As the endothelial dysfunction associated with the development of PAH results in decreased production of the endogenous vasodilatory mediators NO and downstream cyclic guanylate monophosphate (cGMP), modulators of the NO pathway continue to be investigated. Riociguat is a novel compound that acts on the NO pathway by stimulating soluble guanylate cyclase (sGC). Unlike PDE-5is, which prevent the breakdown of cGMP, riociguat promotes the production of cGMP by both sensitizing sGC to endogenous NO and directly stimulating sGC independently of NO ¹⁴ .

The efficacy of riociguat was tested in the PATENT-1 (PAH Soluble Guanylate Cyclase-Stimulator Trial 1) and PATENT-2 trials. PATENT-1 was a multicenter, randomized, double-blind, placebo-controlled trial of riociguat in 443 World Health Organization (WHO) group 1 PAH patients with or without background therapy with ERAs or prostacyclins or both ¹⁵ . Background PAH therapy did not include a PDE-5i or other stimulators of the NO pathway. This study found that riociguat was beneficial for PAH patients regardless of underlying functional class (FC) or background therapy, as demonstrated by a statistically significant increase in 6-minute walk distance (6MWD) of 30 m in the treatment group compared with a decrease of 6 m in the placebo group at 12 weeks ( P ≤0.001). The active drug group also had improvements in secondary endpoints, including PVR, N-terminal pro-brain natriuretic peptide (NT-proBNP), FC, and time to clinical worsening (TTCW) ¹⁵ . Riociguat was approved by the US Food and Drug Administration (FDA) for the treatment of WHO group 1 PAH in October 2013. PATENT-2, the long-term open-label extension trial, enrolled 396 of the 443 patients from PATENT-1, and all patients were transitioned to active treatment with riociguat at 2.5 mg three times per day ¹⁶ . Trial investigators found that the improvements in 6MWD and WHO FC were maintained for up to 1 year. Compared with PATENT-1 baseline values, the 6MWD improved by 51 ± 74 m and the WHO FC improved in 33% of the patients.

In 2015, the PATENT PLUS study, a blinded, randomized, extension study of riociguat in PAH, evaluated the safety and efficacy of riociguat in combination with the PDE-5i, sildenafil ¹⁷ . A total of 18 PAH patients receiving sildenafil 20 mg three times per day were randomly assigned to placebo or riociguat for 12 weeks. There was no significant clinical benefit to combination riociguat/sildenafil therapy, and long-term follow-up (mean total treatment duration of 305 days) showed higher rates of discontinuation of therapy in the combination arm because of hypotension. Although the study was small, the lack of a positive risk-benefit ratio and potential for adverse long-term effects concluded that concomitant use of riociguat with a PDE-5i is contraindicated.

The SERAPHIN (Study with an Endothelin Receptor Antagonist in PAH to Improve Clinical Outcomes) study was a randomized, double-blind, placebo-controlled, phase 3 trial designed to test macitentan, a once-daily oral dual endothelin A/B (ETA/ETB) receptor antagonist that exhibits high binding affinity to ETA and greater tissue penetration than the parent molecule, bosentan ¹⁸ . The primary endpoints of SERAPHIN, in contrast to those of prior studies with ERAs which have looked at changes in 6MWD at short time intervals (12 to 16 weeks), were morbidity and mortality measured through a composite TTCW event, defined as worsening PAH, initiation of parenteral prostanoids, lung transplantation, atrial septostomy, or death. Changes in exercise capacity, FC, and hemodynamics were collected as secondary endpoints. In total, 742 predominantly WHO FC II and III patients were recruited from 151 centers in 39 countries and randomly assigned to receive placebo (n = 250) or macitentan 3 mg (n = 250) or 10 mg (n = 242). Most patients (64%) were on background therapy with PDE-5i or prostanoids or both, whereas 36% were treatment naïve at baseline. Over a period of 115 weeks, the primary endpoint occurred in 46.4% of patients in the placebo group, 38.0% of patients in the macitentan 3 mg group, and 31.4% of patients in the macitentan 10 mg group. Worsening PAH was the most frequently documented endpoint regardless of whether patients were on background therapy. Although there was no significant difference in mortality among the three groups, there was significant improvement in secondary endpoints at 6 months (FC, exercise capacity, and hemodynamics). The major side effects noted with macitentan were headache, nasopharyngitis, and anemia; however, there were no differences in rates of transaminitis or edema. Based on the clinical efficacy and safety profile, the FDA approved macitentan 10 mg in 2013 as an oral therapy for WHO group 1 patients with FC II and III symptoms. Of note, a study published in 2015 showed that disease progression was reduced in the treatment-naïve cohort in SERAPHIN in both incident (diagnosis <6 months, n = 110) and prevalent (>6 months, n = 157) patients taking macitentan ¹⁹ .

Although there is evidence that prostanoid therapy improves both morbidity and mortality in PAH, such therapy is under prescribed ²⁰ . As a result, the search for effective and well-tolerated routes of delivery for prostanoid therapy continues. The series of FREEDOM studies (FREEDOM-M, -C, and -C2) trialed the use of treprostinil diolamine, an oral form of the prostacyclin analogue treprostinil. In FREEDOM-M, a randomized, placebo-controlled, phase 3 study of 349 treatment-naïve PAH patients, there was significant improvement in 6MWD by 23 m at 12 weeks (95% confidence interval of 4 to 41 m, P = 0.0125) but no improvement in FC or TTCW ²¹ . Based on these results, oral treprostinil was FDA approved as monotherapy in PAH patients in 2013. Oral treprostinil is contraindicated in patients with Child-Pugh stage 3 hepatic impairment because of hepatic metabolism of the drug and is discouraged for use in pregnant women ²² .

In the first completed oral treprostinil study, FREEDOM-C, up-titration of the drug was limited by drug tolerance ²³ . In contrast, FREEDOM-M showed that divided low-dose administration, starting at 0.125 or 0.25 mg and increased gradually every 3 or 4 days, improved tolerance. This ultimately may aid in improved patient adherence and ability to prescribe the drug early in the disease course. Future directions from this study include investigations of whether the effects seen with escalating doses of intravenous (IV) prostanoid therapy are also seen with oral therapy, as well as assessing the efficacy of oral treprostinil compared with other oral therapies ²⁰ .

As stated above, given the efficacy of prostanoid therapy, much focus has been placed on the development of oral medications that target this pathway. Selexipag is one such drug; it is a highly selective, high-affinity agonist of the prostacyclin receptor. In a placebo-controlled, phase 2 trial, selexipag was shown to increase cardiac index and significantly reduce PVR by 33% at week 17 in patients who were already receiving PAH treatment ²⁴ . The subsequent GRIPHON (Prostacyclin Receptor Agonist in PAH) study was an event-driven, multicenter, double-blind, placebo-controlled, phase 3 trial of 1,156 patients randomly assigned to selexipag or placebo ²⁵ . Patients eligible for enrollment included treatment-naïve patients and those who were receiving an ERA or PDE-5i (or both) at stable doses. Patients receiving prostanoid therapy were excluded. The primary endpoint, a composite of all-cause mortality and any PAH complication, occurred in 42% of patients in the placebo arm and 27% of patients in the selexipag arm (hazard ratio of 0.60, P <0.001). This effect was similar in the subgroups of treatment-naïve patients and patients on background PAH treatment, suggesting a potential for selexipag to be used as combination therapy with other currently available oral treatments. There was a significant reduction in 6MWD but no significant difference in mortality between the two study groups. Future directions from the GRIPHON study may include investigation for the efficacy of selexipag compared with parenteral prostanoid therapy, or its effects in patients with earlier disease course, as more than half of all patients in the study were classified as FC III or IV.

Current methods for delivery of treprostinil include subcutaneous (SC) continuous infusion, IV continuous infusion, inhaled, and, now, oral. The highest doses achievable with treprostinil are with the SC or IV infusion. However, significant adverse events may be associated with both of these. The SC infusion is associated with significant site pain, whereas the IV administration via central venous catheters is associated with an increased risk for bloodstream infections and accidental interruption. To mitigate these events, a new, fully implantable intravascular delivery system for treprostinil infusion was investigated in the DelIVery trial ²⁶ . In this multicenter, prospective, single-arm clinical trial, an implantable drug delivery system was studied in 60 WHO group 1 PAH patients, with stable WHO FC I, II, or III symptoms, on a steady dose of IV treprostinil. System implantation consisted of the placement of a pump device in an abdominal pocket, which was connected to a tunneled catheter that inserted into the superior vena cava via a subclavian, cephalic, jugular, or axillary vein. At 6 months after implantation, there were no catheter-related bloodstream infections or catheter occlusions. Complications included those related to the implantation procedure, the catheter itself including catheter dislocation and venous stenosis, the pump e.g. pump pocket seroma, and the process of refilling the pump. The complication rate was 0.27 per 1,000 patient-days, and the 97.5% upper one-sided confidence bound (0.59 per 1,000 patient-days) was significantly less when compared with an objective performance criterion (2.5 complications per 1,000 patient-days). Additionally, there was a high rate of patient satisfaction with the implantable pump system, and WHO FC and 6MWD were maintained.

This study was limited by the absence of a parallel control group, and the authors noted a decrease in delivered drug past 6 months after implantation. As such, further investigation is needed to document the safety and accuracy of the delivery system prior to receiving FDA approval.