麻豆传媒

CLEVELAND -- Lower doses of copper chelator trientine hydrochloride (Syprine) appeared safe and potentially promising for heart failure with low ejection fraction in a phase IIa trial, despite a missed primary endpoint.

Twice daily 300-mg doses significantly improved proportional NT-proBNP change at 4 and 8 weeks compared with placebo (ratio of geometric least-squares means 0.82 vs 1.03, P=0.05, and 0.79 vs 1.02, P=0.03, respectively). However, no advantage emerged for the primary endpoint on that measure at 12 weeks (P=0.99), as .

That 12-week point in the study fell right when the COVID-19 peak hit in China, where most of the patients had been enrolled, which might have hampered follow-up and the potential to show an impact, noted James L. Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School in Boston.

At the Heart Failure Society of America (HFSA) meeting, he presented a subanalysis of significant treatment effect interactions with left ventricular ejection fraction (LVEF).

The NT-proBNP impact was significant at all three follow-up timepoints, including 12 weeks, in the 101 patients with LVEF of 30% or less.

Trientine has been used as an oral copper chelator for more than 40 years for Wilson's disease, a rare genetic condition that leads to damaging copper buildup in organs. At low doses, though, the drug acts as a copper chaperone to restore normal intracellular copper concentrations.

Copper plays important roles in the myocardium, such as serving as a cofactor for ATP production and calcium flux, Januzzi noted.

"While clinical copper deficiency, quite rare, is associated with the risk for a non-ischemic cardiomyopathy, it turns out that depletion of cellular copper, even in normal circulating copper concentrations, is associated with myocardial remodeling and drop in ejection fraction," he said. "Conversely, experimental restoration of normal intracellular copper reverses this process with improvements in ejection fraction."

Indeed, what was really noteworthy in the phase IIa trial was the LV remodeling, he told attendees. In those with baseline LVEF of 30% or less, significant trends were seen that weren't seen for the higher LVEF group.

In the low EF group, LVEF improvement was 3.4% at 50 mg, 5.6% at 150 mg, and 6.3% at 300 mg twice-daily dose groups versus 3.1% with placebo (P=0.17 for dose interaction).

LV end-systolic volume and LV end-diastolic volume mean absolute change from baseline showed similar patterns, with notable differences for the 300-mg dose group compared with placebo for both measures (-15.3 vs +5.5 mL and -5.7 vs +20.0 mL, respectively), although neither was significant for trend (P=0.19 and 0.13).

The highest dose group likewise had notable quality of life gains averaging 11 points on the Kansas City Cardiomyopathy Questionnaire over 12 weeks (P=0.009 vs baseline) whereas the placebo group lost 0.9 points over the same period. Six-minute walk distance improvements were also directionally consistent, Januzzi said.

The study enrolled 190 patients (mean age 57.3, 20% women) in North America and China with New York Heart Association Class II or III symptoms and an LVEF of 40% or less, elevated NT-proBNP, and stable medical treatment that included loop diuretics. They were randomized to placebo or trientine at 300 mg, 150 mg, or 50 mg doses twice daily.

The trial largely enrolled in China, with 90% of the total participants being Asian. The trial launched in December 2019, then was suspended from April 2020 to January 2021 as a result of the COVID pandemic; thereafter, the focus of enrollment shifted to China.

The 101 patients with LVEF of 30% or less and 89 with LVEF of 31-40% were comparable for other characteristics and had high treatment rates for other drugs, including more than 90% on beta-blockers, 98% on ACE inhibitors/angiotensin receptor blockers/angiotensin receptor/neprilysin inhibitor (83% on sacubitril/valsartan [Entresto]), and 44% on SGLT2 inhibitors. "This is relevant when we think a little bit about where a new therapy for individuals with very low EF might fit in," Januzzi noted.

Blood pressure and heart rate were not significantly affected by trientine, "so this has a null effect on vital signs in very well-managed patients such as the ones in this study," he added.

HFSA session discussant Harriette Van Spall, MD, MPH, of McMaster University in Hamilton, Ontario, noted the long history of safety in trientine use in Wilson's disease at higher doses.

The study was limited as a post hoc observation from a small size clinical trial designed to evaluate safety and identify doses for further studies. "Lastly, the endpoints that we analyzed were mechanistic, so we can make no assertions about impact on prognosis," Januzzi cautioned.

Van Spall, while calling the results promising, also cautioned about the potential for type I error and the small subgroups analyzed.

"This trial and substudy generates important information for a phase III trial that will definitively establish efficacy or not," she concluded. "If efficacious, [it] could fill a treatment gap in patients with [heart failure with reduced ejection fraction] and severely reduced ejection fraction who are commonly limited by symptomatic hypotension that limits our utilization of guideline-directed medical therapy."

Comment