An inhaled sGC modulator can lower PH in COPD patients without deteriorating oxygenation

This study uses a highly fidelity computational simulator of pulmonary physiology to evaluate the impact of a soluble guanylate cyclase (sGC) modulator on gas exchange in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH) as a complication. Three virtual COPD patients were configured in the simulator based on clinical data. In agreement with previous clinical studies, modeling systemic application of a soluble guanylate cyclase (sGC) modulator results in reduced partial pressure of oxygen (PaO2) and increased partial pressure of carbon dioxide (PaCO2) in arterial blood, if a drug-induced reduction of pulmonary vascular resistance (PVR) equal to that observed experimentally is assumed. In contrast, for administration via dry powder inhalation (DPI), our simulations suggest that the treatment results in no deterioration in oxygenation. For patients under exercise, DPI administration lowers PH while oxygenation is improved with respect to baseline values

Riociguat for the Treatment of Raynaud's Phenomenon: A Single-Dose, Double-Blind, Randomized, Placebo-Controlled Cross-Over Pilot Study (DIGIT)

Background and Objective Raynaud's phenomenon (RP) is characterized by transient digital ischemia and is commonly associated with connective tissue disease. Treatment remains unsatisfactory. Here we evaluate the efficacy, safety, and pharmacokinetics of a single dose of the soluble guanylate cyclase stimulator riociguat in RP. Methods DIGIT was a double-blind, randomized, placebo-controlled pilot study. Patients with primary or secondary RP were randomized to a single oral dose of riociguat 2mg or placebo in a cross-over design (73days). Efficacy was assessed as placebo-corrected change in digital blood flow 2h post-dose at room temperature (RT) or following cold exposure (CE), measured by laser-speckle contrast analysis. Patients were regarded as responders if placebo-corrected digital blood flow increased by10% from baseline at RT or after CE. Results Of 20 eligible patients, 17 (85%) were female and mean [standard deviation (SD)] age was 52 (13.8) years. Placebo-corrected changes in digital blood flow were + 46% [90% confidence interval (CI) -6 to + 98] at RT and -9% (90% CI -63 to + 44) after CE, with high inter-individual variability. Eight patients (40%) were responders at RT, and 12 (60%) after CE. Riociguat increased mean (SD) digital blood flow in responders at RT by + 136% (114) and in responders following CE by + 39% (53). Riociguat was well tolerated, with few adverse events. Conclusion In this pilot study, single-dose riociguat was well tolerated in patients with RP and resulted in improved digital blood flow in some patient subsets, with high inter-individual variability. Long-term evaluation is warranted

Riociguat for pulmonary arterial hypertension associated with congenital heart disease

Objective The Pulmonary Arterial hyperTENsion sGC-stimulator Trial-1 (PATENT-1) was a randomised, doubleblind, placebo-controlled phase III trial evaluating riociguat in patients with pulmonary arterial hypertension (PAH). PATENT-2 was an open-label long-term extension to PATENT-1. Here, we explore the efficacy and safety of riociguat in the subgroup of patients with persistent/recurrent PAH after correction of congenital heart disease (PAH-CHD) from the PATENT studies. Methods In PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo for 12 weeks; efficacy assessments included change from baseline to study end in 6-min walking distance (6MWD; primary), pulmonary vascular resistance (PVR), N-terminal of the prohormone of brain natriuretic peptide (NT-proBNP), WHO functional class (WHO FC) and time to clinical worsening. In PATENT-2, eligible patients from PATENT-1 received long-term riociguat (maximum 2.5 mg three times daily); the primary assessment was safety and tolerability. All PAH-CHD patients had a corrected cardiac defect. Results In PATENT-1, riociguat increased mean+/-SD 6MWD from baseline to week 12 by 39+/-60 m in patients with PAH-CHD versus 0+/-42 m for placebo. Riociguat also improved several secondary variables versus placebo, including PVR (-250+/-410 vs -66+/-632 dyn.s/cm(5)), NT-proBNP (-164+/-317 vs -46+/-697 pg/mL) and WHO FC (21%/79%/0% vs 8%/83%/8% improved/stabilised/worsened). One patient experienced clinical worsening (riociguat 1.5 mg group). Riociguat was well tolerated. In PATENT-2, riociguat showed sustained efficacy and tolerability in patients with PAH-CHD at 2 years. Conclusions Riociguat was well tolerated in patients with PAH-CHD and improved clinical outcomes including 6MWD, PVR, WHO FC and NT-proBNP

BAY 2253651 for the treatment of obstructive sleep apnoea: a multicentre, double-blind, randomised controlled trial (SANDMAN)

BAY 2253651 is a nasally applied genioglossus muscle activator via pharyngeal mucosal receptor stimulation (potassium channel blocker) aimed to treat obstructive sleep apnoea. Although well-tolerated and safe, there was no significant therapeutic effect. https://bit.ly/3zDbyi