Bayer Now Enrolling Patients into a Global Pulmonary Arterial Hypertension Study

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Jun 29, 2017, 09:00 ET

WHIPPANY, N.J., June 29, 2017 /PRNewswire/ -- Bayer has enrolled the first patient in a global Phase IV study assessing the clinical effects of riociguat in patients with pulmonary arterial hypertension (PAH), who were being treated with a Phosphodiesterase-5 inhibitors (PDE-5 inhibitors), either as monotherapy or in combination with an endothelin receptor antagonist (ERA), and who did not reach their therapeutic goal. The study, which is a part of the collaboration between Bayer and Merck, is seeking to enroll patients at 26 sites in the U.S. with a total of 100 study sites worldwide.

"Bayer is committed to improving the lives of patients living with pulmonary arterial hypertension through ongoing research that addresses important clinical questions on how to manage the disease," said Aleksandra Vlajnic, M.D., vice president of medical affairs at Bayer. "This study will help improve our understanding of therapeutic choices and how they may impact these patients."

About the Study
Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy (REPLACE) is an international, multicenter, randomized, controlled, open-label, Phase IV 24-week study to assess the clinical effects of transitioning from a PDE-5 inhibitor to riociguat. The study will enroll 218 patients with PAH who are not at treatment goal and on stable treatment for at least 6 weeks with PDE-5 inhibitor therapy (sildenafil or tadalafil) with or without endothelin receptor antagonist (ERA) combination.

In the study, a patient's inability to reach or maintain their treatment goal is defined as meeting the following classifications: being in World Health Organization Functional Class (WHO FC) III; having a 6-minute walk distance (MWD) of between 165 and 440 meters; taking a stable dose of diuretics, if used, for at least 30 days prior to and at randomization; and having pulmonary hemodynamics confirming a diagnosis of PAH. Patients will be excluded from the study if they have forms of pulmonary hypertension other than PAH, have been treated previously with riociguat, or have other clinically significant lung diseases. Patients will be randomized to transition from PDE-5 inhibitors to riociguat or to maintenance of their current treatment regimen.

The primary composite endpoint in this study includes the absence of clinical worsening, and improvement in two out of three of the following parameters: 6 MWD increase by equal to or more than 10 percent or equal to or more than 30 meters, WHO FC I or II, N-terminal pro-brain natriuretic peptide (NT-proBNP) decrease by at least 30 percent.

For more information about the inclusion and exclusion criteria of the REPLACE study and enrollment, go to www.clinicaltrials.gov.

Since October 2014, the worldwide strategic collaboration between Bayer and Merck (known as MSD in Europe) in the field of sGC modulators, brings together the two leading companies in this field, who both have the stated intent to make full use of this promising class of compounds and the potential it holds for the benefit of patients. Riociguat, which is marketed as Adempas^® in the U.S., is the first sGC stimulator approved and made available to patients, is the first product which is part of this collaboration.

About Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is defined by elevated pressure in the arteries going from the right side of the heart to the lungs.ⁱTypical symptoms of PAH include shortness of breath on exertion, fatigue, weakness, chest pain and syncope.ⁱⁱ PAH is caused by abnormalities in the walls of the pulmonary arteries that include constriction, inflammation and fibrosis.ⁱⁱⁱ

About Adempas^® (riociguat)

Riociguat, licensed in the U.S. as Adempas, is a stimulator of soluable guanylate cyclase (sGC) and is the only treatment approved in the U.S. for use in two types of pulmonary hypertension (WHO Groups 1 and 4).

INDICATIONS

Adempas (riociguat) tablets is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class.
Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening.*
Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominantly patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%).

*Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO functional class.

IMPORTANT SAFETY INFORMATION

WARNING: EMBRYO-FETAL TOXICITY

Do not administer Adempas (riociguat) tablets to a pregnant female because it may cause fetal harm.

Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception.

For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.

Contraindications

Adempas is contraindicated in:

Pregnancy. Adempas may cause fetal harm when administered to a pregnant woman. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form.
Concomitant administration with specific phosphodiesterase (PDE) -5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil.
Patients with Pulmonary Hypertension Associated with Idiopathic Interstitial Pneumonias (PH-IIP).

Warnings and Precautions

Embryo-Fetal Toxicity. Adempas may cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For females, Adempas is only available through a restricted program under the Adempas REMS Program.

Adempas REMS Program. Females can only receive Adempas through the Adempas REMS Program, a restricted distribution program.

Important requirements of the Adempas REMS program include the following:

Prescribers must be certified with the program by enrolling and completing training.
All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program.
Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements.
Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas.

Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4ADEMPAS.

Hypotension. Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension.

Bleeding. In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.

Pulmonary Veno-Occlusive Disease. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and if confirmed, discontinue treatment with Adempas.

Most Common Adverse Reactions

The most common adverse reactions occurring more frequently (>3%) on Adempas than placebo were headache (27% vs 18%), dyspepsia/gastritis (21% vs. 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), hypotension (10% vs 4%), vomiting (10% vs 7%), anemia (7% vs 2%), gastroesophageal reflux disease (5% vs 2%), and constipation (5% vs 1%).

Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema.

For important risk and use information, please see the full Prescribing Information, including Boxed Warning, at www.adempas-us.com.

Bayer: Science For A Better Life

Bayer is a global enterprise with core competencies in the Life Science fields of health care and agriculture. Its products and services are designed to benefit people and improve their quality of life. At the same time, the Group aims to create value through innovation, growth and high earning power. Bayer is committed to the principles of sustainable development and to its social and ethical responsibilities as a corporate citizen. In fiscal 2016, the Group employed around 115,200 people and had sales of EUR 46.8 billion. Capital expenditures amounted to EUR 2.6 billion, R&D expenses to EUR 4.7 billion. These figures include those for the high-tech polymers business, which was floated on the stock market as an independent company named Covestro on October 6, 2015. For more information, go to www.bayer.us.

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Bayer Forward Looking Statement
This news release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer Web site at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

ⁱ Rosenkranz S. Pulmonary hypertension: current diagnosis and treatment. Clin Res Cardiol. 2007;96(8):527-541.
ⁱⁱ McKenna SP et al. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR): a measure of health-related quality of life and quality of life for patients with pulmonary hypertension. Qual Life Res 2006;15(1):103-115.
ⁱⁱⁱ Galiè, N et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.