Clinical Trials

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:

chronic thromboembolic pulmonary hypertension (CTEPH)

Therapeutic area: Cardiovascular diseases

Country: 26 countries

Trial details:

CHEST (Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial) is a Phase III program to assess the efficacy and safety of oral riociguat in the treatment of patients with either inoperable chronic thromboembolic pulmonary hypertension or pulmonary hypertension which had persisted or reoccurred after pulmonary endarterectomy. CHEST is a multi-center, multi-national program with centers in 26 countries. The program included a randomized, double-blinded, placebo-controlled pivotal trial phase (CHEST-1) and an open label extension trial phase (CHEST-2).
CHEST-1 : In the CHEST-1 study, 261 patients with inoperable CTEPH or with persistent or recurrent pulmonary hypertension after surgery were randomized and treated with either riociguat or placebo orally for 16 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 a day. After the titration phase, patients were followed up for another eight weeks to the completion of the study.
CHEST-2 : Following CHEST-1, patients from both arms then had the option of participating in the open label extension study (CHEST-2) after completing an eight-week blinded sham titration. CHEST-2 is investigating the sustainability of the efficacy results as well as longer-term safety aspects of riociguat for CTEPH patients.

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 severity and a predictor of survival in patients suffering from pulmonary hypertension,  after 16 and 12 weeks respectively.
In the CHEST-1 study, patients treated with riociguat showed an improvement of 46 meters (95%-CI [25-67 meters] p<0.0001) from baseline in the 6MWT after 16 weeks compared with placebo. The CHEST-1 study enrolled both inoperable CTEPH patients and patients whose disease persists or is recurrent after a surgical intervention. 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).
At the beginning of February 2013, Bayer HealthCare submitted riociguat, the first drug to demonstrate efficacy in two distinct forms of pulmonary hypertension, namely inoperable CTEPH for regulatory approval in the United States and in the European Union. In April, the FDA granted priority review to the New Drug Application.
* On March 4, 2013, Bayer HealthCare has announced positive data from the interim analysis of the on-going CHEST-2 trial with riociguat, the open-label long-term extension of the pivotal Phase III study CHEST-1, at the 5th World Symposium of Pulmonary Hypertension (WSPH) in Nice, France. The results of the CHEST-2 trial support the positive data of the pivotal CHEST-1 trial, showing long-term safety and sustained clinical benefits in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or with persistent or recurrent CTEPH after a surgical procedure called pulmonary endarterectomy (PEA). In the first interim analysis in CHEST-2, riociguat was shown to be well tolerated with a good long-term safety profile in patients with CTEPH. 
After 12 weeks in CHEST-2, the 6MWD had increased by 63 meters (former riociguat) and 35 meters (former placebo) against CHEST-1 baseline. In the cohort of patients that have reached one year of study treatment the increase in 6MWD was 48 meters compared with CHEST-1 baseline. However, this result must be interpreted with caution until the complete 1-year data set for the overall population in CHEST-2 is available.
After 12 weeks in CHEST-2, improvement in WHO FC was observed in 41% and 38 % of former ricoguat and former placebo groups respectively. In the cohort of patients that have reached one year of study treatment, WHO FC had improved in 51%, stabilized in 47% and worsened in 2% of patients compared with CHEST-1 baseline. Again, this promising result must be interpreted with caution until the complete 1-year data set for the overall patient population is available. Improvements in 6MWD and WHO FC were seen consistently in both subgroups of inoperable CTEPH patients and those with persistent or recurrent CTEPH after PEA.
At one year, 97% of patients in CHEST-2 were still alive and 87% were free from clinical worsening.  
Adverse events were reported in 173 (89%) of patients during CHEST-2, of which 83 (43%) patients developed drug -related adverse events.The most frequent drug-related adverse events (>5%) were dizziness (8%), dyspepsia (7%) and hypotension (6%). Serious adverse events were reported by 59 (30%) patients, of which eight (4%) were considered drug related by the investigator.  
* On October 23, 2012, Bayer HealthCare has announced positive data from the pivotal Phase III CHEST-1 trial, which investigated riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or with persistent or recurrent pulmonary hypertension after surgery. The results, presented as a late breaker at CHEST 2012, the annual meeting of the American College of Chest Physicians (ACCP) in Atlanta, USA, showed that the CHEST-1 study met its primary endpoint, demonstrating a statistically significant improvement in the six-minute walk test (6MWT). Patients treated with riociguat showed an improvement of 46 meters (95%-CI [25-67 meters] p<0.0001) from baseline after 16 weeks compared with placebo. 
In the CHEST-1 trial, riociguat also showed statistically significant improvements in secondary endpoints including pulmonary vascular resistance (PVR), N-terminal prohormone brain natriuretic peptide (NT-proBNP) and WHO functional class (FC). A positive trend was observed in time to clinical worsening (TTCW), Borg dyspnea score, European quality of life 5-dimensions questionnaire (EQ-5D) and living with pulmonary hypertension questionnaire (LPH). 
The study also showed that riociguat was well tolerated with a good safety profile in patients with CTEPH. The most frequent treatment emergent adverse events with riociguat were headache, dizziness, peripheral edema, and gastrointestinal symptoms such as dyspepsia and nausea. Bayer plans  to submit an application for marketing authorization during the first half of 2013.

Is general: Yes