Bayer Terminates Phase II Study With Riociguat In Patients with PH-IIP

WHIPPANY, N.J., May 12, 2016 /PRNewswire/ -- Following the recommendation of an independent Data Monitoring Committee (DMC), Bayer is terminating its Phase II study investigating riociguat in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) (NCT02138825) with immediate effect. The DMC is an independent committee which monitors the safety of patients during the course of the study. In the ongoing review of the data, the DMC observed that patients receiving riociguat were at a possible increased risk for death and other serious adverse events as compared to patients in the placebo group. The DMC did not identify any specific cause or common feature among the patients who died except that many appeared to have more serious and advanced underlying lung disease than the study population as a whole. The patients in this trial will be continuously monitored for safety immediately after stopping treatment and for a period of at least four months.

PH-IIP is a serious and rare disease. According to the clinical classification system of pulmonary hypertension (PH), there are five types of PH based on the different underlying causes (Nice Classification 2013)ⁱ. While PH-IIP belongs to Group 3, the etiology and patient characteristics of this type of PH are distinct from other types of PH. Patients with PH-IIP are a high-risk patient population who suffer both from pulmonary hypertension and idiopathic interstitial pneumonias. Prognosis is poor as there are no approved treatments.ⁱⁱ The unmet medical need is high with an estimated mortality rate of over 20% within one year.ⁱⁱⁱ

Pulmonary arterial hypertension (PAH) is classified as PH Group 1, and CTEPH is classified as PH Group 4. 

The positive benefit-risk profile of riociguat in its approved indications based on a large, controlled clinical database and supported by the available postmarket pharmacovigilance information remains unchanged. Bayer is closely monitoring the safety and efficacy of riociguat on an ongoing basis. Medical monitoring of safety in other ongoing studies with riociguat in other patient populations supports the continuation of those studies.

"We understand that the need to terminate the study in PH-IIP is very disappointing for patients suffering from this disease, as well as for their doctors and healthcare providers. There is a significant unmet medical need for PH-IIP patients as there are no approved treatments, and finding an effective treatment remains a challenge," said Dr. Joerg Moeller, Member of the Bayer Pharmaceuticals Executive Committee and Head of Global Development. "Bayer remains committed to identifying new therapeutic options and to improving the lives of patients in disease areas where there is a high unmet medical need such as pulmonary hypertension."

About Riociguat
Riociguat, licensed in the U.S. as Adempas (riociguat), 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).

Adempas 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 also 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 of riociguat included predominately patients with WHO functional class IIIII 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.

The development and commercialization of riociguat is part of the worldwide strategic collaboration between Merck & Co., Inc (through a subsidiary) and Bayer AG in the field of soluble guanylate cyclase (sGC) modulators.

INDICATIONS

• Adempas (riociguat) tablets are 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 IIIII 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

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-5 (PDE-5) inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline).

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 2015, the Group employed around 117,000 people and had sales of EUR 46.3 billion. Capital expenditures amounted to EUR 2.6 billion, R&D expenses to EUR 4.3 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.

© 2016 Bayer Pharmaceuticals Inc.
BAYER and the Bayer Cross are registered trademarks of Bayer.

Forward-Looking Statements
This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer 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 website 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 Simonneau G et al. Updated clinical classification of PH. JACC 2013.
ⁱⁱ Emerging drugs for pulmonary hypertension. Expert Opin Emerg Drugs 2010; Girgis RE. 15(1):71-85.
ⁱⁱⁱLettieri CJ¹, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2006 Mar;129(3):746-52.

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