A New Pulmonary Arterial Hypertension Drug on the Horizon

Mary Blanton Wheeler, PharmD, MPH

Tracy E. Macaulay, PharmD, AACC , BCPS (AQ Cardiology)

Review

Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340.

Pulmonary arterial hypertension (PAH) is characterized by chronically increased pulmonary arterial pressure and is associated with a 3- to 5-year survival rate ranging from 50% to 80%, depending on underlying etiology. The mean age of diagnosed patients is 50 years, and women are affected more commonly than men.¹ Pharmacologic options are limited and treatments for severely symptomatic disease are very complex. Additional pharmacologic alternatives that decrease progression of disease and delay requirement of IV or subcutaneous treatment modalities are needed.

The pathophysiology of idiopathic PAH involves a defect in the ability of the pulmonary vasculature to appropriately dilate in response to increased pressure and vascular shear forces secondary to the flow of blood. Current FDA-approved drug therapies promote vasodilation. In properly functioning vessels, increased blood flow forces open calcium channels in the endothelium, thus leading to a calcium- dependent activation of endothelial nitric oxide (NO) synthase (eNOS), which causes a release of NO. NO diffuses in the vascular smooth muscle and activates soluble guanylate cyclase (sGC), which increases the production of cGMP, subsequently leading to smooth muscle relaxation.^2,3

Current therapy options include calcium channel blockers, phosphodiesterase-5 inhibitors, endothelin antagonists, and prostacyclin analogues. Prostacyclin treatments are administered as continuous parenteral infusions or may be inhaled or delivered subcutaneously. Stability issues and pharmacokinetic properties of these medications make for complicated, error-prone dosing schemes; health literacy and patient accountability are also issues when prescribing prostacyclin analogues. Therefore, development of safe and efficacious oral agents that can postpone the need for parenteral/inhaled therapy is of great value to the PAH community.³

Study Details

The Pulmonary Arterial Hypertension Soluble Guanylate Cyclase- Stimulator trial-1 (PATENT-1) was a randomized, double blind, placebo- controlled trial comparing riociguat, a novel guanylate cyclase stimulator agent, with placebo in patients with symptomatic PAH.³ PATENT-1 was supported by Bayer Healthcare.

Patients were included in the study if they had a pulmonary vascular resistance >300 dyn∙sec∙cm^-5, a mean pulmonary-artery pressure of at least 25 mm Hg, and a 6-minute walk distance of at least 150 m to 450 m. Patients were either treatment naïve or receiving concomitant therapy with endothelin-receptor antagonists or prostanoids (excluding IV) at stable doses for at least 90 days. Diuretics and anticoagulants were permitted, although patients receiving phosophodiesterase-5 inhibitors were excluded. A total of 443 patients were enrolled from December 2008 to February 2012. The primary end point was change from baseline in 6-minute walk distance after 12 weeks of therapy.

Patients were randomized in a 2:4:1 ratio to receive placebo, highdose riociguat (up to 2.5 mg 3 times/d), or low-dose riociguat (up to 1.5 mg 3 times/d), with a starting dose of riociguat in both groups of 1 mg 3 times/d, titrated as systolic blood pressure would allow. End points of the low-dose group were considered exploratory, and results were not included in the analysis. In the higher-dose riociguat group, 75% achieved the maximum total daily dose of 7.5 mg, while 3% received dose reductions and were taking only 0.5 mg 3 times/d.

The groups were well matched at baseline. The majority of patients were WHO functional class II and III, and most had idiopathic PAH. At baseline, both the placebo and treatment groups had pulmonary capillary wedge pressure of ~9 mm Hg, evidence that neither group had hemodynamically significant left ventricular systolic dysfunction. Roughly 44% of patients were also receiving an endothelin-receptor antagonist, while only 6% were on a prostacyclin analogue. The average 6-minute walk distance was 363 (± 69) m.

In the modified intention-to-treat population, the high-dose riociguat group was found to be statistically superior to placebo for the primary efficacy outcome of 6-minute walk distance. In the riociguat group, the distance was increased by 30 m; in the placebo group, the distance had decreased by 6 m (P <0.001). The secondary end points of pulmonary-artery pressure, cardiac output, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, WHO functional class, and Borg dyspnea scale scores were also improved with riociguat therapy as compared with placebo (all P values <0.003). Patients in the riociguat group also showed significantly lower incidence of events indicating clinical worsening. Exploratory end points including EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D) score and Living with Pulmonary Hypertension Questionnaires (LPH) were nominally different between treatment and control.

Safety outcomes were reported descriptively and did not include P values. In the high-dose riociguat group 3% of patients discontinued riociguat because of adverse events, while 7% in the placebo group discontinued. The most common adverse effect was headache (27% in the riociguat group vs 20% in placebo), and the most frequently occurring serious adverse effect was hypotension (1% in the riociguat group vs 4% in placebo).

CommentaryA Promising New Agent for PAH

Riociguat is a new agent with a unique mechanism of action. A member of the soluble guanylate stimulator class, riociguat increases sensitivity to low levels of NO to stimulate guanylate cyclase. Additionally, riociguat directly stimulates sGC in order to promote vasodilation in the pulmonary artery.³ The drug’s mechanism of action offers a new approach to modifying the pathophysiology of PAH, and if FDA approved will expand the armamentarium of therapies for the treatment of this disease.

Phosphodiesterase-5 inhibitors are another class of PAH medications with mechanisms acting on the NO signaling pathway.⁴ Sildenafil and tadalafil are FDA approved for treatment of PAH; both agents inhibit the breakdown of cGMP through the inhibition of phosphodiesterase-5, implying a dependence on the presence of NO to stimulate the pathway. This reliance on the intact NO-sGCcGMP axis may explain why some patients are not responsive to treatment with agents such as sildenafil. Riociguat bypasses NO by increasing sensitivity to low levels and directly stimulating sGC, suggesting it may have a role for patients not responsive to PDE-5 agents.

The Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) trial compared multiple doses of sildenafil with placebo (n = 256). The patient population and end points studied in this trial were similar to PATENT-1, including exercise capacity (6-minute walk distance), pulmonary pressure, Borg dyspnea score, and time to progression of disease. However, no concomitant medications intended for the treatment of PAH were permitted in the study. SUPER patients in the sildenafil group had a statistically significant improvement in 6-minute walk distance and in hemodynamics.⁴ However, unlike the results in PATENT-1, sildenafil did not show improvement in the Borg dyspnea score, nor did it prove to have a statistically significant impact on time to clinical worsening or incidence of clinical worsening. Comparison may be made with the ~50% of patients (n = 66) in PATENT-1 who were on riociguat monotherapy, in whom riociguat was able to demonstrate added benefit to the primary end point of 6-minute walk distance with a least squares mean improvement of 38 m (95% confidence interval [CI]; 16-60).

Combination tadalafil and stable-dose bosentan was allowed in the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) trial, and this combination was present in 53% of patients. In PHIRST, patients with baseline bosentan therapy did not have a statistically significant improvement in the primary end point of 6-minute walk distance (change of 24 m; P = 0.09).⁵ In PATENT-1, improvement was shown in both treatment-naïve and pretreated groups with a least squares mean improvement in the concomitant endothelin receptor antagonist group of 24 m (95% CI; 1-48) and in the concomitant prostanoid group of 106 m (95% CI; 38-173). Most of the statistical improvement in the pretreated group was driven by improvements in the prostanoid group; nevertheless, this suggests that riociguat may have a greater role as additive therapy compared with PDE-5 inhibitors.³ Progression of PAH ultimately requires utilization of prostacyclin therapy; thus, increasing the time and/or trajectory of decline is likely an important end point and may highlight an advantage of riociguat over PDE-5 inhibitors, although direct comparison with sildenafil and randomized trials to evaluate combination therapy is warranted.

Regarding safety, riociguat had an extremely low incidence of severe adverse reactions, with hypotension being the most common. In PATENT-1, however, there were few cases of serious hypotension (none were symptomatic) and these were not significant relative to placebo. Another potential disadvantage of riociguat is the requirement of frequent dosing; therefore, barriers to adherence are to be expected.⁶ This regimen is still far simpler than those of prostacyclin analogues and similar to sildenafil. The other oral agent alternative, endothelin antagonists, may be dosed once daily; however, the toxicity profile (including teratogenicity) of these agents supports the first-line use of sildenafil or potentially riociguat.⁷

The primary end point of 6-minute walk distance has proposed prognostic significance in patients with PAH, and has been used as the primary end point for studies in the approval of at least 7 drugs for PAH. However, the use of 6-minute walk distance has been challenged by some as a surrogate end point in PAH drug studies. Gabler et al⁸ conducted a validation study of the 6-minute walk distance for PAH and concluded that this end point explains only a small portion of treatment effect, and may not be sufficient as a lone primary end point. Therefore, there is no conclusive information regarding the clinical relevance or mortality benefit associated with these oral medications, and further analysis that provides more information regarding end points such as mortality is warranted.

In conclusion, riociguat serves as a reasonable first-line alternative to PDE-5 inhibitors for PAH WHO functional class II or III, or in combination therapy with an endothelin antagonist or inhaled prostacyclin analogues. There are several advantages of this medication over sildenafil, including utility in PDE-5 refractory patients because of the NO bypassing mechanisms. PATENT-1 was also able to show statistically significant improvement in secondary end points such as clinical worsening and Borg dyspnea score, end points in which sildenafil failed to demonstrate a difference when compared with placebo. PATENT-1 was not designed to show the impact of riociguat on mortality outcomes, so conclusions about long-term outcomes associated with this medication cannot be made at this time. However, PATENT-2, an extension study of PATENT-1, seeks to provide information regarding longer-term outcomes of patients on riociguat therapy.

References

1. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023-1030.

2. Giles TD, Sander GE, Nossaman BD, Kadowitz PJ. Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial- derived hyperpolarizing factors, and prostaglandins. J Clin Hypertens (Greenwich). 2012;14(4):198-205.

3. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330- 340.

4. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005; 353:2148-2157.

5. Galie N, Brundage BH, Gofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894-2903.

6. Pullar T, Birtwell AJ, Wiles PG, Hay A, Feely MP. Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily. Clin Pharmacol Ther. 1988;44:540-545.

7. Grimminger F, Weimann G, Frey R, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009;33:785-792.

8. Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012;126:349-356.

About the Author

Mary Blanton Wheeler, PharmD, MPH, is a Cardiology Pharmacy Specialty Resident at University of Kentucky HealthCare Pharmacy Services and Jack and Linda Gill Heart Institute in Lexington, KY. She was assisted in the writing of this article by Tracy E. Macaulay, PharmD, AA CC, BCPS-AQ Cardiology, Clinical Pharmacy Specialist- Cardiology, PGY2 Residency Program Director-Cardiology, and Adjunct Assistant Professor at University of Kentucky HealthCare in the Department of Pharmacy Services and Division of Cardiovascular Medicine, Lexington, KY.