Riociguat is the active ingredient of Adempas, an oral drug is marketed by Bayer and approved in the U.S., Europe, and Japan to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat works by helping arteries relax, so as to increase blood flow and decrease blood pressure. It is now in clinical testing as a potential treatment for other diseases, including scleroderma and cystic fibrosis (CF).

History of riociguat

In the U.S., riociguat was approved by the U.S. Food and Drug Administration (FDA) in October 2013 to treat both PAH and CTEPH. In Europe and Japan, the therapy was approved the following year for the same indications. Previously, riociguat was designated an orphan drug, or potential rare disease treatment, by both the FDA and the European Medicines Agency, the regulatory agency for the European Union.

A Phase 2 clinical trial (NCT02170025) is now testing riociguat for safety and tolerability, and signs of early efficacy, in CF patients homozygous for the F508del mutation in the CFTR gene who are not taking Orkambi (lumacaftor/ivacaftor).

How riociguat works

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme of the cardiopulmonary system that acts as a receptor for nitric oxide (NO).  Once sGC bonds to NO, another enzyme — cyclic guanosine monophosphate (cGMP) — is created, and studies report that this system, the sGC-NO-cGMP pathway, may regulate CFTR channel conductivity. In stimulating the sGC enzyme, riociguat is known to support vasodilation by relaxing smooth muscle cells in vessel walls.

In clinical studies that led to its approval for PAH and CTEPH, riociguat was seen to offer sustained benefits to patients, as measured by improvements in the 6-minute walk distance test. Evidence from preclinical testing points to riociguat’s potential to improve the function of the CFTR protein as a chloride channel, so that salt and fluids more readily in and out of cells.

Next steps for riociguat

The Phase 2 study (NCT02170025) now underway in CF patients homozygous with the F508del mutation is actually a two-part study. In the first part, a double-blind and randomized study, two doses of riociguat (0.5 mg and 1 mg) will be compared to placebo in adults patients not using Orkambi or other CFTR modulators. The lower dose will be given for the first 14 days and the higher over the following 14 days. The second part is intended to be open-label, and will test four increasing dose levels of riociguat (0.25 mg, 0.5 mg, 1 mg and 2 mg), each again given over 14 days, in two patient groups: those using Orkambi and those not using it.

This study is currently recruiting eligible CF patients in the United States, across Europe, and in Ontario, Canada; information is available through the trials identification number, above.

Final data is expected in 2018.

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