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Clinical Trials

Date: 2013-07-24

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The New England Journal of Medicine

Company: Bayer (Germany)

Product: riociguat

Action mechanism:

soluble guanylate cyclase (sGC) stimulator. Riociguat (BAY 63-2521) is an oral agent being investigated as a new approach to treating different types of pulmonary hypertension. Riociguat is the first member of a novel class of compounds, the stimulators of enzyme found in the cardiopulmonary system, soluble guanylate cyclase (sGC). When nitric oxide (NO) binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP), which plays an important role in regulating vascular tone, proliferation, fibrosis, and inflammation.
The ability of riociguat to directly stimulate sGC independent of NO while also increasing the sensitivity of sGC to NO is potentially important in PAH. Endothelial dysfunction associated with PAH can be related to low levels of NO.

Disease:

pulmonary arterial hypertension (PAH)

Therapeutic area: Rare diseases - Cardiovascular diseases

Country: 30 countries

Trial details:

PATENT (Pulmonary Arterial Hypertension sGC-Stimulator Trial) is a Phase III program to assess the efficacy and safety of oral riociguat in the treatment of treatment naïve and pre-treated patients with symptomatic PAH. PATENT is a multi-center, multi-national program with centers in 30 countries. The program included a randomized, double-blind, placebo-controlled pivotal trial phase (PATENT-1) and an open label extension trial phase (PATENT-2).
PATENT-1: In the PATENT-1 study, 443 patients with symptomatic PAH were randomized and treated with either placebo or two different doses of riociguat orally over a period of 12 weeks. Riociguat was titrated, over a period of eight weeks, in 0.5 mg increments from 1.0 mg up to 2.5 mg three times daily, or up to 1.5 mg in an exploratory arm. After the titration phase, patients were followed up for an additional four weeks to the completion of the study.
PATENT-2: Following PATENT-1, patients then had the option of participating in the open label extension study (PATENT-2) after completing an eight-week blinded sham titration. PATENT-2 is investigating the sustainability of the efficacy results, as well as longer-term safety aspects of riociguat.
The results of PATENT-2 will be presented at an upcoming scientific congress in 2013.

Latest news:

* On July 24, 2013, Bayer has announced that data from two pivotal, global Phase III studies published in the New England Journal of Medicine confirm the robust clinical efficacy and the good safety and tolerability profile of the oral investigational drug riociguat in two life-threatening pulmonary hypertension indications. The Phase III studies investigated safety and efficacy of riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH, CHEST-1 study) and in patients with pulmonary arterial hypertension (PAH, PATENT-1 study). Both studies met their primary endpoint by demonstrating a statistically significant improvement in the six-minute walk test (6MWT), a marker of disease severity3 and a predictor of survival in patients suffering from pulmonary hypertension, (4,5) after 16 and 12 weeks respectively. Results from PATENT-1 demonstrate that both treatment-naïve patients and patients pre-treated with endothelin receptor antagonists (ERAs) or non-iv prostanoid monotherapy benefit from treatment with riociguat, as patients improved 36 meters (95%-CI [20-52 meters] p<0.0001) from baseline in the 6MWT after 12 weeks compared with placebo.
In addition, riociguat also demonstrated statistically significant improvements over a broad range of parameters in secondary endpoints in both studies, including pulmonary vascular resistance (PVR), N-terminal prohormone brain natriuretic peptide (NT-proBNP) and WHO functional class (FC).Furthermore, PATENT-1 also showed statistically significant improvements with regard to the secondary endpoints time to clinical worsening (TTCW) and Borg dyspnea score.
Both pivotal studies also showed that riociguat was well tolerated with a good safety profile. The most frequent treatment emergent adverse events with riociguat were headache, dizziness, peripheral edema, and gastrointestinal symptoms such as dyspepsia and nausea.
At the beginning of February 2013, Bayer has submitted riociguat for regulatory approval in the United States and in the European Union. In April, the FDA granted priority review to the New Drug Application (NDA) in both indications (chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension).

* On October 23, 2012, Bayer has announced that data for riociguat from the pivotal Phase III study PATENT-1 have been presented in the late-breaking abstracts session at CHEST 2012, the annual meeting of the American College of Chest Physicians (ACCP) in Atlanta, USA. (Ghofrani, HA. et al. Riociguat for the treatment of pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study (PATENT-1). Oral presentation. Abstract 1462799). The study met its primary endpoint by demonstrating a statistically significant improvement in the six-minute walk test (6MWT), a predictor of improved outcome in patients suffering from pulmonary arterial hypertension (PAH). Patients treated with riociguat showed an improvement of 36 meters (95%-CI [20-52 meters] p<0.0001) from baseline after 12 weeks compared with placebo.
The PATENT-1 study included both treatment-naïve patients and those pre-treated with ERAs or non-iv prostanoid monotherapy. A statistically significant improvement in exercise capacity, as measured by the 6MWT, was seen in both groups of patients treated with riociguat monotherapy (38 meters from baseline [95%-CI 15-62 meters]) and patients on combination treatment (36 meters from baseline [95%-CI 15-56 meters])
Statistically significant improvements were also observed across secondary endpoints including pulmonary vascular resistance (PVR) (p<0.0001), N-terminal prohormone brain natriuretic peptide (NT-pro BNP) (p<0.0001), WHO functional class (FC) (p=0.0033), time to clinical worsening (TTCW) (p=0.0046) and Borg dyspnea score (p=0.0022). A positive trend was observed in European quality of life 5-dimensions questionnaire (EQ-5D) (p=0.0660) and living with pulmonary hypertension questionnaire (LPH) (p=0.0019).(11) The questionnaires results are based on hierarchical testing: a sequential testing procedure was performed for the secondary efficacy variables, strictly in the order: PVR, NT-proBNP, WHO functional class, time to clinical worsening, Borg dyspnea score, EQ-5D, and LPH questionnaires.
The study also showed that riociguat was well tolerated with a good safety profile as monotherapy or in combination with ERAs or non-iv prostanoid monotherapy in patients with PAH. The most frequent treatment emergent adverse events with riociguat were headache, dizziness, peripheral edema, and gastrointestinal symptoms such as dyspepsia and nausea.
The PATENT-1 study showed that riociguat was well tolerated with a good safety profile as monotherapy or in combination with ERAs or non-iv prostanoid monotherapy in patients with PAH. The ten most frequently reported treatment emergent adverse events with riociguat vs. placebo were: headache (27% vs. 20%), dyspepsia (19% vs. 8%), peripheral edema (17% vs. 11%), nausea (16% vs. 13%), dizziness (16% vs. 12%), diarrhea (14% vs. 10%), nasopharyngitis (10% vs. 11%), dyspnea (6% vs. 11%), cough (5% vs. 10%) and vomiting (10% vs. 9%).
Bayer now plans to submit riociguat for marketing authorization during the first half of 2013.

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