Bayer Announces Publication of Phase IV Adempas® (riociguat) Data in The Lancet Respiratory Medicine

The pivotal PATENT-1 trial, a 12-week, multicenter, double-blind, randomized, placebo-controlled study, investigated the efficacy and safety of riociguat for the treatment of adult patients (n=443) with PAH (WHO Group 1) who were treatment-naïve or were pretreated with endothelin receptor antagonists (ERA) or prostanoids (oral, inhaled or subcutaneous [SC]). Improvements were demonstrated in clinically relevant endpoints, including 6-minute walk distance (6MWD) 36 meters (m) (95 percent CI: 20m – 52m; p<0.0001), WHO functional class (FC) (p=0.0033; majority of patients had a WHO FC II or III at baseline), time to clinical worsening (TTCW) (p=0.0046) and pulmonary vascular resistance (–226 dyn·s·cm–5 [95 percent CI: -281 to -170], p<0.001), N-terminal pro b-type natriuretic peptide [NT-proBNP]; –432 ng/mL [95 percent CI: –782 to –82], p<0.001).

In the PATENT study, the most common AEs occurring more frequently (in more than or equal to 3 percent of patients) on Adempas than placebo were headache (27 percent versus 18 percent), dyspepsia/gastritis (21 percent versus 8 percent), dizziness (20 percent versus 13 percent), nausea (14 percent versus 11 percent), diarrhea (12 percent versus 8 percent), hypotension (10 percent versus 4 percent), vomiting (10 percent versus 7 percent), anemia (7 percent versus 2 percent), gastroesophageal reflux disease (5 percent versus 2 percent) and constipation (5 percent versus 1 percent). 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.

“The scientific rationale for the REPLACE study comes from ESC/ERS guidelines suggesting the need to set a treatment goal of low-risk status in patients with pulmonary arterial hypertension, and from clinical practice where many intermediate-risk patients do not reach or maintain specific treatment goals when treated with a PDE5i-based regimen¹,” said Sameer Bansilal, M.D., M.S., Executive Director, U.S. Medical Affairs at Bayer. “We remain dedicated to providing ongoing research to reinforce the value of Adempas that may further help adult patients with PAH (WHO Group 1), a chronic and often debilitating condition of the heart and lungs.”

Adempas has a warning for embryo-fetal toxicity. Adempas cannot be used in pregnant women because it may cause fetal harm. In females of reproductive potential, pregnancy must be excluded before the start of treatment, monthly during treatment and one month after stopping treatment. To prevent pregnancy, females of reproductive potential must use effective forms of contraception during treatment and for one month after stopping treatment. For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.

About the REPLACE Study

REPLACE (Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i thErapy) was a prospective global, multicenter, double-arm, randomized, controlled, open-label Phase IV study.^1,2 Conducted in 81 sites in 22 countries, the 24-week study assessed the clinical effects of transitioning to Adempas from PDE5i therapy in 226 patients with PAH who demonstrated an insufficient clinical response to stable treatment with PDE5i (sildenafil or tadalafil) either as monotherapy or in combination with an ERA. The 24-week study involved patients with PAH at intermediate risk despite treatment with PDE-5 inhibitors (sildenafil or tadalafil) with or without ERA combination.¹ Intermediate risk was defined as WHO functional class (WHO FC) III, with a 6MWD of 165-440m, despite receiving stable doses of PDE5i, an ERA based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) treatment guidelines.¹

The blinded, centrally adjudicated composite primary efficacy endpoint was clinical improvement at week 24 (defined as two of the following: ≥10 percent/≥30 meter increase in 6MWD from baseline, WHO FC I/II, or ≥30 percent reduction in NT-proBNP from baseline) in the absence of clinical worsening (death from any cause, hospitalization for worsening PAH or disease progression).¹ 6-minute walking distance and WHO FC were assessed blind and clinical worsening events were independently adjudicated. Response rates were consistent with the overall results across the different types of PAH and pre-treatment therapies. The safety results are consistent with the known safety profile of riociguat.

About Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is defined by elevated pressure in the arteries going from the right side of the heart to the lungs.³ Typical symptoms of PAH include shortness of breath on exertion, fatigue, weakness, chest pain and syncope.⁴ Pulmonary arterial hypertension is caused by abnormalities in the walls of the pulmonary arteries.⁵

About Adempas^® (riociguat)

Riociguat, licensed in the U.S. as Adempas, is a stimulator of soluble 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).

In October 2013, the U.S. Food and Drug Administration (FDA) approved riociguat under the name Adempas^® for use in patients with PAH, as well as inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH) or persistent/recurrent CTEPH after surgery. In March 2014, the European Medicines Agency approved riociguat under the name Adempas^® for use in patients with PAH and inoperable CTEPH or persistent/recurrent CTEPH after surgical treatment. Riociguat has been granted orphan drug designation (ODD) in both the European Union and the U.S. In Japan, riociguat has been granted ODD for use in patients with inoperable CTEPH or persistent/recurrent CTEPH after surgical treatment; it was approved in Japan for this indication in January 2014, and for use in patients with PAH in February 2015.

Bayer and Merck (known as MSD outside the United States and Canada) are in a worldwide collaboration in the field of sGC modulators. The collaboration brings together two leading companies that have stated their intent to fully evaluate this therapeutic class in areas of unmet medical need. Adempas^®, the first sGC stimulator of this collaboration, is developed by Bayer and MSD. It has received marketing authorization in the U.S., Canada, EU, Japan and several other countries around the world. Bayer retains marketing rights for Adempas in the U.S.

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, improve 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

Contraindications

Adempas is contraindicated in:

• Pregnancy. Based on data from animal reproduction studies, Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated in females who are pregnant. 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. Based on data from animal reproduction studies, Adempas may cause embryo-fetal toxicity when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test before the start of treatment, monthly during treatment, and for one month after stopping treatment. Advise females of reproductive potential to use effective contraception during treatment with Adempas and for at least one month after the last dose.

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.

About Bayer

Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to help people and planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to drive sustainable development and generate a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2020, the Group employed around 100,000 people and had sales of 41.4 billion euros. R&D expenses before special items amounted to 4.9 billion euros. For more information, go to www.bayer.com.

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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.

References:

1. Hoeper M et al. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. The Lancet Respiratory Medicine 2021; www.doi.org/10.1016/S2213-2600(20)30532-4. Accessed on March 25, 2021.
2. ClinicalTrials.gov. Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy (REPLACE). Accessed on February 18, 2021. https://clinicaltrials.gov/ct2/show/NCT02891850
3. Rosenkranz S. Pulmonary hypertension: current diagnosis and treatment. Clin Res Cardiol. 2007;96(8):527-541.
4. 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.
5. Galiè N, Humbert M, Vachiery JL, et al; ESC Scientific Document Group. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67-119.

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