INNOVATION IN PHARMACEUTICAL TREATMENT OF PULMONARY ARTERIAL HYPERTENSION: STIMULATOR OF SOLUBLE GYANYLATE CYCLASE - RIOCIGUAT

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease, diagnosed at a late stage with low functional class III or IV (WHO). PAH leads to severe right heart failure and ultimately, death. The modern researches aim at exploring the potential therapeutic targets, as at developing new drugs that can affect the previously set target. Impaired NO production plays an important role in PAH pathogenesis; this is determined by the powerful vasodilatory action, as well as anti-inflammatory, anti-proliferative, and antiaggregatory effects. Riociguat is the first in a new class of soluble guanylatecyclase stimulators to have proved efficacy in phase II of clinical trials. In the randomized, double-blind, placebo-controlled phase III study PATENT-1 (Pulmonary Arterial Hypertension soluble Guanilatcyclase-Stimulator Trial) study, 443 patients with PAH symptoms were randomized to receive placebo of riociguat in a single dose of 2,5 mg (with a dose titration based on tolerability to 2,5 mg TID a day) or a dose of 1,5 mg (with a dose titration according to portability to 1,5 mg TID three times a day). The study included naïve patients treated with endothelin receptor antagonists or prostanoids (except for parenteral ones). To 12wk of riociguat treatment the mean distance in 6-MWT increased by an average of 30 m in the group treated with the maximum single dose of 2,5 mg TID, or decreased by an average of 6m in the placebo group (difference between groups, 36 m, 95% confidence interval 20-52 m, p p<0,001). Riociguat improved 6-MWT in patients not previously treated with PAH-specific therapy (38 m), and in patients, taking endothelin receptor antagonists or prostanoids (36 m). In riociguat groups compared with placebo a decrease in PVR and PAPm (p<0,01) was noted, as well as an increase in cardiac index (p<0,0001) , a reduction in NT-proBNP (p<0,0001) , FC (p=0,003) and in the Borg index (p=0,002), ), the time of development of clinical deterioration (p=0,005) prolonged as well. Riociguat therapy was also characterized by good tolerance. Efficacy of treatment was maintained during long-term observation of PATENT-2study. The mean value of 6-MWT changed to 51±74 м