHO FC II or III, were randomized to selexipag or placebo (1:1) and titrated to the highest tolerated dose (range: 200 mcg to 1,600 mcg orally twice daily). Groups received study treatment as monotherapy or as add-on to stable single or double background PAH drugs (PDE5 inhibitor and/or ERA). The median duration on treatment in the selexipag group was 70.7 weeks and was 63.7 weeks in the placebo group.

The majority of patients were female (80%), had idiopathic PAH (56%), were classified as WHO FC II (46%) or III (53%) and had a mean time since PAH diagnosis of slightly greater than two years. Eighty per cent of patients were receiving stable doses of one or two concomitant medications for PAH at baseline. ▬ were enrolled in Canada. Prognostic factors at baseline were well balanced, but the initiation of concomitant medications for PAH (e.g., PDE5 inhibitors and ERAs) during the study occurred in ▬ of patients in the selexipag and ▬ in the placebo groups and this may have introduced treatment bias. The direction of the bias cannot be ascertained with precision, but if ▬ ▬ ▬ ▬ ▬ ▬ ▬ ▬ ▬ ▬ ▬

The primary outcome in the GRIPHON study was time to first Critical Event Committee–confirmed morbidity or mortality event up to seven days after the last study drug intake. This was a composite of all cause of death or PAH-related morbidity events, including disease progression or worsening of PAH that resulted in hospitalization, initiation of parenteral prostanoid therapy or long-term oxygen therapy, or the need for lung transplantation or balloon atrial septostomy. Disease progression was defined as a decrease from baseline of at least 15% in the six-minute walk distance (6MWD), accompanied by a worsening in WHO FC or the need for additional treatment of PAH. Secondary outcomes were subject to a hierarchical statistical testing procedure.

The number of patients who discontinued the study drug prior to study closure was high and was slightly lower in the selexipag group (49%) compared with placebo (55%).

Selexipag is indicated for mono, dual, or triple therapy. Treatment with stable doses of ERAs and/or PDE5s was permitted at the study start and new ERAs or PDE5s could be added during the study. The overall trial population was heterogeneous with respect to the number and type of concomitant PAH drugs and the trial was not specifically designed to compare monotherapy versus dual therapy versus triple therapy. Therefore, there is uncertainty regarding the population to which the results are generalizable, with respect to concomitant therapies.

Efficacy

The occurrence of death as a first primary outcome event from any cause up to seven days after the last dose of study drug was ▬ in the selexipag group ▬ compared with the placebo group ▬ ▬. This analysis of deaths is difficult to interpret because of competing events in the primary composite outcome. There were several other analyses of deaths that included a total of 100 and 105 patients in the selexipag and placebo groups, respectively, who died up to study closure (hazard ratio [HR] 0.97; 99% confidence interval [CI], 0.68 to 1.39).

The annualized numbers of hospitalizations per year for all causes were ▬ for the selexipag group and ▬ for the placebo group. There were no statistically significant differences in overall hospitalization rates or number of days spent in hospital after these rates were adjusted for cumulative time on study at the group level.

Overall, 140 selexipag patients (24.4%) and 212 patients (36.4%) had a clinical worsening (morbidity/mortality event; primary composite outcome). The results of the primary outcome were driven by hospitalization for PAH and disease progression. The HR for the primary outcome in the selexipag group was 0.61 (99% CI, 0.46 to 0.81), relative to placebo. This corresponds to a relative risk reduction of 39% and absolute risk reduction of 12% (see Table 1). The group-sequential trial design used a one-sided, family-wise, overall type I error rate of 0.005 for the primary and secondary end points based on a conditional hierarchy.

Table 1

Summary of Results.

Absence of worsening from baseline in WHO FC at week 26 was reported for 444 of 571 (77.8%) of patients in the selexipag group and 430 of 574 (74.9%) in the placebo group (odds ratio [OR] 1.16; 99% CI, 0.81 to 1.66; P = 0.19). There was no statistically significant difference in absence of WHO FC worsening and the hierarchical testing procedure was therefore halted at this stage. The 6MWD was the first secondary end point in the hierarchy to be tested. There were statistically significant improvements in the 6MWD results favouring selexipag compared with placebo (median difference of change 12 m), but this change is lower than the estimated minimal clinically important change of 33 m (see Appendix 5). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire was used in a subset of GRIPHON patients to assess PAH symptom changes, functioning, and quality of life; only changes on the Symptoms and Breathlessness scales were analyzed in the trial. There were no statistically significant differences between selexipag and placebo in the CAMPHOR questionnaire subscales. There were no statistically significant differences between selexipag and placebo in dyspnea score as measured by the Borg dyspnea index.

Harms

Most patients experienced an adverse event during GRIPHON and the difference in incidence of specific adverse events between selexipag and placebo was 5% or greater for headache, diarrhea, pain in jaw, nausea, myalgia, vomiting, pain in extremity, and flushing. Prostacyclin-like adverse events such as headache, diarrhea, nausea, pain in jaw, myalgia, pain in extremity, vomiting, and flushing were more common during the titration phase than in the maintenance dose phase.

Serious adverse events were reported in 252 patients (44%) in the selexipag group compared with 272 patients (47%) in the placebo group. Other than PAH worsening, the most common serious adverse events were right ventricular failure, pneumonia, dyspnea, syncope, and atrial fibrillation, all of which occurred at similar rates in the selexipag and placebo groups.

Fewer patients discontinued the study drug regimen in the selexipag group (32%) compared with the placebo group (37%). This was mainly due to worsening of PAH (Table 1).

Overall, 182 patients (32%) in the selexipag group and 214 patients (37%) in the placebo group discontinued their study regimen prematurely because of an adverse event. The most frequent adverse events leading to discontinuation in the selexipag group (events for which there was a greater than 1% difference between the selexipag and placebo groups) were headache (3%), diarrhea (2%), and nausea (2%). Hyperthyroidism occurred in eight patients in the selexipag group and led to treatment discontinuation in one patient.

Potential Place in Therapy

This information in this section is based on that provided in draft form by the clinical expert consulted by CADTH Common Drug Review (CDR) reviewers for the purpose of this review.

The clinical expert consulted by CDR discussed the unmet needs in this patient population, which included:

• Persistent symptoms and significant morbidity and mortality in patients despite aggressive combination therapy
• Lack of therapeutic options for patients with persistent symptoms who are not candidates for intravenous prostacyclin therapy.⁵

According to the clinical expert, selexipag has the potential to address both unmet needs, and it has a place in the pharmacotherapy of PAH. The data from the GRIPHON study suggest that selexipag delays clinical worsening in a population of patients that would be very similar to those whom PAH specialists treat in Canada. There is no way to make conclusions with respect to the comparative benefits and safety with selexipag versus other drugs, as no head-to-head studies or indirect comparisons have been done.

In practice, selexipag would not be a replacement for intravenous prostacyclins in patients who require and are candidates for such therapy, according to the clinical expert consulted. In addition, given the complexity of the drug with respect to administration and monitoring, relative to others available, it would likely not be used as a first-line drug.

The place in therapy rests on patients who fail to meet treatment goals despite background mono or dual therapy. This might include a New York Health Association (NYHA) II or early NYHA III patient who does not yet require escalation to intravenous prostacyclins; selexipag can be an option in this population, similar to all other oral drugs when making this decision. The other potential use for this drug would be in patients who are not candidates for intravenous prostacyclin therapies, such as those with advanced WHO FC III (IIIB) or IV symptoms, and/or those with cognitive, physical, or medical contraindications that would preclude safe use of a chronic indwelling intravenous catheter. This represents a very small percentage of patients; however, there is no evidence from the reviewed trial on outcomes for this specific subpopulation.

There are no additional specific diagnostic tests required to prescribe this drug beyond what is routinely done. The monitoring and titration is more complex, but with patient support programs, much of this could be done remotely.

The barriers to prescribing will largely involve tolerance, as the adverse effect profile is considerable and in line with other drugs targeting the prostacyclin pathway.