Riociguat Demonstrates Significant Clinical Benefit in PAH Patients Inadequately Responding to PDE-5 Inhibitors: Positive Phase IV REPLACE Trial Results

· Phase IV clinical study REPLACE met its primary composite endpoint, Angio^®(Riociguat) Yields Positive Results in Treating Pulmonary Hypertension with Inadequate Response to PDE-5 Inhibitors

· Compared with the PDE-5i treatment group, Angio^®The number of patients in the (riociguat) treatment group who achieved the primary composite endpoint of clinical improvement doubled;

· The REPLACE study confirmed that Angio^®(Riociguat) was generally well tolerated in patients switching from PDE-5 inhibitors to riociguat.

· Angio^®(Riociguat) The unique dual mechanism of action, which is independent of nitric oxide (NO) concentration, may be the reason why riociguat provides significant benefits to patients with pulmonary arterial hypertension (PAH) who have an inadequate response to phosphodiesterase-5 inhibitors (PDE-5i).

MSD recently announced the results of the REPLACE study. The REPLACE study is a global, multicenter, two-arm, randomized, controlled, open-label Phase IV clinical trial conducted across 81 centers in 22 countries, aiming to evaluate the switch to Angio^®Feasibility of (riociguat) treatment. The study met its primary endpoint, and the safety results were consistent with the known safety profile of riociguat. The REPLACE study is part of a collaboration between Bayer and MSD, and its data were presented as an oral report at the European Respiratory Society (ERS) Congress held from September 7–9, 2020.

The REPLACE study results demonstrate that patients with pulmonary arterial hypertension (PAH) who have an inadequate response to phosphodiesterase-5 inhibitors (PDE-5i) can derive significant benefit from switching to riociguat therapy.

The 24-week REPLACE study evaluated the clinical efficacy of switching from PDE-5 inhibitor (PDE-5i) therapy to riociguat in 226 patients with pulmonary arterial hypertension who remained at intermediate risk despite receiving PDE-5i (sildenafil or tadalafil) therapy, with or without concurrent endothelin receptor antagonist (ERA) therapy. In the REPLACE study, patients were randomized into two groups: one group switched from PDE-5i to riociguat, while the other continued their current PDE-5i regimen.

The REPLACE study met its primary endpoint—a composite endpoint of clinical improvement without clinical worsening. The proportion of patients achieving the composite endpoint of clinical improvement was doubled in the riociguat group compared with the PDE-5 inhibitor (PDE-5i) group (41% vs 20%; OR = 2.78; 95% CI [1.53–5.06]; p = 0.0007). The improvement rate with riociguat remained consistent regardless of PAH subtype or prior treatment regimen.

Riociguat Significantly Reduced the Number of Patients with Clinical Worsening Events and Delayed Time to First Event: The number of patients with adjudicated clinical worsening events was significantly lower in the riociguat group (1%) than in the PDE-5i group (9%) (OR = 0.10; 95% CI [0.013–0.725]; p = 0.0047). Compared with the PDE-5i group, the time to first clinical worsening event was significantly prolonged in the riociguat group (p = 0.007).

Switching from PDE-5 inhibitors to riociguat was well tolerated: the overall incidence of adverse events was similar between the two treatment groups (71% in the riociguat group vs. 66% in the PDE-5 inhibitor group), but the incidence of serious adverse events was higher in the PDE-5 inhibitor group (17%) than in the riociguat group (7%).

The unique dual mechanism of action of riociguat, which is independent of nitric oxide (NO) concentration, may be the reason why riociguat can bring significant benefits to PAH patients who have an inadequate response to PDE-5 inhibitors.

NO-sGC-cGMP (Nitric Oxide–Soluble Guanylate Cyclase–Cyclic Guanosine Monophosphate) is a critical pathway influencing pulmonary arterial hypertension: Under physiological conditions, nitric oxide (NO), a biological messenger produced by endothelial cells, binds to soluble guanylate cyclase (sGC), catalyzing the conversion of guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). cGMP plays a pivotal role in regulating vascular smooth muscle cells, including vasodilation, anti-fibrotic effects, anti-inflammatory actions, and inhibition of excessive smooth muscle cell proliferation. In patients with pulmonary arterial hypertension, endothelial dysfunction leads to reduced endogenous NO and decreased cGMP synthesis, thereby impairing its normal physiological functions. Furthermore, as the disease progresses, NO levels in patients with pulmonary arterial hypertension gradually decline.

Both riociguat and PDE-5 inhibitors (PDE-5i) act on the NO-sGC-cGMP pathway, but their mechanisms of action are distinctly different. PDE-5i exert their effects by inhibiting the degradation of cGMP, thereby increasing cGMP levels; however, this mechanism is dependent on the presence of nitric oxide (NO). In contrast, riociguat features a unique dual mechanism of action that is independent of NO concentration. In conditions of NO deficiency, riociguat can directly bind to soluble guanylate cyclase (sGC) independently of NO, thereby enhancing cGMP synthesis. Additionally, riociguat stabilizes the NO-sGC complex, increasing the sensitivity of sGC to endogenous NO and further promoting cGMP production. Through these complementary mechanisms, riociguat induces vasodilation and reduces pulmonary arterial hypertension (PAH). This may explain why riociguat provides significant clinical benefits to PAH patients who exhibit an inadequate response to PDE-5i therapy.

As the first soluble guanylate cyclase (sGC) stimulator introduced to China, riociguat was approved by the China Food and Drug Administration in 2017 for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). It is the only targeted therapy for pulmonary hypertension in China indicated for both PAH and CTEPH, and it is currently included in the National Reimbursement Drug List.