Introduction

In a surprising turn of events at the American Heart Association (AHA) Scientific Sessions, the novel myeloperoxidase (MPO) inhibitor, mitiperstat, failed to show significant improvements in quality of life or functional capacity for patients with heart failure with preserved and mid-range ejection fraction (HFpEF and HFmrEF), according to findings from the phase II ENDEAVOR trial.

Trial Findings

The trial's primary endpoint, which measured quality of life via Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS) scores, revealed a meager -1.4 point difference compared to placebo, far below the clinically significant threshold of 5 points on the 100-point scale (P=0.29). Additionally, mitiperstat did not positively impact the co-primary endpoint of six-minute walk distance (6MWD) either, with a +3.8 meters change noted (P=0.28), nor did it demonstrate benefits in any of the secondary endpoints assessed.

Exploratory Analysis and Hope

Despite these disappointing results, there are glimmers of hope for mitiperstat. An exploratory analysis suggested that the drug may reduce hospitalizations due to heart failure, myocardial infarction, or death, achieving a hazard ratio of 0.71 compared to placebo. This reduction was primarily driven by a 36% decline in heart failure hospitalizations, prompting researchers to call for further investigation in larger randomized controlled trials.

Historical Context

Historically, some successful heart failure treatments, such as SGLT2 inhibitors and angiotensin receptor neprilysin inhibitors, have shown similar patterns, improving hospitalization rates without impacting 6MWD or quality of life scores.

Mechanism of Action

Mitiperstat targets myeloperoxidase, an enzyme produced predominantly by neutrophils. While systemic inflammation has been a focus for developing therapeutic interventions in heart failure, previous treatments aimed at this inflammatory state have yielded mixed results. Amanda Vest, head of heart failure and transplant cardiology at the Cleveland Clinic, noted that previous contenders in this arena have either been ineffective or even harmful.

Further Analysis

Further analysis through proteomics suggested that mitiperstat might affect clinical outcomes by decreasing monocyte activation and alleviating mitochondrial stress—an insight worth exploring further. The ENDEAVOR trial enrolled 709 adults aged 40 to 85 across 18 countries with symptomatic heart failure but no significant kidney dysfunction or severe blood pressure abnormalities.

Trial Design and Safety

Participants were randomly assigned to a double-blind treatment regimen of either mitiperstat (at doses of 2.5 or 5.0 mg) or placebo for 48 weeks. Although treatment did not lead to significant results for the secondary endpoints or improve inflammatory biomarker levels, the safety profile appeared similar across treatment groups, with the most prominent side effect being a maculopapular rash occurring in a small percentage of patients.

Substudy Insights

Interestingly, a substudy within the trial, which measured 2,824 proteins at baseline and 16 weeks, indicated changes in protein clusters linked to immunity and metabolism in the mitiperstat group. Among these, a stress resistance protein called GRPEL1 emerged as a potential biomarker for heart failure hospitalizations, highlighting the need for personalized medicine approaches in future research.

Conclusion

While the immediate trial results for mitiperstat may seem underwhelming, insights from proteomics and the potential for subgroup identification could lead to a reexamination of the drug's therapeutic role in heart failure management. The research community remains hopeful that further studies will clarify the effectiveness of MPO inhibition, illuminating pathways to better treatment options for this challenging condition. Stay tuned for updates as new trials emerge!