Rationale and study design of RESPITE: An open-label, phase 3b study of riociguat in patients with pulmonary arterial hypertension who demonstrate an insufficient response to treatment with phosphodiesterase-5 inhibitors

Abstract

Patients with pulmonary arterial hypertension (PAH) who do not have an adequate response to therapy with phosphodiesterase-5 inhibitors (PDE-5i) may have insufficient synthesis of cyclic guanosine monophosphate (cGMP). These patients may respond to a direct soluble guanylate cyclase (sGC) stimulator such as riociguat. RESPITE (NCT02007629) was an open-label, multicenter, uncontrolled, single-arm phase 3b study of riociguat in patients with PAH who demonstrated an insufficient response to treatment with PDE-5i. Insufficient response was defined as World Health Organization functional class (WHO FC) III despite PDE-5i therapy for at least 90 days; 6-min walk distance (6MWD) of 165-440 m, and right-heart catheterization showing mean pulmonary artery pressure >30 mmHg, cardiac index <3.0 L/min/m, and pulmonary vascular resistance >400 dyn s cm. PAH patients with an insufficient response to stable doses of sildenafil or tadalafil-either as monotherapy or in combination with an endothelin receptor antagonist-for at least 90 days were switched to riociguat for 24 weeks. Starting at 1.0 mg TID, the dose of riociguat was increased during the 8-week titration phase in 0.5-mg increments in 2-week intervals if the patient had no signs or symptoms of hypotension. In the ensuing 16-week maintenance phase, riociguat was continued at the optimal individual dose. All efficacy outcomes were exploratory and include change from baseline to 24 weeks in 6MWD, cardiac index, N-terminal pro-brain natriuretic peptide, WHO FC, and quality of life and the proportion of patients with clinical worsening. The following biomarkers were to be measured: cGMP, asymmetric dimethyl arginine, growth-differentiation factor-15, and ST2. Results from RESPITE will help to determine if PAH patients who do not respond to PDE-5i are likely to benefit from treatment with an sGC stimulator. The study may also identify biomarkers that are able to suggest which patients are more likely to respond to sGC stimulators.

Initial Riociguat Monotherapy and Transition from Sildenafil to Riociguat in Patients with Idiopathic Pulmonary Arterial Hypertension: Influence on Right Heart Remodeling and Right Ventricular–Pulmonary Arterial Coupling

“…This can be corrected by direct stimulation of sGC [3]. Riociguat is the first direct sGC stimulator and has a dual mode of action: sensitizing sGC to endogenous NO by stabilizing NO–sGC binding, while also directly stimulating sGC via a separate binding site, independently of NO.…”

“…A proportion of patients with PAH will fail to achieve their therapeutic goals with PDE5is, even in combination [5]. An sGC stimulator such as riociguat may be able to increase intracellular cGMP levels and achieve clinical benefits under conditions (such as NO depletion) that restrict the effectiveness of PDE5is [3, 5]. …”

Aspects of Modern Combination Specific Therapy of Pulmonary Arterial Hypertension: the Pros and Cons

“…Clinical Effects Studied in Patients With Insufficient Treatment Response to Phosphodiesterase-5 Inhibitor) [21]. Целью исследования явилась оценка безопасности и эффектив-ности перехода с терапии ИФДЭ5 на терапию риоцигуа-том у пациентов ЛАГ, не достигших целей лечения при применении ИФДЭ5.…”

“…По данным промежуточного анализа, к 24-й неделе у 50% пациентов отмечалось улучшение ФК с III (ВОЗ) до II (ВОЗ) [23]. По сравнению с исходными дан-ными к 24-й неделе отмечалось увеличение Д6МХ с 353 ± 78 м до 392 ± 112 м (n = 25); снижение ЛСС с 856 ± 266 дин*cек*см -5 до 772 ± 465 дин*cек*см -5 (n = 25); увеличение СИ с 2,2 ± 0,3 л/мин/мин 2 до 2,6 ± 0,6 л/мин/мин 2 (n = 25) и снижение уровня NT-proBNP с 2208 ± 2961 пг/мл до 817 ± 1066 пг/мл (n = 26) [21,23]. Следовательно, данная терапевтическая стратегия ЛАГ -замена терапии ИФДЭ5 на риоцигуат у пациентов с недостаточным ответом -явля-ется перспективной и требуется проведение РКИ для даль-нейшего изучения этого аспекта лекарственной терапии.…”

Positioning Newer Agents: Riociguat, Selexipag, and Oral Treprostinil in the Current Landscape

“…This concept was tested in the open-label phase 4 Riociguat in Patients with PAH and an Inadequate Response to Phosphodiesterase 5 Inhibitors (RESPITE) study. 9,10 Patients with suboptimal clinical status on PDE5 inhibitor (nearly three quarters also on background ERA) were converted from PDE5 inhibitor to riociguat. Endpoints included functional class, 6-minute walk distance, NT-proBNP level, and hemodynamics, all of which improved.…”