Riociguat is an oral medication that stimulates an enzyme called guanylate cyclase. It is approved (and marketed by Bayer under the brand name Adempas) for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

Pulmonary hypertension — a type of high blood pressure that affects the blood vessels (arteries) in the lungs and the right side of the heart — also can occur in patients with sickle cell disease. Because of that, riociguat also is being studied in a clinical trial (NCT02633397) conducted by researchers at the University of Pittsburgh, to treat pulmonary hypertension in patients with sickle cell disease.

How riociguat works

Riociguat works by increasing the activity of guanylate cyclase, an enzyme that produces cyclic guanosine monophosphate (cGMP) upon activation by nitric oxide (NO), which is an important regulator of vascular function in the lungs and other parts of the body. cGMP functions as a smooth muscle relaxant that causes the blood vessels (arteries) to relax and widen.

In sickle cell disease, the NO signaling pathway is disrupted. So, therapies enhancing this pathway may improve blood vessel function and reduce symptoms of the disease.

Riociguat-mediated activation of guanylate cyclase increases the availability of cGMP in the blood vessels within the lungs, which leads to their relaxation and widening. This reduces the blood pressure within the lungs, improving heart function and the ability to be more active.

Riociguat in clinical trials

A case series of 6 patients with sickle cell disease was published in 2018. Riociquat was found to be safe and well-tolerated in 4 of the 6 patients. Riociguat was also found to be effective in half of the patients, shown through significant improvements in the six-minute walk test, World Health Organization functional class scale, right ventricular systolic pressure, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. The study results were encouraging but the authors stressed the need for a larger, long-term clinical trial.

A multi-center, randomized, double-blind, placebo-controlled, parallel-group Phase 2 study (NCT02633397) aims to evaluate the safety, tolerability, and effectiveness of riociguat compared to placebo in approximately 100 patients with sickle cell disease.

This study includes a treatment period of 12 weeks (with riociguat or placebo) and a follow-up period of 30 days after treatment. The blood pressure and the well-being of the patients will be monitored every two weeks to adjust the dose of the treatment. Patients will undergo several tests (including physical examinations, assessment of vital signs, blood tests, and questionnaires assessing well-being), which will be performed every two weeks during the treatment. The treatment phase will begin and end with the assessment of echocardiogram, urine tests, six-minute walk test, and questionnaires.

The study is recruiting at various sites across the U.S. and is expected to be completed in June 2021. Click here for more information about recruiting and trial locations.

Other information

Riociguat is generally well-tolerated. The most common side effects are headache, dizziness, indigestion, nausea, diarrhea, low blood pressure, vomiting, anemia, and constipation.

Riociguat should not be taken before, during or after pregnancy because it may cause serious birth defects. Riociguat should not be taken by patients with severe liver disease or severe kidney dysfunction. Nursing mothers also should not take riociguat.

The safety and effectiveness of riociguat in children are not known.


Last updated: Dec. 27, 2019


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