Adempas® (riociguat) Efficacy and Safety in PAH

ADEMPAS DELIVERS SIGNIFICANT IMPROVEMENTS ACROSS 4 CRITICAL PARAMETERS¹

Improvement in 6MWD
Improvement in WHO FC
Improvement in time to clinical worsening*
Improvement in PVR and NT-proBNP

Improvement in 6MWD

Improvement in WHO FC

Improvement in time to clinical worsening*

Improvement in PVR and NT-proBNP

6MWD=6-minute walking distance; NT-proBNP=n-terminal prohormone of brain natriuretic peptide; PVR=pulmonary vascular resistance; WHO FC=World Health Organization Functional Class.

*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 FC.

PATENT-1 STUDY DESIGN^1,2

Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1) was a randomized, double-blind, multinational, multicenter, placebo-controlled, 12-week phase 3 study.

Graphic showing PATENT-1 study design for 443 PAH patients, including 126 placebo group (3x daily), 254 Adempas group titrated up to 2.5 mg (3x daily), and 63 Adempas exploratory arm titrated up to 1.5 mg (3x daily, capped titration).

BASELINE CHARACTERISTICS

Mean age: 51 years (~80% female)

PAH cause: Idiopathic (61%), familial (2%), associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen/‌‌amphetamine use (1%)

WHO FC: II (42%); III (54%)

Mean 6MWD baseline: 363m

Exclusions: Patients with SBP <95 mm Hg

TREATMENT CHARACTERISTICS

Treatment status: Treatment-naïve (50%), pretreated with endothelin receptor antagonist (ERA) (44%), and pretreated with prostacyclin analog (PCA) (6%)

Pretreatment definition: On stable treatment for 3 months with an ERA or PCA; Adempas was combined with these therapies

Concomitant medications: Oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed

DOSING CHARACTERISTICS

Initiation: 1 mg 3x daily

Groups: Adempas at 2.5 mg 3x daily; Adempas at 1.5 mg 3x daily; placebo

Titration: ~75% were titrated to 2.5 mg 3x daily by Week 12

Adempas titrated every 2 weeks based on SBP and signs or symptoms of hypotension

FC=functional class; mPAP=mean pulmonary arterial pressure; SBP=systolic blood pressure.

EXERCISE CAPACITY (6MWD)

START WITH A TREATMENT THAT SHOWED EARLY IMPROVEMENT IN EXERCISE CAPACITY AND SIGNIFICANT RESULTS AT WEEK 12¹

Improvement in 6MWD was observed at 2 weeks and continued through 12 weeks¹

SIGNIFICANT IMPROVEMENT IN 6MWD AT WEEK 12¹

Line chart showing 6MWD improvement from baseline in PAH patients over 12 weeks.

PATIENT SUBGROUPS

START WITH ADEMPAS FOR PROVEN RESULTS ALONE OR IN COMBINATION WITH AN ERA OR PCA¹

Adempas demonstrated improvements in 6MWD

As monotherapy
In combination with ERAs
In combination with PCAs

6MWD AT WEEK 12 BASED ON PATIENT CHARACTERISTIC¹

Comparison chart showing mean treatment difference in 6MWD from baseline to Week 12 for PAH patients by prespecified subgroups.

WHO FUNCTIONAL CLASS (FC) IMPROVEMENT

START WITH A TREATMENT THAT PROVIDED STRONG IMPROVEMENT IN WHO FC¹

50% more patients improved WHO FC vs placebo¹

CHANGE IN WHO FC IN THE 12-WEEK PATENT-1 STUDY¹

Bar chart showing WHO functional class change in 12-week PATENT-1 study

ITT=intention to treat.

CLINICAL WORSENING

START WITH A TREATMENT THAT SIGNIFICANTLY DELAYED TIME TO CLINICAL WORSENING^1*

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 FC.

The Kaplan-Meier plot of time to clinical worsening is presented in the figure above. Patients treated with Adempas experienced a significant delay in time to clinical worsening vs placebo-treated patients (p=0.0046; stratified log-rank test). Significantly fewer events of clinical worsening up to Week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285, Mantel-Haenszel estimate).

ADEMPAS SIGNIFICANTLY REDUCED EVENTS ASSOCIATED WITH CLINICAL WORSENING^1*

In just 12 weeks, patients receiving Adempas demonstrated significantly fewer events of clinical worsening than those receiving placebo^*

ANY CLINICAL WORSENING EVENT^*

Graph showing clinical worsening events for Adempas versus placebo in the PATENT-1 study.

^*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 FC.
^†Patients with any clinical worsening events in the 12-week trial.
^‡Patients may have had more than one event of clinical worsening.

HEMODYNAMICS (PVR AND NT-PROBNP)

START WITH A TREATMENT THAT DELIVERED STRONG IMPROVEMENTS IN PVR AND NT-proBNP¹

Infographic showing changes in hemodynamic parameters for PAH patients treated with Adempas.

Right heart catheterization was performed at the beginning and end of the study period in 339 patients.
NT-proBNP=n-terminal prohormone of brain natriuretic peptide; PCWP=pulmonary capillary wedge pressure; PVR=pulmonary vascular resistance.
Placebo-adjusted mean change from baseline.

LONG-TERM DATA

MORE THAN 90% OF ADEMPAS PATIENTS SURVIVED AT 2 YEARS¹

Graph showing probability of survival data for PAH patients over time

An open-label extension PATENT-2 study included 396 patients who had completed PATENT-1. At the cut-off date in the PATENT-2 study, the mean treatment duration for the total population was 1146 days (±479). Without a control group, these data must be interpreted cautiously.

MOST COMMON ADVERSE EVENTS

ADVERSE REACTIONS (FROM POOLED DATA)^1||

Table comparing adverse events between Adempas and placebo groups in a clinical study.

GERD=gastroesophageal reflux disease.

^||Pooled from PATENT-1 and CHEST-1.

Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were:

SEE REPLACE STUDY RESULTS

SEE TREATMENT-NAÏVE + PRETREATED SUBGROUP DATA

SEE PAH-CTD SUBGROUP DATA

SEE PAH-CHD SUBGROUP DATA

MORE IMPORTANT SAFETY INFORMATION LESS IMPORTANT SAFETY INFORMATION

Important Safety Information and Indications

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 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.

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 concomitant use of other soluble guanylate cyclase (sGC) stimulators.
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.

Indications

Adempas (riociguat) 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.

For important risk and use information, please see the full Prescribing Information, including Boxed Warning.

References:

Adempas Prescribing Information. Whippany, NJ. Bayer Pharmaceuticals Inc., 2021.
Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340.
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.
McLaughlin VV, Gaine SP, Howard LS, et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25):D73-D81.

EFFICACY + SAFETY RESULTS

Start with a PAH (WHO Group 1) treatment
that delivers significant improvements
across 4 critical parameters