In patients with heart failure (HF) and reduced ejection fraction (HFrEF), the copper chelator trientine reduced NT-proBNP levels up to 8 weeks by restoring normal intracellular copper.
In models of HF, intracellular copper depletion is associated with myocardial hypertrophy and fibrosis, and thus an increased risk for cardiac remodeling, James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, Massachusetts, told attendees at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023.
Although trientine has been used for over 40 years to treat Wilson disease — a rare inherited disease characterized by copper overload — “paradoxically, it acts as a copper chaperone and can restore intracellular copper concentrations at low doses,” Januzzi explained during his May 20 presentation of the TRACER-HF results.
Although the dose-ranging study found that at 300 mg twice daily trientine effectively reduced NT-proBNP levels at 4 and 8 weeks, by 12 weeks, the effect had disappeared.
Nevertheless, Januzzi told the meeting attendees that the same dose was “most consistently” associated with most favorable Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) changes, as well as improvements in left ventricular (LV) function and 6-minute walk distance.
‘Challenging Is an Understatement’
Asked why the improvement in NT-proBNP levels was no longer evident at week 12, Januzzi acknowledged, “We just don’t know.” However, the team speculates that the disrupted nature of the study might play a role.
The phase 2, placebo-controlled trial started recruiting at 27 sites in North America in 2019. When the pandemic hit in 2020, enrollment was suspended, then pivoted to China in 2021. A total of 190 participants were ultimately enrolled.
However, 91% of participants in China were finishing their follow-up in late 2022, when the country was hit by a COVID-19 surge, which might have affected the 12-week outcomes — though this is speculation for now.
Overall, participants had a mean age of 57 years; about 80% were men; 91% were Asian; the mean left ventricular ejection fraction (LVEF) was 30%; and most (77%) were New York Heart Association class II. All were stable on optimal drug therapy, including chronic loop diuretics.
All had elevated NT-proBNP: ≥ 400 pg/mL without atrial fibrillation or flutter, or ≥ 1200 pg/mL with atrial fibrillation or flutter.
Participants were randomized to placebo or twice-daily trientine doses of 50 mg, 150 mg, or 300 mg.
The primary endpoint was the proportional change in NT-proBNP from baseline to 12 weeks. Key secondary endpoints included the effect of trientine compared with placebo on mechanistic outcomes such as change in cardiac remodeling indices, 6-minute walk distance, and the KCCQ-OSS.
As noted, the greatest reduction in NT-proBNP at 4 and 8 weeks was in the 300 mg group, with a geometric mean ratio of 0.82 at week 4 vs. 1.03 for placebo; 0.92 for 50 mg; and 0.83 for 150 mg; and 0.79 at week 8 vs 1.02 for placebo; 0.85 for 50 mg; and 0.91 for 150 mg.
LV volumes improved at all doses, though by the most at 50 mg (-11.7 mL).
The change in 6-minute walk distance was greatest at the 300 mg dose at 42 meters.
The responder analysis showed that 300 mg was most consistently associated with most of the favorable KCCQ changes.
From a safety standpoint, trientine was well tolerated without any adverse outcomes. Notably, Januzzi told meeting attendees, blood pressure and heart rate were not affected by the addition of trientine to background medical care.
In addition, a post-hoc interaction was identified between treatment response and a baseline LVEF ≤ 30%, data that, for now, are “compelling but hypothesis-generating,” he said. Data on secondary endpoints specifically for that group “are forthcoming.”
Looking Ahead
Januzzi told theheart.org | Medscape Cardiology that the team is now finalizing their main report “and will turn our attention to the interaction analyses suggesting exaggerated benefit in those with lower LVEF.”
“We are examining all possible options for this novel therapy, which may include progressing to phase 3,” he said.
Challenges going forward include the need to understand which patients are most appropriate for the drug. “Given that it does not affect blood pressure or heart rate, it is an attractive consideration for any patient on guideline-directed medical therapy, but we need to have more clarity about the mechanism of benefit and understanding about the subgroup interactions that we have detected.
“Even in a well-managed population of patients with heart failure, there may still be room for therapies with benefit,” he concluded.
Danyaal Moin, MD, an assistant professor of medicine at NYU Grossman School of Medicine in New York City and a specialist in advanced heart failure and transplantation, commented on these findings for theheart.org | Medscape Cardiology.
“It is always exciting to consider new pathways to treat patients with systolic dysfunction, given the residual risk even for patients on contemporary quadruple therapy for HFrEF,” he said. “However, certain challenges with this phase 2 study will need to be addressed in an eventual phase 3 clinical trial.
“The study sample was predominately recruited in China and is not necessarily representative of a heart failure population in many clinical practices,” he said.
In addition, “It would be important that future studies with trientine-HCL assess endpoints such as heart failure hospitalizations and mortality that would help elucidate where this therapy would stand relative to current established heart failure therapies.”
Longer follow-up is needed and, he noted, “while it appears the investigators will ultimately favor the 300 mg dosage, it is interesting that left ventricular volume indices changed most favorably with the 50 mg dose of the therapy.”
The study was sponsored by Innolife Pharmaceuticals and coordinated by the Baim Institute for Clinical Research in Boston, Massachusetts. Januzzi has received grant support from Innolife. Moin declares no relevant financial relationships.
Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023: Presented May 20, 2023.
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