Volenrelaxin

Early-stage study data suggest an oral relaxin receptor agonist being developed by AstraZeneca led to improvements in cardiac remodeling and haemodynamics in patients with chronic heart failure (HF), potentially offering a new glimmer of hope for a treatment approach that has stumbled before.Results from the Phase IIb LUMINARA study, presented at the European Society of Cardiology (ESC) and published simultaneously in Circulation, showed that AZD5462 was well tolerated on top of guideline-directed HF therapy, with effects observed across a range of left ventricular ejection fractions (LVEFs).The trial randomised 375 chronic HF patients to once-daily AZD5462 at 20 mg, 80 mg or 360 mg, or placebo. The study included 235 patients with LVEF ≤35% (cohort A) and 140 with LVEF of 41% to 55% (cohort B).The primary endpoint in cohort A was change in end systolic volume index from baseline to week 24, a measure of adverse cardiac remodelling. The lowest dose produced the most benefit on this metric, with a placebo-adjusted change of −5.4 mL/m² (p=0.054). Effects on secondary endpoints, including change in LVEF, were also greatest at the lowest dose.For cohort B, the primary endpoint looked at change in systemic vascular resistance index from baseline to week 24, a measure of the resistance the heart has to pump against. AZD5462 significantly lowered the index across all three doses, by 19%, 21% and 15% at the 20-, 80- and 360-mg doses, respectively (all p≤0.021)."The observed effects on cardiac remodeling in heart failure with reduced ejection fraction and vascular resistance in patients with heart failure with mildly reduced/preserved ejection fraction suggest that oral relaxin family peptide receptor 1 (RXFP1) agonism may have relevance across multiple heart failure phenotypes," the study authors said.Past challengesThe peptide hormone relaxin-2 acts on RXFP1, leading to effects that may be beneficial in HF in terms of vasodilation, easing the heart's workload, and reducing inflammation and myocardial fibrosis.However, the authors noted that the history of relaxin-based therapies has yielded a "disconnect between short-term physiological promise and long-term clinical efficacy and safety."Earlier studies of Novartis' short-acting relaxin analogue serelaxin generated encouraging signals in acute HF, though subsequent trials failed to demonstrate longer-term clinical benefit. That spurred the development of longer-acting RXFP1 agonists, though a Phase II HF study of one of these, Eli Lilly's volenrelaxin (LY3540378), was terminated early last year after patients with preserved ejection fraction showed worsening fluid buildup and no significant kidney benefit.The overall incidence of adverse events in the LUMINARA study was comparable between the pooled AZD5462 and placebo groups. Investigators noted a "modest blood pressure–lowering effect" that was in line with what was seen in Phase I. "The clinical significance of this finding is unclear; notably there were no imbalances in clinically reported AEs of hypotension in cohort A despite extensive background [guideline-directed medical therapy]," they said.

Eli Lilly removed eczema and heart failure prospects from its pipeline. \n Eli Lilly has thinned its pipeline in two critical therapeutic areas, axing clinical-phase Alzheimer’s disease and obesity candidates as part of its quarterly clear-out.The removal of ceperognastat, Lilly’s oral O-GlcNAcase anti-tau agent, from the pipeline comes months after the candidate failed (PDF) to slow clinical decline in early symptomatic Alzheimer’s disease patients in a phase 2 trial. At the time, Daniel Skovronsky, M.D., Ph.D., chief scientific officer at Lilly, spotlighted biomarker data that suggested “potential impacts on tau pathology, brain volume and neuro-inflammation.”Lilly initially kept ceperognastat in its pipeline as it carried out safety follow-ups. With the phase 2 trial set to end this month, Lilly axed the candidate in its fourth-quarter update. Lilly linked the molecule to a 50% reduction of tau pathology and a 40% reduction in brain atrophy in preclinical studies but failed to translate those benefits into humans.The news is another blow to Lilly’s work on tau. In 2021, ceperognastat moved into phase 2 testing just as Lilly was removing another tau drug candidate, zagotenemab, from its pipeline. Last summer, when the company disclosed ceperognastat’s midphase miss, Skovronsky said Lilly remained committed to tau “as a high conviction target.\"In obesity, Lilly removed a dual amylin calcitonin receptor agonist (DACRA) from its phase 1 pipeline. Lilly got into DACRAs by partnering with KeyBioscience in 2017. At one time, the Big Pharma was advancing a DACRA alongside tirzepatide, the active ingredient in Mounjaro and Zepbound, but the GLP-1 candidate emerged as the more promising program.Lilly maintained an interest in the mechanism, though, extending its agreement with KeyBioscience last year and listing a DACRA candidate in its phase 1 pipeline. The phase 1 trial ended last year, and Lilly removed the candidate, which it called DACRA QW II and LY3541105, from its pipeline Thursday. The drugmaker also removed ucenprubart and volenrelaxin from its pipeline. Ucenprubart is a CD200R1 agonist that Lilly was studying as a treatment for eczema. Lilly stopped enrollment in a phase 2 trial of the candidate, which is also known as LY3454738, last month before reaching its recruitment target.Volenrelaxin was in development in heart failure and chronic kidney disease (CKD). Lilly updated the CKD study on ClinicalTrials.gov last month, revealing it had terminated the trial over “a lack of foreseeable clinical benefit in the proposed” population. The decision followed the “termination of a related heart failure study that demonstrated no benefit in an overlapping patient group,” Lilly said.“I was disappointed with the results from the phase 2 trial for sure,” Lilly’s CSO Skovronsky said during the Q&A portion of a Feb. 6 investor call. “Relaxin is an interesting mechanism, sort of validated by normal human physiology during pregnancy. But unfortunately, the results that we got in this trial didn\'t support proceeding with this molecule. I read that as speaking to the mechanism rather than the molecule. But I know others are pursuing this mechanism, and I wish them success where we didn\'t have it.”Editor\'s note: This article was updated on at 12 p.m. ET on Feb. 6 to include comment from Lilly leadership. Gabrielle Masson contributed to reporting for this article.