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

REPLACE study data
follows PATENT-1 data

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PATENT-1 Study Design
PATENT-1: A CLINICAL STUDY DESIGNED TO EVALUATE CRITICAL ENDPOINTS2,3
PAH
PIVOTAL TRIAL IN ADULT PATIENTS WITH PAH (WHO GROUP 1)2,3

Randomized, double-blind, multinational, placebo-controlled, 12-week, phase 3 study2,3

 

Primary endpoint2,3

  • Change in 6MWD from baseline to Week 12

Baseline characteristics2,3

  • 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
improvement

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
improved
START WITH A TREATMENT THAT SIGNIFICANTLY DELAYED TIME TO CLINICAL WORSENING2†

Adempas significantly delayed time to clinical worsening2†

patent
START WITH A TREATMENT THAT DELIVERED STRONG IMPROVEMENTS IN PVR AND NT-proBNP2,3‡
hermodynamics
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

story webpage

 

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 as1:

  • WHO FC III
  • 6MWD 165 m–440 m

 

Baseline PDE5i monotherapy or combination therapy1

 

 

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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.

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 worsening1†

clinical improvement
24weeks-clinical worsening

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
change in 6MWD
Per hierarchical testing procedures, these results are considered exploratory
CHANGE IN NT-proBNP ON ADEMPAS VS THOSE CONTINUING TREATMENT WITH A PDE5i1
change in ntprobnp
Per hierarchical testing procedures, these results are considered exploratory
WHO FC ON ADEMPAS VS THOSE CONTINUING TREATMENT WITH A PDE5i1
change in whofc
Per hierarchical testing procedures, these results are considered exploratory
CLINICAL WORSENING ON ADEMPAS VS THOSE CONTINUING TREATMENT WITH A PDE5i
time to clinical worsening
ADVERSE EVENTS IN THE REPLACE STUDY1
adverse events

 

 

  • 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

adverse frequency

 

 

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

 

 

personalised content

 

MORE IMPORTANT SAFETY INFORMATION LESS IMPORTANT SAFETY INFORMATION
References:
  1. Clinical Study Report No. PH-41313. Data on File. Bayer Healthcare LLC.

  2. Adempas Prescribing Information. Whippany, NJ. Bayer Pharmaceuticals Inc., 2018.

  3. 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.

  4. 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.

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

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