Astrazeneca Novel Anti-Inflammatory Flops in Heart Failure

 The novel myeloperoxidase (MPO) inhibitor mitiperstat failed to improve quality of life or functional capacity in heart failure with mid-range to preserved ejection fraction (HFmrEF, HFpEF), the phase II ENDEAVOR trial showed.

For the primary endpoint of Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS) quality of life scores, the drug had only a -1.4 point least squares (LS) mean difference compared with placebo (P=0.29), which was less than the 5-point difference considered to be clinically important on the 100-point scale.

Mitiperstat also failed to impact the co-primary endpoint of 6-minute walk distance (6MWD, LS mean difference +3.8 meters, P=0.28) or any of the secondary endpoints, Sanjiv J. Shah, MD, of Northwestern University in Chicago, reported at the American Heart Association (AHA) Scientific Sessionsopens in a new tab or window.

However, there were some signals that could keep the anti-inflammatory agent in the game.

An exploratory composite outcome of heart failure hospitalization, myocardial infarction, or death was numerically reduced with mitiperstat compared with placebo (HR 0.71, 95% CI 0.42-1.19, P=0.196), driven by a relative 36% reduction in heart failure hospitalization, "and that requires further exploration in larger confirmatory [randomized controlled trials]," Shah told attendees.

There is precedent for effective heart failure medications that cut heart failure hospitalizations without an impact on 6MWD or quality of life score, for example SGLT2 inhibitors and angiotensin receptor neprilysin inhibitors.

Mitiperstat targets the inflammatory enzyme MPO, which is mainly produced by neutrophils and can be detected in the circulation.

"While systemic inflammation presents itself as a valid opportunity for therapeutic targets, ... treatments for the inflammatory state in the heart failure setting have thus far either yielded neutral studies, very lukewarm benefits, or in the case of the [tumor necrosis factor] alpha blockers in HFrEF, the potential for harm," noted session study discussant Amanda Vest, MBBS, MPH, head of heart failure and transplant cardiology at the Cleveland Clinic.

Proteomics analysis supported a potential benefit of mitiperstat on clinical events and identified a potential mechanism -- reducing monocyte activation by decreasing mitochondrial stress, Shah said.

The phase IIb trial included 709 adults age 40-85 (mean 72, about 45% women) in 18 countries who had symptomatic heart failure with left ventricular (LV) ejection fraction greater than 40%. They were randomly assigned to double-blind treatment for 48 weeks with mitiperstat at 2.5 or 5.0 mg or placebo.

Patients couldn't have kidney dysfunction with an estimated glomerular filtration rate under 30 ml/min/1.73 m2, systolic blood pressure less than 90 or greater than 180 mm Hg, or heart rate outside the 50-110 bpm range. Enrollment required New York Heart Association II-IV disease that was impacting quality of life (KCCQ-TSS ≤90 points) and function (6MWD 30-400 m), with elevated NT-proBNP levels plus at least one risk factor from among LV hypertrophy, left atrial enlargement, elevated LV filling pressure, and recent heart failure hospitalization.

Results were pooled between the two mitiperstat dose groups.

None of the secondary endpoints showed an advantage to the drug, including 24- and 48-week results on the KCCQ-TSS and 6MWD and 16-, 24-, and 48-week results on inflammatory markers interleukin 6 and high-sensitivity C-reactive protein, NT-proBNP, or echocardiography parameters.

Overall and serious adverse event rates were similar among groups, as were infection and serious infection risk. Maculopapular rash was more common with mitiperstat, with rates of 2.6% on the lower dose and 5.4% on the higher dose compared with 0.4% in the placebo group. Mitiperstat-induced rash typically appeared within about 30 days, with a hazard ratio of 1.97 (95% CI 1.10-3.55) compared with placebo.

The ENDEAVOR proteomics substudy included 397 patients with 2,824 proteins measured using the Olink Explore platform at baseline and 16 weeks. Three clusters of proteins were seen to change with mitiperstat treatment related to the immune system; metabolism and biological oxidation; and platelets, cell surface receptors, and chemokines.

Six of the 30 most central "hub proteins" across the three clusters changed to a greater extent in the pooled mitiperstat groups versus placebo (P<0.05). The only one of these associated with incident heart failure in U.K. Biobank data after Bonferroni correction was GRPEL1, which is a "stress resistance protein that helps maintain mitochondrial protein quality control under stress conditions," Shah explained.

While the overall trial results were neutral, the plasma proteomics "are aligned with a profile seen in external cohorts to associate with lower hospitalizations for heart failure and may give us the opportunity to define perhaps a more responsive subgroup to this medication," Vest suggested. "Whether MPO inhibition is the right clinically effective strategy, we'll continue to look forward to seeing in further trials."

Disclosures