TRACER-HF: Trientine reduced biomarkers up to 8 weeks

Therapy wit copper chelator failed to reduce NT-proBNP levels in patients with heart failure and reduced ejection fraction at 12 weeks but promising trends were observed at earlier time points. This beneficial effect can be explained by the restoration of normal intracellular copper.

In models of HF with reduced ejection fraction, cellular copper depletion has been associated with myocardial remodelling [1]. As Prof. James Januzzi (Harvard Medical School, MA, USA) pointed out, copper scavenges oxygen-free radicals, serves as a cofactor for ATP production, and promotes iron and zinc uptake. Trientine-HCL (INL 1) is an oral copper chelator that acts as a copper chaperone at low doses, restoring normal intracellular copper concentrations that have been shown to reverse cardiac remodelling in experimental models.

The phase 2a TRACER-HF trial (NCT03875183) examined multiple doses of trientine-HCL (from 50 mg twice daily to 300 mg twice daily) in participants with HF and reduced ejection fraction. In this trial, 190 participants were enrolled at 27 sites in North America and China. All patients had HF with a left ventricular ejection fraction ≤40% and were randomised to treatment with trientine-HCL or placebo for 12 weeks. The primary study endpoint was the effect of trientine-HCL on the proportional NT-proBNP change from baseline to 12 weeks. In addition, cardiac remodelling indices, 6-minute walk distances, and Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score were assessed as secondary endpoints.

In the highest dose arm (i.e. 300 mg trientine-HCL twice daily), a significant reduction in NT-proBNP was noted at 4 and 8 weeks but not at 12 weeks compared with the placebo group. At week 4, the geometric mean ratio (GMR) least square mean difference was 0.82 in the highest dose group (vs 1.03; P=0.05), at week 8 it was 0.79 vs 1.02 (P=0.03). As for the secondary endpoints, trientine-HCL in the 150 mg and 300 mg doses improved left ventricular end-systolic volumes. Participants treated with the highest dose improved by 42 m in the 6-minute walking distance and had a better overall score on the KCCQ. “The 300 mg dose was most consistently associated with favourable KCCQ changes,” Prof. Januzzi commented.

Treatment with the chelating agent was generally well tolerated. Moreover, copper and iron concentrations were not significantly different across treatment arms. “Notably and interestingly, blood pressure and heart rate were not significantly affected by trientine-HCL,” Prof. Januzzi said.

To answer why NT-proBNP concentrations were not lowered at week 12, Prof. commented that this conflicting result may have been influenced by the pandemic. Prof. Januzzi explained that this trial was delayed due to the COVID-19 pandemic and that enrolment was affected. He believes that further studies of trientine-HCL in HF are justified in light of the current results.

1. Liu J, et al. Exp Biol Med (Maywood)2018;243:1141-52.
2. Januzzi J. A randomised, double-blind, placebo-controlled phase 2A study to evaluate the effects of trientine-HCL in patients with heart failure and reduced ejection fraction: the TRACER-HF trial. Session Late breaking clinical trials: Chronic HF and cardiomyopathies, Heart Failure 2023, 20–23 May, Prague, Czechia.

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Posted on 8 August 20238 August 2023