Relaxin-2 for heart failure with preserved ejection fraction: a comment on the termination of a phase-II trial investigating the relaxin-2 analogue, LY3540378

On November 25, 2024, Eli Lilly and Company informed the public about the decision to terminate their phase-2 study, J3E-MC-EZDB with the relaxin-2 analogue, LY3540378, after data analysis of 40% of participants had indicated futility without immediate signs of patient risk. The study enrolled patients with heart failure with preserved ejection fraction within 2 weeks of an event of worsening heart failure with volume overload to receive 3 different doses of LY3540378 or placebo as weekly subcutaneous injection.
In this Editorial, we compare LY3540378 and related long-acting relaxin-2 analogues with native relaxin-2. It is demonstrated that the modifications to native relaxin-2 to increase its half-life in circulation have been achieved at the cost of i) safety and ii) signalling pathways pivotal to the treatment of HFpEF.  In terms of safety concerns, elevated immunogenicity attributed to the fusion to Fc or antibody fragments is forwarded, as well as impairment of therapy control in blood pressure-labile HFpEF patients due to overly prolonged administration intervals. With respect to signalling, we elaborate on the glucocorticoid-receptor and Wnt1 pathways that control anti-inflammatory and anti-arrhythmic therapy effects. It is highly unlikely that those pathways are activated by the long-acting relaxin-2 analogues. Using the Wn1 pathway, native relaxin-2 increases markedly the expression of the fast sodium channel, Nav1.5 in cardiomyocytes from aged rats, to ~200 % after 48 hours. In contrast, increasing doses of a single-chain analogue of relaxin-2, B(7-33) have no effect on Nav1.5.
In summary, we make a case for the therapeutic use of full-length, native-structure human relaxin-2 in HF, especially in HFpEF. We need the full pleiotropy of the native peptide for a most complex clinical syndrome.