Potential future therapies

Macitentan 
Macitentan, also called ACT-064992, is a novel, highly potent, tissue-targeting dual ET-1 receptor antagonist characterized by a high lipophilicity [247]. Macitentan has been tested in the largest, long-term, event-driven randomized, controlled study (SERAPHIN, Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve clinical outcome) [246]. The Seraphin study was designed to evaluate the efficacy and safety of macitentan through the primary endpoint of time to first morbidity and all-cause mortality event in 742 patients with symptomatic PAH. Patients were treated for up to three and a half years.
Macitentan has met its primary endpoint, decreasing the risk of a morbidity/mortality event over the treatment period versus placebo. Secondary efficacy endpoints, including change from baseline to month six in 6-MWD, change from baseline to month six in NYHA FC and time – over the whole treatment period - to either death due to PAH or hospitalization due to PAH, also showed a dose-dependent effect. Treatment with macitentan in this study was well tolerated; headache, nausea and vomiting were reported as minor adverse events [248]. The safety set comprised 741 patients, who received at least one dose of study treatment (placebo, 3 mg or 10 mg). The number of adverse events reported and patients discontinuing treatment due to adverse events was similar across all groups. Similar elevations of liver aminotransferases greater than three times the upper limit of normal were observed in all groups. In addition, no difference was observed between macitentan and placebo in terms of fluid retention (edema). A decrease in hemoglobin - reported as an adverse event - was observed more frequently on macitentan than placebo, with no difference in treatment discontinuation between groups.

Vardenafil 
Vardenafil is another PDE5 inhibitor. Recently published data from a prospective, randomised study including 66 patients with PAH suggests improvement in 6-MWD and hemodynamic parameters after 3 months of treatment with vardenafil as compared to placebo. Side effects are not reported and proposed dosage is 5 mg twice daily [249]. However, further studies are needed.

Riociguat 
Endothelium-derived NO regulates vascular homeostasis through pulmonary arteries SMC relaxation via the activation of the second messenger cGMP. The clinical benefits associated with the PDE-5 inhibitor class has led to interest in testing whether other agents that modulate NO signaling might be similarly beneficial in PAH. Riociguat is a first-in-class drug that augments cGMP biosynthesis through direct stimulation of the enzyme soluble guanylate cyclase (sGC) promoting vasodilatation by direct stimulation of sGC in an NO-independent fashion, and by sensitization of sGC to low endogenous NO levels [250].
A phase I randomized placebo-controlled study in 58 healthy male subjects were given riociguat orally was designed to test the safety profile, pharmacokinetics and pharmacodynamics of single oral doses of riociguat (0.25–5 mg). A proof-of-concept study was conducted to investigate oral riociguat in patients with moderate to severe PH in a two-part, non-randomized, open-label, single center trial [251]. Riociguat was well tolerated in doses up to 2.5 mg, whereas 5 mg caused asymptomatic hypotension in one patient. Therefore the 2.5 mg dose was used in the second part of the trial to demonstrate efficacy. Riociguat significantly reduced mPAP, PVR and systemic vascular resistance and increased cardiac index [251]. Results from a multicenter, open-label, uncontrolled phase II trial involving 75 patients with PAH (n = 33) and chronic thrombo-embolic PH (n = 42) showed that 12 weeks of oral riociguat given 3 times daily conferred improvements in symptoms, NYHA FC, exercise capacity, NT-proBNP level, and pulmonary hemodynamics [252]. Riociguat is also under investigation in other form of PH as PH associated with chronic obstructive pulmonary disease, with interstitial lung disease or with left ventricular dysfunction [253-255].
The Phase III, double-blind, randomized, placebo-controlled PATENT-1 study investigated the efficacy and safety of riociguat in patients with symptomatic PAH [256]. Treatment-naïve patients and patients pre-treated with ERAs or prostacyclin analogues were eligible. Riociguat was titrated from a starting dose of 1 mg three times daily (t.i.d.) [range 0.5–2.5 mg t.i.d.]. The primary outcome was the change from baseline in 6-MWD at week 12. Secondary endpoints included the change from baseline in pulmonary vascular resistance (PVR), NT-proBNP, NYHA FC, clinical worsening, living with PH questionnaire and Borg dyspnea score. A total of 445 patients were randomized. Preliminary analysis showed a significant increase in 6-MWD from baseline of 35.8 m with riociguat versus placebo (95% CI 20.1–51.5 m, p < 0.0001). Predefined exploratory analyses indicated that riociguat improved 6-MWD in pretreated patients (+35.7 m [95% CI 15.0–56.3 m]) as well as treatment naïve patients (+38.4 m [95% CI 14.5–62.3 m]). Significant improvements were also seen in PVR (p < 0.0001), NT-proBNP (p < 0.0001), functional class (p = 0.003), clinical worsening (p = 0.0046), living with PH questionnaire (p = 0.002) and Borg dyspnea score (p = 0.002). Riociguat was well tolerated and had a favorable safety profile. Thus, riociguat may represent a new treatment option for patients with PAH. An open-label extension study (PATENT-2) will evaluate the long-term safety of riociguat in patients with PAH.

Selexipag 
Selexipag is an orally active prodrug metabolized to the highly selective prostacyclin IP receptor agonist ACT-333679 (previously known as MRE-269), which has a half-life of over 6 h [257]. With in high selectivity for the IP receptor over other prostanoid receptors (at least 130-fold selectivity), selexipag can be distinguished from beraprost or iloprost currently used in the management of PAH [258]. With no affinity for the prostaglandin E receptor 3 (EP3), selexipag exerts similar vasodilatory activity on both large and small pulmonary arterial branches [259] and its relaxant efficacy is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease such as ET-1 [260]. Preclinical study results showed that twice-daily administration of selexipag attenuates right ventricular hypertrophy, improves pulmonary hemodynamics, and significantly increases survival in MCT-treated PH rats [259].
A phase II study, involving 43 PAH patients showed that treatment with selexipag for 17 weeks conferred significant improvements in PVR (−30.3% versus placebo) compared with placebo [261]. Treatment with selexipag was well tolerated by most patients in this study. Adverse events were consistent with the known side effect profile of IPr agonism such as headache, pain in extremity, pain in jaw, nausea, and diarrhea. These side effects decreased over time in patients treated with selexipag [261].
A phase III randomized trial GRIPHON [262] to examine the effect of selexipag on morbidity and mortality in PAH is underway and will afford more information regarding efficacy and safety of selexipag.

Tyrosine kinase inhibitors 
One of the most promising targets in PAH is platelet-derived growth factor (PDGF). PDGF has been implicated in endothelial cell dysfunction and proliferation and migration of smooth muscle cells. It has been suggested that PDGF may play a role in PAH [263-265]. Pulmonary vascular remodelling in different animal models of PAH was shown to regress with the administration of imatinib mesylate (Gleevec®), a PDGF receptors antagonist approved for the treatment of chronic myeloid leukaemia [266]. Moreover, case reports suggest a beneficial effect of imatinib among severe PAH patients and a first randomized (imatinib vs placebo), double-blind, 24 weeks Phase II study was performed in 59 PAH patients in NYHA functional class II to IV receiving specific PAH therapies [267]. The primary endpoint (6-MWD after 24 weeks) was not different between 2 groups (+22 m in imatinib group as compared to placebo) even if a significant improvement of hemodynamic parameters was observed, especially among the patients with the most severe hemodynamic compromise [267]. This preliminary study does not allow concluding on the potential benefits of imatinib in PAH, but led to development of a phase III clinical trial (IMPRES) evaluating imatinib in a randomized controlled double-blind trial of 24-week, in 202 severe PAH patients treated with at least two PAH specific drugs. After 24 weeks, a significant improvement in the primary endpoint, 6MWD, was observed (+32 m in imatinib group vs. placebo) as well as an improvement of secondary endpoints including hemodynamic parameters [268]. However, several cases of subdural hematoma were reported in patients treated with imatinib: 2 cases in the double-blind period of 24 weeks and 7 supplemental cases in an open-label extension phase of the study. The mechanism of these subdural hematomas is not elucidated and the high incidence observed may be partly favored by anticoagulation recommended for PAH patients. Subdural hematoma is a complication of imatinib previously reported in other settings where it has been used, including oncology or pulmonary fibrosis. Netherless, this complication has rarely been reported in previous clinical trials in PAH or in registries. In addition, it has been demonstrated that tyrosine kinase inhibitors, including imatinib, may have possible cardiac adverse effects on long term use that might limit its benefice in PAH [269]. According to these results, the benefit/risk ratio of imatinib in PAH was not considered to be sufficient and to date, the use imatinib was not recommended in PAH.