Bayer Adempas is used for clinical success in phase IV in underreacted PAH patients treated with PDE5i.

On September 7th Bayer announced the positive results of the Phase IV study REPLACE at the 2020 European Respiratory Society (ERS) Virtual Annual Meeting.
in this study, moderate-risk pulmonary hypertension (PAH) adult patients switched to Ademas (riociguat, Leosi) after insufficient response to treatment with phosphate dylase-5 inhibitors (PDE5i), data show that 41% of patients transitioning to Ademas treatment were not clinically Clinical improvement was achieved in the case of deterioration, while 20% of patients in the PDE5i treatment group achieved clinical improvement (ratio ratio of 2.78, 95% CI (1.53-5.06) ;p =0.0007), and the study reached a composite main endpoint.
, REPLACE is a forward-looking global, multi-center, two-arm, randomized, controlled, open-label phase IV study.
The 24-week study assessed the clinical effectiveness of the transition from PDE5i treatment to riociguat in 226 PAH patients who did not respond clinically to PDE5i (Sidnavo or tadaraf) monodruplisal therapy or in a combined treatment with endopisin-ligand antagonists (ERA).
same time, the study included patients with PDE-5i who received single-drug treatment or who were treated with ERA in the same way as those who were still at moderate risk.
The moderate risk as defined by the World Health Organization's Functional Rating (WHO FC) III is to receive a stable dose of PDE5i and ERA based on the Guidelines for treatment of the European Society of Cardiology/European Respiratory Society (ESC/ERS), with a 6-minute walk distance (6MWD) of 165-440m.
The study's compound main endpoint, determined by blind method, was clinical improvement in patients at week 24 without clinical deterioration (involving death for any cause, PAH deterioration, or hospitalization for disease progression), including two indicators: 6MWD increase of 10% / 30 m from baseline, WHO FC I/II or NT-proBNP decreased by 30% from baseline.
6-minute walk and WHO FC were assessed using blind methods, and clinical deterioration events were independently determined.
, the most common adverse events (AEs) in the study were usually consistent with what was seen in the critical study PATENT.
Bayer, a 12-week multi-center, double-blind, randomized, placebo-controlled, critical PATENT-1 study, was designed to observe the effectiveness and safety of PAH adult patients (n-443) who were not treated or pretreated with ERA or prosthetic drugs (oral, inhaled, or subsurface injections).
study showed that the most common AEs in the riociguat treatment group (-3%) were headache (27% to 18%), indigestion/gastritis (21% to 8%), dizziness (20% to 13%), and nausea (14) % to 11%), diarrhea (12% to 8%), low blood pressure (10% to 4%), vomiting (10% to 7%), anemia (7% to 2%), gastroesoesopia reflow disease (5% to 2%) and constipation (5% to 1%).
compared to the placebo group, riociguat treated other common AEs with palpitations, nasal congestion, nosebleeds, difficulty swallowing, bloating and surrounding edema.
PAH refers to an increase in arterial pressure from the right side of the heart to the lungs, caused by abnormal pulmonary wall, typical symptoms including shortness of breath, fatigue, weakness, chest pain and fainting during fatigue.
in healthy individuals, nitric oxide (NO) acts as a signaling molecule for blood vessel smooth muscle cells, inducing vascular diastopathy.
NO is combined with soluble bird nucleotide cyclase (sGC) to mediate the synthesis of secondary messenger ring bird nucleotide monophosphate (cGMP).
synthesized cGMP as a second messenger, activates cGMP-dependent protein kinases to regulate in-cell calcium ion concentrations and alter the contraction of actin-myoglobulin, leading to blood vessel dilation.
NO is produced by endotred nitric oxide enzyme (eNOS), while eNOS levels decrease in patients with pulmonary hypertension.
resulting in lower levels of endoskin cell-origin NO in general and lower vascular esopathy in smooth muscle cells.
can also reduce the growth of smooth muscle cells in the lungs and antagonate platelet suppression, which play a key role in the pathogenesis of PAH.
compared to NO-and-haem independent sGC activators such as cinemacguat, the sGC stimulator riocicuat directly stimulates sGC activity that is not dependent on NO and works in synergy with NO to produce anti-aggregation, anti-proliferation, and vascular throosity.
Riociguat molecular structure (Photo: Wikipedia) Riociguat is the first sGC regulator developed in collaboration with Bayer and Mercedon and is the only treatment approved in the United States for both types of PAH (WHO-mandated Groups 1 and 4).
October 2013, the FDA approved riociguat for the treatment of PATIENT patients, as well as postoperative nonoperative or persistent/recidective CTEPH patients.
in 2014, riociguat was approved in Japan.
but Bayer warns that riociguat has embryo-fetal toxicity and cannot be used in pregnant women.
for women with reproductive capacity, pregnancy must be avoided before treatment begins, during the month of treatment and one month after discontinuation of treatment.
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