The US Food and Drug Administration’s (FDA’s) Cardiovascular and Renal Drugs Advisory Committee has recommended approval of Bayer HealthCare's oral soluble guanylate cyclase (sGC) stimulator, riociguat, in two forms of pulmonary hypertension. The Committee voted 11 to 0 that riociguat should be approved for the treatment of pulmonary arterial hypertension (PAH) of WHO Group 1.

The Committee also voted 11 to 0 that riociguat should be approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) of WHO Group 4.

In February 2013, Bayer submitted a new drug application for riociguat in two indications: the treatment of PAH to improve exercise capacity, WHO functional class and to delay clinical worsening; and the treatment of inoperable CTEPH, or persistent or recurrent CTEPH after surgical treatment to improve exercise capacity and WHO functional class.

“We appreciate the Advisory Committee’s recommendation”, said Dr Kemal Malik, member of the Bayer HealthCare Executive Committee and head of Global Development. “Riociguat addresses a high unmet medical need. It is the first drug to demonstrate efficacy in two forms of pulmonary hypertension – for which one of these, CTEPH, has no drug treatment approved to date. The committee’s vote confirms the positive benefit-risk profile of this new first-in-class therapeutic option. We hope we will soon be in the position to make riociguat available for patients and doctors in the US Bayer appreciates the scientific discussions by the Advisory Committee, and looks forward to working with the FDA as they finalize their review.”

PAH and CTEPH are both life-threatening forms of pulmonary hypertension that cause significantly increased pressure in the pulmonary arteries. Data presented at the Advisory Committee meeting included results from the two randomized, double-blind, placebo-controlled, global phase III studies CHEST-1 and PATENT-1. These assessed the efficacy and safety of oral riociguat in the treatment of CTEPH and PAH respectively. Both phase III studies with riociguat met their primary endpoint, a change in exercise capacity, after 16 and 12 weeks respectively. Riociguat also demonstrated consistent improvements across multiple, relevant secondary endpoints, and was generally well-tolerated, with a good safety profile. Results of both studies were published in the New England Journal of Medicine (NEJM) in July 2013.

The FDA granted a Priority Review designation to the New Drug Application (NDA) for riociguat filed by Bayer in February 2013. The Advisory Committee’s recommendations will be considered by the FDA in its review of the riociguat NDA, but the FDA is not required to follow the expert panel’s advice.

Riociguat was discovered by Bayer and is the first member of a novel class of compounds, the stimulators of soluble guanylate cyclase (sGC). It is the first member of a novel class of compounds, discovered and developed by Bayer as an oral treatment to target a key molecular mechanism underlying PH. Riociguat is being investigated as a new and specific approach to treat different types of PH. sGC is an enzyme found in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme enhances synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). cGMP plays an important role in regulating vascular tone, proliferation, fibrosis, and inflammation.

PH is associated with endothelial dysfunction, impaired synthesis of NO and insufficient stimulation of sGC. Riociguat has a unique 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, as a stimulator of sGC, addresses NO deficiency by restoring the NO-sGC-cGMP pathway, leading to increased generation of cGMP.

With its novel mode of action, Riociguat has the potential to overcome a number of limitations of currently approved PAH therapies, including NO dependence, and is the first drug which has shown clinical benefits in CTEPH, where no pharmacological treatment is approved.

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