TETA4 Noninferior to Penicillamine for Stable Wilson's Disease

Oral maintenance therapy with trientine tetrahydrochloride (TETA4; Cuvrior) was noninferior to penicillamine for patients with stable Wilson's disease, the phase III randomized CHELATE trial showed.

In an intention-to-treat analysis involving 53 patients, the mean difference in serum non-ceruloplasmin-bound copper (NCC) by speciation assay between those who received TETA4 and penicillamine was -9.1 μg/L (95% CI -24.2 to 6.1) after 24 weeks, which fell within the lower limit of the noninferiority margin of -50 μg/L, reported Michael Schilsky, MD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues.

TETA4 continued to show noninferiority to penicillamine at 48 weeks (mean difference in NCC -15.5 μg/L, 95% CI -34.5 to 3.6), they noted in Lancet Gastroenterology & Hepatology.

"This finding is important because, although drug regulatory agencies are still indicating penicillamine as first-line treatment for patients with Wilson disease, many, if not most, clinicians will actually prescribe trientine formulations at the time of diagnosis or switch from penicillamine to trientine to prevent or limit side-effects," wrote Valentina Medici, MD, and Marie Heffern, PhD, both of the University of California Davis, in an accompanying editorial.

Those who received TETA4 also had significantly lower urinary copper excretion at 24 weeks compared with those who received penicillamine (mean difference 237.5 μg/24 hours, 99% CI 115.6-359.4), though this difference lost significance at 48 weeks, when urinary copper excretion levels fell within the expected range for both groups (mean difference 124.8 μg/24 hours, 99% CI -37.6 to 287.1).

Wilson's disease is a rare inherited copper transport disorder, characterized by mutations impacting the function of the ATP7B gene, which causes copper buildup and damage to the liver, and can progress to the brain and other organs, Schilsky's group noted.

Penicillamine, the first FDA-approved copper chelator, was used for over half a century to re-establish the balance of copper, while TETA4 came decades later to treat patients with Wilson's disease who are intolerant to penicillamine. Nearly 30% of patients have discontinued penicillamine after developing early hypersensitivity and severe adverse effects. Results from this trial led to the FDA approval of TETA4 in May.

"This is the first clinical study to use liquid chromatography inductively coupled plasma mass spectroscopy on speciated copper-bound proteins and total serum copper to quantify NCC (NCC by speciation assay), our primary endpoint," Schilsky and team explained.

Medici and Heffern pointed out that the trial's execution was challenging, noting that "the key questions regard the validation of this tool, the correlation between NCC-Sp [speciated copper] and clinical manifestations, the potential of NCC-Sp to predict worsening clinical manifestations, and ultimately how and when NCC-Sp will be available to clinicians."

For this open-label study, Schilsky and colleagues randomly assigned 53 patients with stable Wilson's disease 1:1 to continue receiving maintenance therapy with oral penicillamine twice daily or be switched to a "mg-for-mg" converted dose of oral TETA4 (150 mg trientine base/tablet) across 15 centers in nine countries -- with most from Brazil, Europe, and the U.S. -- from June 2018 to March 2020. To be eligible, patients had to be treated with a stable dose of penicillamine for at least 1 year.

Mean patient age was 42-45, and 46-59% were women. Most were white (76-89%), with an ATPB7 mutation on both chromosomes (69-88%). Over half had neurological features.

The mean change in serum total copper from baseline to 24 weeks was 17.6 μg/L with penicillamine and -6.3 μg/L with TETA4, while serum total ceruloplasmin levels were 1.8 mg/L and -2.2 mg/L, respectively.

Liver enzymes were similar between groups at 24 and 48 weeks, except for elevated alanine transaminase (ALT) levels among the TETA4 group at 48 weeks.

No serious adverse events (SAEs) occurred with TETA4 compared with three SAEs in the penicillamine group, including cholangiocarcinoma, hepatocellular cancer, and leukopenia, but only leukopenia was treatment-related.

The most common treatment-emergent adverse events were headache in the penicillamine group (19% vs 8% in the TETA4 group) and abdominal pain in the TETA4 group (15% vs 4% in the penicillamine group).

Schilsky and colleagues noted that their study was large for a rare disease, but was not diverse, with 83% of patients being white. "Further larger studies with more diverse ethnicities are needed to improve generalizability of our findings," they wrote.

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