ESC26: AstraZeneca's heart failure drug shows promise in ph. 2 trial

AstraZeneca’s oral relaxin agonist delivered encouraging phase 2b results in chronic heart failure, improving measures of cardiac function across two patient groups. The phase 2b data from the Luminara trial, presented during the European Society of Cardiology Congress in Munich, Germany, included 235 patients with heart failure and a left ventricular ejection fraction (LVEF) of 35% or less, or moderately to severely reduced heart pumping function, and 140 patients with heart failure and an LVEF of 41% to 55%. The study was a double-blind, dose-ranging trial in which patients were randomized to receive placebo or the oral relaxin agonist AZD5462 at 20 mg, 80 mg or 360 mg once daily. The primary endpoint for patients with LVEF of 35% or less was the change from baseline in the end-systolic volume index, a measure of the amount of blood left in the heart’s ventricle at the end of a contraction. The primary endpoint in patients with LVEF of 41% to 55% was the change from baseline in systemic vascular resistance index, a measure of the resistance the heart must push against to pump blood through the body. The researchers found that in the moderate-to-severe heart failure cohort with LVEF of 35% or less, the lowest dose of AZD5462 decreased the end-systolic volume index by 5.4 mL/m2 compared with baseline. In the LVEF 41% to 55% cohort at 24 weeks, AZD5462 reduced systemic vascular resistance index by 19%, 21% and 15% at doses of 20 mg, 80 mg and 360 mg, respectively. Relaxin is a pregnancy hormone heavily produced by the placenta to help relax joints and prepare the body for childbirth. The hormone also has a role in heart failure by helping dilate blood vessels and reduce fluid congestion, which is why AstraZeneca has been working on developing a cardiovascular disease pipeline for more than 10 years, Mina Makar, SVP of global cardiovascular, renal and metabolism at AstraZeneca, explained to Fierce. AZD5462 is an oral, small-molecule selective agonist of the relaxin family peptide receptor 1 (RXFP1). It mimics the role of relaxin, aiming to bind to the RXFP1 receptor to trigger downstream signaling, reduce systemic vascular resistance and reverse cardiac remodeling in heart disease. Targeting this pathway has been challenging. Earlier this year, AstraZeneca canned its long-acting relaxin-2 analog, AZD3427, from the pipeline after underwhelming efficacy in a phase 2 trial. Eli Lilly had a similar RXFP1-targeting relaxin analog, volenrelaxin, that it axed from the pipeline around the same time. Finding the right dose that properly balances safety and efficacy has been a tough task in developing a noninjectable candidate, Makar admitted. “We believe we’ve identified the right dose that allows us to get the right benefit within heart failure,” Makar told Fierce. While it’s “always going to be about the outcomes eventually,” AstraZeneca feels “this is at least a good sign that we have a small molecule that delivers early signals of positive effect in heart failure, particularly in the reduced ejection fraction patient, with the type of tolerability you would want to see.”