Clinical Data in Naïve and Pretreated PAH Patients | ADEMPAS® (riociguat)

Efficacy data in PATENT-1 were only measured for the Adempas 2.5 mg and placebo arms. The data in the treatment-naïve and pretreated subgroup analyses should be considered exploratory and were not designed to detect statistically significant differences in these subgroups.

PATENT-1 Full Data Set

PATENT-1 Study Design

PIVOTAL TRIAL IN ADULT PATIENTS WITH PAH (WHO GROUP 1)¹

Randomized, double-blind, multinational, placebo-controlled, 12-week, phase 3 study

Graphic of study design with 443 PAH patients of which 126 patients were on placebo, 254 patients were on up to 2.5mg and 63 patients exploratory arm up to 1.5mg, given 3 times daily

Primary endpoint¹

Change in 6MWD from baseline to Week 12

Baseline characteristics¹

Mean age: 51 years (approximately 80% female)
PAH etiologies: idiopathic (61%), associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), familial (2%), or anorexigen or amphetamine use (1%)
Mean 6MWD was 363 m
Concomitant medications: oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed
Patient population: 50% treatment naïve, 44% pretreated with an endothelin receptor antagonist (ERA), and 6% pretreated with a prostacyclin analog (PCA)
The majority of patients had WHO FC II (42%) or III (54%) at baseline
Patients with systolic blood pressure <95 mm Hg were excluded

6MWD = 6-minute walk distance; m = meters; mPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PATENT-1 = Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial; PVR = pulmonary vascular resistance; WHO FC = World Health Organization Functional Class.

PATENT-1 Results

IMPROVEMENT IN 6MWD WAS OBSERVED AT 2 WEEKS AND CONTINUED THROUGH 12 WEEKS¹

SIGNIFICANT IMPROVEMENT IN 6MWD AT WEEK 12

Graph of mean change from baseline to 6MWD showcasing 36m improvement in 6MWD at week 12

Adempas can be used as monotherapy or in combination

In WHO FC II and III
As monotherapy
In combination with endothelin receptor antagonists (ERAs)
In combination with prostacyclin analogs (PCAs)

50% MORE PATIENTS IMPROVED WHO FC ON ADEMPAS VS PLACEBO

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

Graph of change in WHO FC on Adempas vs Placebo patients in the 12-week PATENT-1 study

ITT = intention-to-treat; WHO FC = World Health Organization Functional Class.

ADEMPAS IMPROVED PVR AND NT-proBNP AT WEEK 12*

Graph of the change in hemodynamic parameters PVR and NT-proBNP at week 12

Right heart catheterization was performed at the beginning and end of the study period in 339 patients.

*Placebo-adjusted mean change from baseline.

NT-proBNP = N-terminal pro-brain natriuretic peptide.

CLINICAL WORSENING EVENTS UP TO 12 WEEKS

Graphic comparing worsening events for Adempas vs Placebo up to week 12

*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 PH, start of new PAH-specific treatment, persistent decrease in 6MWD, and persistent worsening of WHO Functional Class.
^†Patients may have had more than one event of clinical worsening.

Treatment-naïve/Pretreated Subgroups

PATENT-1 Study Design

PIVOTAL TRIAL IN ADULT PATIENTS WITH PAH (WHO GROUP 1)^1,2

Randomized, double-blind, multinational, placebo-controlled, 12-week phase 3 study

Graphic of study design for treatment-naïve and pretreated subgroups

PATENT-1 primary endpoint

Change in 6MWD from baseline to Week 12

Secondary endpoints included changes from baseline to Week 12 in²:

WHO FC
Time to clinical worsening event
PVR and NT-proBNP

Efficacy data were only measured for the Adempas 2.5 mg and placebo arms.

PATENT-1 Baseline Patient Characteristics³

Table of patient characteristics comparing between overall population, treatment-naïve and pretreated subgroups

*Data may not add up to 100% owing to rounding.

^†n=59.

PATENT-1 Results

6MWD AT WEEK 12 BASED ON PATIENT CHARACTERISTICS¹

Mean Treatment Difference in Change From Baseline to Week 12* in 6MWD by Prespecified Subgroups

*Week 12/last observation until Week 12.

PATENT-1 (n=443): Improvement in 6MWD was observed at 2 weeks and continued through 12 weeks²

Primary Endpoint: Mean Change from Baseline in 6MWD

Graph of the mean change from baseline in 6MWD for Adempas vs Placebo for overall population

Exploratory post hoc subgroup analyses

PATENT-1 Subgroup Analysis: Change in 6MWD from baseline to Week 12¹

MEAN CHANGE FROM BASELINE IN 6MWD

Graph of the mean change on Adempas vs Placebo for pretreated subgroup

The data in this analysis should be considered exploratory and not designed to detect statistically significant differences in these subgroups.

PATENT-1 (n=443): 50% more patients improved WHO FC vs placebo

CHANGE IN WHO FC

Exploratory post hoc subgroup analyses

PATENT-1 Subgroup Analysis: Change in WHO FC from baseline to Week 12¹

Change from baseline in WHO FC

Bar chart of the change in WHO FC from baseline vs placebo for treatment-naïve subgroup at week 12

Change in WHO FC from baseline vs placebo for pretreated subgroup

The data in this analysis should be considered exploratory and not designed to detect statistically significant differences in these subgroups.

PATENT-1 (n=443): Improved PVR and NT-proBNP at Week 12^2*

Change in hemodynamic parameters

Illustration of the hemodynamic parameter in overall population comparing PVR and NT-proBNP

*Placebo-adjusted mean change from baseline.

Right heart catheterization was performed at the beginning and end of the study period in 339 patients.

Exploratory post hoc subgroup analyses

Clinical worsening events up to 12 weeks

Illustration of the clinical worsening event in Adempas vs Placebo observed up to Week 12 post hoc subgroup analysis.

The data in this analysis should be considered exploratory and not designed to detect statistically significant differences in subgroups.

*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 may have had more than one event of clinical worsening.

Exploratory post hoc subgroup analyses

PATENT-1 Subgroup Analysis: Change in PVR and NT-proBNP from baseline to Week 12¹

MEAN CHANGE FROM BASELINE IN PVR AND NT-proBNP

Illustration of the mean change in PVR and NT-proBNP from baseline to Week 12 for treatment-naïve subgroup

Mean change in PVR and NT-proBNP from baseline to Week 12 for pretreated subgroup

The data in this analysis should be considered exploratory and not designed to detect statistically significant differences in these subgroups.

6MWD = 6-minute walk distance; ERA = endothelin receptor antagonist; m = meters; mPAP = mean pulmonary arterial pressure; mm Hg = millimeters mercury; NT-proBNP = N-terminal pro-brain natriuretic peptide; PAH = pulmonary arterial hypertension; PATENT-1 = Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial; PCA = prostacyclin analogues; PVR = pulmonary vascular resistance; SD = standard deviation; WHO FC = World Health Organization Functional Class.

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:

Ghofrani H-A, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340.
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.

References:

Data on file. Clinical study report No. A62510. Bayer HealthCare Pharmaceuticals, 2012.
Ghofrani H-A, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340.
Galiè N, Grimminger F, Grünig E, et al. Comparison of hemodynamic parameters in treatment-naïve and pre-treated patients with pulmonary arterial hypertension in the randomized phase III PATENT-1 study. J Heart Lung Transplant. 2017;36(5):509-519.

Results in Treatment-naïve and Pretreated PAH Patients from the PATENT-1 Study

PATENT-1 Study Design

PIVOTAL TRIAL IN ADULT PATIENTS WITH PAH (WHO GROUP 1)1

PATENT-1 Results

IMPROVEMENT IN 6MWD WAS OBSERVED AT 2 WEEKS AND CONTINUED THROUGH 12 WEEKS1

SIGNIFICANT IMPROVEMENT IN 6MWD AT WEEK 12

50% MORE PATIENTS IMPROVED WHO FC ON ADEMPAS VS PLACEBO

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

ADEMPAS IMPROVED PVR AND NT-proBNP AT WEEK 12*

CLINICAL WORSENING EVENTS UP TO 12 WEEKS

PATENT-1 Study Design

PIVOTAL TRIAL IN ADULT PATIENTS WITH PAH (WHO GROUP 1)1,2

PATENT-1 Baseline Patient Characteristics3

PATENT-1 Results

6MWD AT WEEK 12 BASED ON PATIENT CHARACTERISTICS1

Mean Treatment Difference in Change From Baseline to Week 12* in 6MWD by Prespecified Subgroups

PATENT-1 (n=443): Improvement in 6MWD was observed at 2 weeks and continued through 12 weeks2

Primary Endpoint: Mean Change from Baseline in 6MWD

Exploratory post hoc subgroup analyses

PATENT-1 Subgroup Analysis: Change in 6MWD from baseline to Week 121

MEAN CHANGE FROM BASELINE IN 6MWD

PATENT-1 (n=443): 50% more patients improved WHO FC vs placebo

Exploratory post hoc subgroup analyses

PATENT-1 Subgroup Analysis: Change in WHO FC from baseline to Week 121

PATENT-1 (n=443): Improved PVR and NT-proBNP at Week 122*

Exploratory post hoc subgroup analyses

Clinical worsening events up to 12 weeks

Exploratory post hoc subgroup analyses

PATENT-1 Subgroup Analysis: Change in PVR and NT-proBNP from baseline to Week 121

WARNING: EMBRYO-FETAL TOXICITY

Results in Treatment-naïve and Pretreated PAH
Patients from the PATENT-1 Study

PIVOTAL TRIAL IN ADULT PATIENTS WITH PAH (WHO GROUP 1)¹

IMPROVEMENT IN 6MWD WAS OBSERVED AT 2 WEEKS AND CONTINUED THROUGH 12 WEEKS¹

PIVOTAL TRIAL IN ADULT PATIENTS WITH PAH (WHO GROUP 1)^1,2

PATENT-1 Baseline Patient Characteristics³

6MWD AT WEEK 12 BASED ON PATIENT CHARACTERISTICS¹

PATENT-1 (n=443): Improvement in 6MWD was observed at 2 weeks and continued through 12 weeks²

PATENT-1 Subgroup Analysis: Change in 6MWD from baseline to Week 12¹

PATENT-1 Subgroup Analysis: Change in WHO FC from baseline to Week 12¹

PATENT-1 (n=443): Improved PVR and NT-proBNP at Week 12^2*

PATENT-1 Subgroup Analysis: Change in PVR and NT-proBNP from baseline to Week 12¹