Bayer and MSD’s Adempas (Riociguat) Demonstrates Strong Efficacy in PAH Patients with Inadequate Response to PDE5 Inhibitors

March 29, 2021/BioValleyBIOON/--Bayer(Bayer) recently announced that the results of the Phase IV REPLACE study, which evaluated Adempas (riociguat) for the treatment of pulmonary arterial hypertension (PAH), have been published in the international medical journal The Lancet Respiratory Medicine. For full details, see:Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial。

The study was conducted in adult patients with intermediate-risk pulmonary arterial hypertension (PAH; World Health Organization [WHO] Group 1) who had an inadequate response to phosphodiesterase-5 inhibitor (PDE5i) therapy. The results showed that switching from PDE5i to Adempas led to a higher proportion of patients achieving clinical improvement without clinical worsening (the composite primary endpoint) compared with continuing PDE5i therapy (41% vs. 20%). These data, part of the collaboration between Bayer and Merck Sharp & Dohme, were previously presented at the European Respiratory Society (ERS) 2020 Virtual Congress.

Adempas is a first-in-class soluble guanylate cyclase (sGC) stimulator that directly stimulates sGC, enhancing its sensitivity to low levels of nitric oxide (NO). This drug is approved in the United StatesFDAThe only therapeutic agent approved for the treatment of two types of pulmonary hypertension (WHO Groups 1 and 4), which can significantly improve patients’ exercise capacity.

PAH (Image source: narayanahealth.org)

Bayer and Merck Sharp & Dohme are engaged in a global collaboration in the field of sGC modulators. Adempas, the first sGC stimulator to emerge from this partnership, was developed by Bayer and Merck Sharp & Dohme and has currently been approved for marketing and sale in the United States, Canada, the European Union, Japan, and several other countries worldwide.

In clinical practice, a substantial proportion of patients with intermediate-risk pulmonary arterial hypertension (PAH) fail to achieve or maintain specific treatment goals when receiving phosphodiesterase-5 inhibitor (PDE5i)-based regimens. The REPLACE study demonstrated that up to 41% of patients achieved satisfactory improvement after switching from PDE5 inhibitors to Adempas, which is highly encouraging. In addition to supporting the concept of treatment optimization, the findings of the REPLACE study complement those of the PATENT study, which showed that Adempas monotherapy or combination therapy effectively manages patients.

Sameer Bansilal, MD, Senior Medical Director of Bayer US Medical Affairs, stated: “The scientific rationale for the REPLACE study is derived from the ESC/ERS guidelines, which recommend establishing a low-risk status as a treatment goal for patients with pulmonary hypertension. In clinical practice, however, many patients at intermediate risk fail to achieve or maintain specific treatment targets when treated with PDE5i-based therapies. We remain committed to generating ongoing evidence to further demonstrate the value of Adempas, which may provide additional benefits for adult patients with pulmonary arterial hypertension (PAH, WHO Group 1), a chronic and often debilitating cardiopulmonary disease.”

REPLACE is a prospective, global, multicenter, two-arm, randomized, controlled, open-label Phase IV study conducted at 81 sites across 22 countriesClinical TrialThe study was conducted in 226 patients with moderate-risk pulmonary arterial hypertension (PAH) who had an inadequate clinical response despite stable treatment with phosphodiesterase-5 inhibitors (PDE5i; sildenafil or tadalafil) alone or in combination with endothelin receptor antagonists (ERA). It evaluated the efficacy and safety of switching from PDE5i to Adempas versus continuing PDE5i therapy. Moderate-risk PAH was defined as World Health Organization functional class (WHO FC) III and a 6-minute walk distance (6MWD) of 165–440 meters, despite receiving stable doses of PDE5i and ERA therapy.

The composite primary endpoint of this study was achieving clinical improvement at Week 24 of treatment, in the absence of clinical worsening (death from any cause, hospitalization due to PAH worsening or disease progression). Clinical improvement was defined as meeting at least two of the following criteria: an increase in 6-minute walk distance (6MWD) from baseline of ≥10% or ≥30 meters, WHO Functional Class I/II, and a reduction in NT-proBNP from baseline of ≥30%.

The results showed that at Week 24 of treatment, a significantly higher proportion of patients who switched to Adempas achieved the composite primary endpoint (clinical improvement without clinical worsening) compared with those who continued PDE5i therapy (41% vs. 20%; OR=2.78, 95% CI: 1.53–5.06; p=0.0007). Response rates were consistent with the overall results across different types of PAH and prior therapies. The most common adverse events (AEs) were generally consistent with those observed in the pivotal PATENT study. These data are part of the collaboration between Bayer and MSD.

The pivotal PATENT-1 trial was a 12-week, multicenter, double-blind, randomized, placebo-controlled study that evaluated the efficacy and safety of Adempas in adult patients with pulmonary arterial hypertension (PAH) (n=443) who were either treatment-naïve or had previously received treatment with an endothelin receptor antagonist (ERA) or prostaglandins (oral, inhaled, or subcutaneous).

The results showed that, compared with the placebo group, the Adempas treatment group demonstrated improvements in multiple clinically relevant endpoints, including: 6-minute walk distance (6MWD) by 36 meters (95% CI: 20–52 meters; p<0.0001), World Health Organization functional class (FC; p=0.0033; most patients were WHO FC II or III at baseline), time to clinical worsening (TTCW; p=0.0046), pulmonary vascular resistance (−226 dyn·s·cm⁻⁵; 95% CI: −281 to −170; p<0.001), and N-terminal pro-B-type natriuretic peptide (NT-proBNP; −432 ng/mL [95% CI: −782 to −82]; p<0.001).

In the PATENT study, compared with the placebo group, the most common adverse events (≥3%) in the Adempas group were headache (27% vs 18%), dyspepsia/gastritis (21% vs 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), hypotension (10% vs 4%), and vomiting (10% vs 7%).Anemia(7% vs 2%), gastroesophageal reflux disease (5% vs 2%), and constipation (5% vs 1%). Compared with the placebo group, events more commonly observed in the Adempas group included palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension, and peripheral edema. (Bioon.com)

Original Source: Bayer Announces Publication of Phase IV Adempas® (riociguat) Data in The Lancet Respiratory Medicine