Adempas (riociguat) is an approved treatment for the symptoms of pulmonary hypertension.

Bayer developed it for chronic thromboembolic pulmonary hypertension, or CTEPH, and pulmonary arterial hypertension, or PAH.

How Adempas works

Both CTEPH and PAH cause lung blood vessels to narrow. The result is higher blood pressure as the blood finds it more difficult to flow through the lungs. Slower blood flow reduces the transport of oxygen from the lungs to the rest of the body, lowering patients’ exercise capacity.

Adempas is designed to relax arterial muscle walls. This causes the arteries to widen, or vasodilate, allowing blood to flow more freely. The result is lower blood pressure and increased oxygen flow around the body.

Normally vasodilation is driven by production of the chemical nitric oxide. Nitric oxide activates an enzyme called soluble guanosine cyclase, or sGC, which can drive the production of a compound known as cyclic guanosine monophosphate, or cGMP. cGMP then triggers vasodilation. In patients with pulmonary hypertension, a reduction in nitric oxide production limits the signaling needed to achieve vasodilation.

Adempas uses two mechanisms to increase the production of cGMP. It activates sGC independently of nitric oxide. And it increases sGC’s sensitivity to nitric oxide, increasing the chance of sGC activation even when there are significantly lower levels of nitric oxide. The higher levels of cGMP trigger vasodilation in pulmonary arteries.

Adempas in clinical trials

The pivotal clinical trial that led to Adempas’ approval as a CTEPH therapy was the Phase 3 CHEST-1 study (NCT00855465). The randomized, double-blind, placebo-controlled trial covered 262 patients at 131 locations worldwide. They received Adempas or a placebo for 16 weeks.

Adempas significantly lowered patients’ pulmonary vascular resistance — a measure of the effort required for blood to flow through lung arteries — compared with a placebo-treated group.

It also increased patients’ exercise ability. Patients who took it added 39 meters to the distance they could walk in six minutes, compared with a decrease of six meters in the placebo-treated group. The study was published in the New England Journal of Medicine.

Patients completing CHEST-1 were eligible to enroll in the long-term extension study CHEST-2 (NCT00910429). The results of CHEST-2, published in The Lancet Respiratory Medicine, showed that  Adempas increased the time it took for patients’ condition to worsen, and was safe for long-term use.

A total of 237 patients enrolled in CHEST-2. After two years, the group’s overall survival rate was 93 percent, with 82 percent not experiencing a significant worsening of their symptoms.

The results of the Phase 3 PATENT-1 study (NCT00810693) were key to Adempas’ approval as a PAH therapy. The randomized, double-blind, placebo-controlled study involved 445 PAH patients at 177 sites worldwide. Patients received either a high or low dose of Adempas three times a day for 12 weeks.

The treatment led to a significant improvement in patients’ exercise capacity. The six-minute walking distance of the high-dose group increased by 30 meters. The placebo group’s distance decreased by six meters. The results were published in the New England Journal of Medicine.

The long-term extension study, PATENT-2 (NCT00863681), involved 396 patients who had completed PATENT-1. The results, discussed in The Lancet Respiratory Medicine and the Annals of the Rheumatic Diseases, supported the safety and potential effectiveness of long-term use of Adempas, researchers said.

Adempas has also been studied in combination with other drugs. For example, Bayer completed a Phase 2 trial (NCT01179334) called PATENT-PLUS that investigated Adempas in combination with Pfizer’s Revatio (sildenafil) in 18 PAH patients. The findings, published in the European Respiratory Journal, showed no evidence of a significant benefit and some safety concerns.

Other information

The U.S. Food and Drug Administration approved Adempas to treat both CTEPH and PAH in October 2013.

The most common side effects associated with Adempas are indigestion, gastritis and headache. Serious side effects include coughing up blood and bleeding in the lungs.

Adempas is also being studied as a treatment for other conditions, including sickle cell anemia (NCT02633397) and scleroderma (NCT02915835).

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