Bayer's Riociguat for Pulmonary Hypertension Receives FDA Orphan Drug Designation and Is Approved in Canada

September 26, 2013—Bayer HealthCare (Whippany, NJ) announced that the US Food and Drug Administration's (FDA) Office of Orphan Products Development has granted two separate orphan drug designations for riociguat, the company's investigational, oral medication for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The Orphan Drug Designation program provides orphan status to drugs and biologics that are defined as those intended for the safe and effective treatment, diagnosis, or prevention of rare diseases and disorders.

In February 2013, Bayer submitted an FDA New Drug Application (NDA) for riociguat for two indications, as designated by the World Health Organization (WHO): (1) the treatment of PAH (WHO Group 1) to improve exercise capacity, improve WHO functional class, and delay clinical worsening; and (2) the treatment of persistent/recurrent CTEPH (WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class.

On August 6, Bayer HealthCare announced that the FDA's Cardiovascular and Renal Drugs Advisory Committee recommended approval for riociguat (proposed tradename: Adempas) for these two forms of pulmonary hypertension (PH). Approval by the FDA would create a new class of drugs available in the United States, stated the company.

On September 23, Bayer announced that Health Canada approved riociguat under the trade name Adempas for the treatment of inoperable or persistent /recurrent CTEPH after surgery in adult patients with WHO Functional Class II or III PH.

“Before today, we had no proven drug treatments for patients with inoperable CTEPH or patients in whom surgery was not successful in curing their CTEPH,” commented John Granton, MD, in the company's announcement of approval in Canada. “Adempas gives us an effective drug treatment with proven clinical efficacy and good tolerability.” Dr. Granton, who is Head, Division of Respirology at Toronto's University Health Network, Mount Sinai Hospital, and Women's College Hospital, added that, because of the complex nature of PH, “Patients should be referred to an expert PH center as soon as possible for a thorough assessment and timely treatment.”

Bayer noted that the standard and potentially curative treatment option for patients who have developed CTEPH is pulmonary endarterectomy, which mechanically clears the blood vessels of the lungs of scar tissue caused by the disease. However, the disease persists or recurs after surgery in up to 35% of patients. Many patients (20% to 50%) with CTEPH are not candidates for surgery and, like patients with residual PH, urgently need effective new treatments to manage their disease. Long-term trials of the riociguat study program in CTEPH are ongoing, and first results show that safety, tolerability, and efficacy (change in 6-minute walk test) are sustained at more than 1 year.

Riociguat (BAY 63-2521) is a soluble guanylate cyclase (sGC) stimulator, 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 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 theNO-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, according to the company.