General Information

Adempas (riociguat) is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). These stimulators help arteries relax to increase blood flow and decrease blood pressure.

Adempas is specifically indicated for persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class and Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening.

Adempas is supplied as a tablet for oral administration. The recommended initial dose is 1 mg taken three times a day. For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg, three times a day. The dose may be increased by 0.5 mg at intervals of no sooner than 2-weeks as tolerated to a maximum of 2.5 mg three times a day.

Clinical Results

FDA Approval
The FDA approval of Adempas was based on CHEST-1 for CTEPH and PATENT-1 for PAH.
CHEST-1
This multi-center, double-blind, randomized, placebo-controlled trial enrolled 261 subjects with inoperable chronic thromboembolic pulmonary hypertension. The subjects were randomized to either riociguat or placebo orally for 16 weeks. Riociguat was titrated, over a period of eight weeks in doses of 0.5 mg increments, from 1.0 mg up to 2.5 mg, three times a day. After the titration phase, subjects were followed up for another eight weeks on their last dose. The study met its primary endpoint by demonstrating a statistically significant improvement in the six-minute walk distance (6MWD); subjects treated with riociguat showed an improvement of 46 meters (p<0.0001) compared to those treated with placebo. Riociguat also showed statistically significant improvements in secondary endpoints including pulmonary vascular resistance (p<0.0001), N-terminal prohormone brain natriuretic peptide (p<0.0001) and WHO functional class (p=0.0026).
PATENT-1
Pulmonary Arterial Hypertension sGC Stimulator Trial. This multi-center, double-blind, randomized, placebo-controlled trial enrolled 445 subjects with pulmonary arterial hypertension who were either treatment-naïve or being treated with an endothelin receptor antagonist or a prostacyclin analog. The subjects were randomized to receive either placebo or two different doses of riociguat orally over a period of 12 weeks. The riociguat dose was titrated over a period of eight weeks in doses of 0.5 mg increments, from 1.0 mg up to 2.5 mg three times daily. Subjects were then followed for an additional four weeks. The primary endpoint was the change from baseline in the six-minute walking distance test after 12 weeks of treatment. A statistically significant improvement was demonstrated for the primary endpoint; subjects treated with riociguat showed an improvement of 36 meters (p<0.0001) after 12 weeks compared with placebo. Trial results also showed a statistically significant improvement in 6MWD both in the treatment-naive group (38 meters after 12 weeks compared with placebo) and the pre-treated group (36 meters after 12 weeks compared with placebo).

Mechanism of Action

Adempas (riociguat) is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.

Literature References

Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. The New England Journal of Medicine 2013 Jul 25;369(4):319-29

Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group Riociguat for the treatment of pulmonary arterial hypertension. The New England Journal of Medicine 2013 Jul 25;369(4):330-40