Study rationale and design - The REPLACE study

Rationale and design

Clinical data indicate that 20–60% of patients
with PAH receiving PDE5i do not reach or
maintain treatment goals

Study rationale

Clinical data indicate that 20–60% of patients with PAH receiving PDE5i do not reach or maintain treatment goals.^{1, 2, 3} Escalation of therapy, including combination therapy, is an option in these patients^{4, 5}; however, combination therapy may have additional side effects,⁶ and important financial considerations.^{7, 8}

Riociguat, an sGC stimulator, acts on the same molecular pathway as PDE5i, the NO– sGC– cGMP pathway, but has a different mode of action and molecular target within the pathway.
In healthy subjects, activation of sGC by NO results in production of cGMP, leading to vasodilation in the pulmonary circulation.⁹ PDE5 degrades cGMP; thus, PDE5i increase intracellular cGMP levels.⁹
However, in patients with PAH, NO bioavailability is reduced,^{10, 11, 12, 13, 14} which may render PDE5i ineffective. Unlike PDE5i, riociguat directly stimulates sGC, increasing intracellular cGMP independently of NO.^{15, 16}
Riociguat may therefore be effective in patients with PAH who do not respond adequately to PDE5i through optimization of the NO–sGC–cGMP pathway.
The uncontrolled, open-label RESPITE pilot study investigated switching therapies that target the same signaling pathway.¹⁷ Switching to riociguat was associated with improvements from baseline in 6MWD, NT-proBNP, and WHO FC.
Given the positive trends seen in RESPITE, further data were required to confirm that patients with PAH on stable PDE5i therapy but not at treatment goal can achieve clinical improvement by switching from PDE5i to riociguat.
The prospective, randomized, controlled REPLACE study investigated the efficacy and safety of switching from PDE5i (±ERA background therapy) compared with remaining on PDE5i.¹⁸

A prospective randomized, international, multicenter, double-arm, controlled, 24-week open-label Phase IV study assessing the effect of switching to riociguat compared with maintenance of stable in patients with at intermediate risk.

Patient population

Patients treated with a stable dose of PDE5i±ERA for 5 weeks, at intermediate risk

Intermediate risk, as indicated by:

WHO FC III
6MWD 165-440 m

Primary endpoint (centrally adjudicated)

Clinical improvement at Week 24, defined as 2 out of 3:
- 6MWD improvements by ≥ 10% or ≥ 30 m
- WHO FC I/II
- NT-proBNP decrease by ≥ 30%
Absence of clinical worsening

Study sites

The REPLACE study was conducted in 81 centers in 22 countries

[interactive-map]

Study overview

Professor Marius Hoeper introduces the study design and its rationale

Study results

See the video presentation of the study results and supporting data

Resources

Find resources associated with the study, including other riociguat publications

References

Chockalingam A et al. Int J Cardiol 2005;99:91–95.
Leuchte HH et al. Chest 2004;125:580–586.
Galiè N et al. N Engl J Med 2015;373:834–844.
Galiè N et al. Eur Respir J 2015;46:903–975.
Lajoie AC et al. Lancet Respir Med 2016;4:291–305.
Liu HL et al. Chest 2016;150:353–366.
Hill NS et al. J Manag Care Spec Pharm 2016;22:S3–S21.
Wilkens H et al. Respir Med 2010;104:902–910.
Ghofrani HA et al. Nat Rev Drug Discov 2006;5:689–702.
Archer SL et al. Am J Respir Crit Care Med 1998;158:1061–1067.
Giaid A and Saleh S. N Engl J Med 1995;333:214–221.
Kielsten JT et al. Arterioscler Thromb Vasc Biol 2005;25:1414–1418.
Migneault A et al. Am J Respir Crit Care Med 2005;171:506–513.
Tsai EJ and Kass DA. Pharmcol Ther 2009;122:216–238.
Stasch JP et al. Nature 2001;410:212–215.
Stasch JP et al. Circulation 2011;123:2263–2273.
Hoeper MM et al. Eur Respir J 2017;50:1602425.
Hoeper, M. M et al. Am J Respir Crit Care Med 195: A2296.