REPLACE STUDY

Transitioning PDE5-i patients who
are at intermediate risk to Adempas

Results from the REPLACE (Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i thErapy) study in adult patients with pulmonary arterial hypertension (PAH) (WHO Group 1) who were receiving PDE5i therapy and still at intermediate risk¹

PATENT-1 study

REPLACE study data
follows PATENT-1 data

PATENT-1 Study Design

PATENT-1: A CLINICAL STUDY DESIGNED TO EVALUATE CRITICAL ENDPOINTS^2,3

PIVOTAL TRIAL IN ADULT PATIENTS WITH PAH (WHO GROUP 1)^2,3

Randomized, double-blind, multinational, placebo-controlled, 12-week, phase 3 study^2,3

Primary endpoint^2,3

Change in 6MWD from baseline to Week 12

Baseline characteristics^2,3

Mean age: 51 years (approximately 80% female)
PAH etiologies: idiopathic (61%), familial (2%), associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), 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 was: 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; mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; WHO FC = World Health Organization Functional Class.

PATENT-1 Results

START WITH A TREATMENT THAT SHOWED EARLY IMPROVEMENT IN EXERCISE CAPACITY AND SIGNIFICANT RESULTS AT WEEK 12²

Improvement in 6MWD was observed at 2 weeks and continued through 12 weeks²

SIGNIFICANT IMPROVEMENT IN 6MWD AT WEEK 12²

6MWD = 6-minute walk distance.

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)

START WITH A TREATMENT THAT PROVIDED STRONG IMPROVEMENT IN WHO FC²

50% more patients improved WHO FC vs placebo²

CHANGE IN WHO FC IN THE 12-WEEK PATENT-1 STUDY²

ITT = intention to treat.

START WITH A TREATMENT THAT SIGNIFICANTLY DELAYED TIME TO CLINICAL WORSENING^2†

Adempas significantly delayed time to clinical worsening^2†

^†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).

START WITH A TREATMENT THAT DELIVERED STRONG IMPROVEMENTS IN PVR AND NT-proBNP^2,3‡

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; PVR = pulmonary vascular resistance.

^‡Placebo-adjusted mean change from baseline.

REPLACE study design

TRANSITIONING TO ADEMPAS IN PATIENTS WITH PAH (WHO GROUP 1) WHO ARE ON TREATMENT WITH A PDE5i AND STILL AT INTERMEDIATE RISK¹

Prospective, randomized, controlled, open-label, international, multicenter study to evaluate the efficacy of Adempas in adult patients with pulmonary arterial hypertension (PAH) (WHO Group 1) who are receiving a stable dose of a PDE5i and still at intermediate risk¹

Patient population

Adult patients with PAH (WHO Group 1) receiving a stable dose of PDE5i with or without concomitant treatment with an ERA for ≥6 weeks and still at intermediate risk¹

Intermediate risk defined as^1:

WHO FC III
6MWD 165 m–440 m

Baseline PDE5i monotherapy or combination therapy¹

Primary endpoint

Composite endpoint of clinical improvement in the absence of clinical worsening at 24 weeks¹

Clinical improvement at 24 weeks defined as¹:

Prespecified improvements in 2 out of 3 parameters¹:
- Improvement in 6MWD of ≥10% or ≥30 m
- Improvement to WHO FC I or II
- Decrease in NT-proBNP ≥30%

Absence of clinical worsening¹
- Defined as death from any cause; hospitalization for worsening PAH (non-elective hospitalization due to PAH or initiation of parenteral prostanoid therapy); or disease progression (decrease in 6MWD ≥15% on two separate days plus either worsening WHO FC, need for new PAH-targeted medication, or decompensated right-sided heart failure)

Secondary endpoints, analyzed hierarchically¹:

Change in 6MWD
Change in NT-proBNP
Change in WHO FC
Time to clinical worsening

Safety

Adverse events (AEs) and other safety outcomes were evaluated throughout the study and at the 30-day safety follow-up¹

6MWD = 6-minute walk distance; ERA = endothelin receptor antagonist; NT-proBNP = n-terminal prohormone of brain natriuretic peptide; PDE5i = phosphodiesterase-5 inhibitor; WHO FC = World Health Organization Functional Class.

REPLACE results

Composite primary endpoint

CLINICAL IMPROVEMENT^§ IN INTERMEDIATE RISK PATIENTS WITH PAH (WHO GROUP 1) TRANSITIONING TO ADEMPAS VS CONTINUING PDE5i THERAPY¹

^§Clinical improvement at 24 weeks defined as pre-specified improvements in 2 out of 3 parameters (6MWD, WHO FC, and/or NT-proBNP) and absence of clinical worsening^1†

6MWD = 6-minute walk distance; NT-proBNP = n-terminal prohormone of brain natriuretic peptide; PDE5i = phosphodiesterase-5 inhibitor; WHO FC = World Health Organization Functional Class.

^||Clinical worsening defined as death from any cause; hospitalization for worsening PAH (non-elective hospitalization due to PAH or initiation of parenteral prostanoid therapy); or disease progression (decrease in 6MWD ≥15% on two separate days plus either worsening WHO FC, need for new PAH-targeted medication, or decompensated right-sided heart failure).

Per hierarchical testing procedures, these results are considered exploratory

CHANGE IN 6MWD ON ADEMPAS VS THOSE CONTINUING TREATMENT WITH A PDE5i¹

6MWD = 6-minute walk distance; PDE5i = phosphodiesterase-5 inhibitor.

Per hierarchical testing procedures, these results are considered exploratory

CHANGE IN NT-proBNP ON ADEMPAS VS THOSE CONTINUING TREATMENT WITH A PDE5i¹

NT-proBNP = n-terminal prohormone of brain natriuretic peptide; PDE5i = phosphodiesterase-5 inhibitor.

Per hierarchical testing procedures, these results are considered exploratory

WHO FC ON ADEMPAS VS THOSE CONTINUING TREATMENT WITH A PDE5i¹

PDE5i = phosphodiesterase-5 inhibitor; WHO FC = World Health Organization Functional Class.

Per hierarchical testing procedures, these results are considered exploratory

CLINICAL WORSENING ON ADEMPAS VS THOSE CONTINUING TREATMENT WITH A PDE5i^1¶

PDE5i = phosphodiesterase-5 inhibitor.

^¶Clinical worsening defined as death from any cause; hospitalization for worsening PAH (non-elective hospitalization due to PAH or initiation of parenteral prostanoid therapy); or disease progression (decrease in 6MWD ≥15% on two separate days plus either worsening WHO FC, need for new PAH-targeted medication, or decompensated right-sided heart failure).

Safety

ADVERSE EVENTS IN THE REPLACE STUDY¹

PDE5i = phosphodiesterase-5 inhibitor.

^#Includes symptomatic and asymptomatic hypotension.

^**Preferred term for worsening of the condition.

^††An additional death occurred in the safety follow-up period.

The safety results are consistent with the known safety profile of Adempas¹
There was no incidence of death in patients transitioned to Adempas during the study or during the 30-day safety follow-up period¹
In patients continuing treatment with PDE5i therapy, 3 deaths were reported during the study period and 1 additional death was reported during the 30-day safety follow-up period¹

OVERALL ADVERSE EVENTS WITH ADEMPAS²

Adverse reactions (pooled from CHEST-1 and PATENT-1)²

GERD = gastroesophageal reflux disease.

Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were²:

Palpitations
Nasal congestion
Epistaxis
Dysphagia
Abdominal distension
Peripheral edema

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 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) 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.

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

References:

Clinical Study Report No. PH-41313. Data on File. Bayer Healthcare LLC.
Adempas Prescribing Information. Whippany, NJ. Bayer Pharmaceuticals Inc., 2018.
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.

REPLACE STUDY

Transitioning PDE5-i patients who are at intermediate risk to Adempas

WARNING: EMBRYO-FETAL TOXICITY

Transitioning PDE5-i patients who
are at intermediate risk to Adempas