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Adempas for PAH-CTD:
A subgroup of the PATENT-1 Study

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THE PAH-CTD PUBLICATION PDF Download

PAH-CTD = pulmonary arterial hypertension
associated with connective tissue disorder.

 

    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

    Chart of PATENT-1 study design

    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

    Chart of PATENT-1 6MWD results 36m improvement over placebo*

    Adempas can be used as monotherapy or in combination

    • In WHO FC II and III—in combination with ERAs
    • As monotherapy—in combination with PCAs

    50% MORE PATIENTS IMPROVED WHO FC ON ADEMPAS VS PLACEBO

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

    Chart of PATENT-1 WHO FC results

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

    ADEMPAS IMPROVED PVR AND NT-proBNP AT WEEK 12

    Display of PATENT-1 hemodynamic results

    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

    Display of PATENT-1 hemodynamic results

    *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.

    Button that links to resources to enroll your patients on Adempas Button that links to resources to enroll your patients on Adempas
    PAH-CTD Subgroup

    PATENT-1 Study Design

    PATENT-1: A RANDOMIZED, DOUBLE-BLIND, MULTINATIONAL, MULTICENTER, PLACEBO-CONTROLLED, 12-WEEK, PHASE 3 STUDY

    Chart of PATENT-1 study design: full data set

    Efficacy data are shown for the Adempas 2.5 mg and placebo arms.

    Data from the PAH-CTD subgroup analysis are exploratory as PATENT-1 was not designed to show statistically significant differences in subgroup populations. The primary efficacy analysis was performed on data from the modified intent-to-treat population (all patients who were randomized and received one or more doses of the study drug). The data presented here are observed values and are analyzed descriptively; observed values were used due to the small sample size and the retrospective, exploratory nature of the analysis.

    BASELINE CHARACTERISTICS2,3

    Table of PATENT-1 full data set and PAH-CTD subgroup baseline characteristics

    *Exploratory subgroup analysis.

    • PAH defined as: PVR >300 dyn·sec·cm-5, mPAP >25 mm Hg
    • PATENT-1 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%)
    • Concomitant medications: oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed
    • Patients with systolic blood pressure <95 mm Hg were excluded

     

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

    PATENT-1: 6MWD at Week 12 based on patient characteristics

    MEAN TREATMENT DIFFERENCE IN CHANGE FROM BASELINE TO WEEK 12*
    IN 6MWD BY PRESPECIFIED SUBGROUPS4

    Alt tag

    *Week 12/last observation until Week 12.
    ERA = endothelin receptor antagonist; PCA = prostacyclin analogues. 

    PATENT-1 Results in the CTD Subgroup

    The data in these analyses should be considered exploratory and not designed to detect statistically significant differences in subgroups. The analysis is limited due to the post hoc sub-classification of patients with PAH-CTD by patients’ medical histories using MedDRA terms. The low patient numbers in the PAH-SSc and PAH-other defined CTD subgroups should be taken into consideration when interpreting the data.3

    CHANGE IN 6MWD FROM BASELINE TO WEEK 121,3  

    EXPLORATORY POST HOC SUBGROUP ANALYSIS 

    Alt tag

    *Week 12/last observation until Week 12.
    ITT population.

    CHANGE IN WHO FC FROM BASELINE TO 12-WEEK PATENT-1 STUDY1

    EXPLORATORY POST HOC SUBGROUP ANALYSIS 

    Alt tag

    *Week 12/last observation until Week 12. ITT population. Missing values, where the patient withdrew or dies, were imputed at Week 12 according to the last observed value.

    PVR AND NT-proBNP IN PATENT-1 PAH-CTD PATIENTS TREATED WITH ADEMPAS VS PLACEBO AT WEEK 123

    EXPLORATORY POST HOC SUBGROUP ANALYSIS 

    Alt tag

    CLINICAL WORSENING EVENTS UP TO WEEK 12

    Alt tag

    *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.

    LONG-TERM DATA: PROBABILITY OF SURVIVAL AT 2 YEARS 

    An open-label extension study (PATENT-2) 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). The probabilities of survival at 1 and 2 years were 97% and 93%, respectively. Without a control group, these data must be interpreted cautiously.

    Alt tag

    PREVALENCE OF PAH-CTD

    • PAH associated with CTD is the second most prevalent type of PAH after idiopathic PAH (IPAH) in the Western world6
    • PAH associated with CTD represents about 30% of the PAH population, as described in the REVEAL registry7
    • PAH-CTD includes systemic scleroderma (SSc), systemic lupus erythematosus (SLE), and mixed CTD6

       – About 10%-18% of patients with SSc or SLE develop PAH over their lifetime8,9

    HOW IS PAH-CTD DIAGNOSED?

    • Resting echocardiography is recommended as a screening test in asymptomatic patients with SSc followed by annual screening with echocardiography, diffusing capacity of the lungs for carbon monoxide (DLCO), and biomarkers6,10 
    • Treatment of underlying condition with medication or right heart catheterization (RHC) is recommended in cases of suspected PAH associated with CTD6,10  

    RISK FACTORS FOR PAH IN PATIENTS WITH CTD INCLUDE:

    • Female gender6
    • Older age6
    • Raynaud’s disease8
    • Active renal disease8
    • Some types of vasculitis (ie, digital gangrene, cutaneous vasculitis)8
    • Limited cutaneous systemic sclerotic disease of >5 years’ duration11
    • Low diffusing capacity of the lung for carbon monoxide (DLCO)11
    • Anti-centromere antibody positive11

    ITT = intention to treat; NT-proBNP = n-terminal pro-brain natriuretic peptide; SLE = systemic lupus erythematosus; SSc = systemic scleroderma.

    CONTACT A BAYER SALES REPRESENTATIVE
     
    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:

    1. 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.
    2. 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.
    3. McLaughlin VV, Gaine SP, Howard LS, et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25):D73-D81.

    References:

    1. Humbert M, Coghlan JG, Ghofrani H-A, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017;76(Suppl):1-19.
    2. 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.
    3. Humbert M, Coghlan JG, Ghofrani H-A, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017;76(2):422-426.
    4. Ghofrani H-A, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(Suppl):1-27.
    5. Data on File.
    6. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;00:1-114.
    7. Farber HW, Miller DP, Poms AD, et al. Five-Year outcomes of patients enrolled in the REVEAL Registry. Chest. 2015;148(4):1043-1054.
    8. Tselios K, Gladman D, Urowitz MB. Systemic lupus erythematosus and pulmonary arterial hypertension: links, risks, and management strategies. Open Access Rheumatol. 2017;9:1-9.
    9. Thakkar V, Lau EMT. Connective tissue disease-related pulmonary arterial hypertension. Best Pract Res Clin Rheumatol. 2016;30:22-38.
    10. Khanna D, Gladue H, Channick R, et al. Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum. 2013;65:3194-3201.
    11. Condliffe R, Howard LS. Connective tissue disease-associated pulmonary arterial hypertension. F1000Prime Rep. 2015;7:06.

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