Winrevair regimen balances efficacy, safety in PAH: Analysis
Data from 3 trials analyzed to better characterize treatment exposure, outcomes
The dosing regimen for Winrevair (sotatercept-csrk) is optimal for balancing efficacy and safety in adults with pulmonary arterial hypertension (PAH), an analysis of clinical trial data shows.
This regimen is “well-justified based on the totality of the observed safety and efficacy data from Phase 2 and Phase 3 studies,” the scientists wrote.
The study, “Population Pharmacokinetic/Pharmacodynamic and Exposure-Response Modeling Analyses of Sotatercept in Healthy Participants and Patients with Pulmonary Arterial Hypertension,” was published in Clinical Pharmacology & Therapeutics.
Winrevair, sold by Merck, is approved for adults with PAH in the U.S., Canada, the European Union, Iceland, Liechtenstein, and Norway. The approvals generally apply to PAH patients in World Health Organization (WHO) functional class 2 or 3, wherein the disease limits physical activity, but people are comfortable at rest, or to improve WHO functional class.
The therapy is given as an injection under the skin, or subcutaneously, every three weeks. In the U.S., Winrevair treatment is also intended to improve exercise capacity and reduce the risk of PAH-related complications. Dosing begins at 0.3 mg/kg, which is increased to a target dose of 0.7 mg/kg if no adverse events occur.
Clinical trials have demonstrated that Winrevair can lower pulmonary vascular resistance (PVR), a measure of the resistance to blood flow in the pulmonary arteries, and enhance exercise capacity, as measured by the distance walked in six minutes (6MWD).
Exposure to treatment and safety, efficacy outcomes
To better understand Winrevair, scientists at Merck and their collaborators used data from several clinical trials to characterize the relationship between treatment exposure and safety and efficacy outcomes. The data used included two Phase 2 trials, SPECTRA (NCT03738150) and PULSAR (NCT03496207), and the Phase 3 trial STELLAR (NCT04576988) in PAH patients.
Exposure to the therapy was assessed via its pharmacokinetics, or its movement into, through, and out of the body, and pharmacodynamics, its effect on the body. Efficacy outcomes included 6MWD, PVR, and the levels of NT-proBNP, a biomarker for heart failure. Safety was evaluated by the therapy’s impact on hemoglobin, the protein that carries oxygen in red blood cells.
The 6MWD generally increased over time in patients treated with Winrevair in the Phase 2 and Phase 3 trials, according to the analysis. Increases in the 6MWD were also seen in those who received a placebo in PULSAR, but not STELLAR.
The 6MWD increased with increasing exposure to the therapy and appeared to plateau at exposures that corresponded to the approved target dose of 0.7 mg/kg once every three weeks. Age was an influencing factor, with 6MWD decreasing for each additional year beyond 48 years.
While the placebo didn’t impact PVR, patients who received Winrevair saw a dose- and concentration-dependent decrease in PVR. Here, treatment with background prostacyclin, a medicine that reduces blood pressure by widening blood vessels, reduced the PVR by about 16% among those who took prostacyclin over those who didn’t. Like the 6MWD, PVR reached an efficacy plateau at exposures that corresponded to the approved target dose.
Treatment exposure levels were a significant predictor of the time it takes for NT-proBNP levels to drop below 300 picograms/mL (pg/mL), at which point heart failure is unlikely. For each increase of 1 nanogram/mL of average Winrevair levels, the probability of NT-proBNP dropping below 300 pg/mL at any given time increased by 0.0297%.
In this analysis, the WHO functional class at the start of the study influenced this outcome. For patients with a WHO functional class 3, the predicted probability of NT-proBNP decreasing below 300 pg/mL was 26.6% higher than those with a WHO functional class 2.
Hemoglobin levels increased with increasing Winrevair exposure in PAH patients and also plateaued at the standard dose. Still, these increases were clinically manageable, as indicated by the low number of patients who required dose reductions in the STELLAR trial. The median change from baseline hemoglobin was slightly higher for those who received iron supplements.
“Altogether, these effects support the dose regimen for sotatercept at a starting dose of 0.3 mg/kg followed by a target dose of 0.7 mg/kg [every 3 weeks] by [subcutaneous] injection,” the scientists wrote, noting, while elevations in hemoglobin are manageable, they need to be monitored and the dose modified to reach an appropriate amount.
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