A newly launched global phase 3 trial will compare once-daily trientine to D-penicillamine as a first-line treatment for patients with Wilson disease, a rare genetic disorder.
Orphalan announced that it has initiated TRADITiONAL (NCT07465718), a new global phase 3 trial comparing an investigational once-daily formulation of tetrahydrochloride (TETA 4HCl) to D-penicillamine (DPA) as first-line treatment for Wilson disease. According to the company, the 48-week study will assess efficacy, safety, tolerability, and treatment satisfaction in patients 8 years or older.1
“Successful management of Wilson disease requires lifelong therapy, and current treatment regimens can be complex and burdensome for many patients, posing significant challenges with adherence,” Omar Kamlin, MD, chief medical officer at Orphalan, said in a statement.1 “The initiation of the global TRADITiONAL Study in the USA reflects Orphalan’s commitment in addressing the unmet needs of Wilson disease patients by investigating a therapeutic approach which may simplify the treatment burden.”
TRADITiONAL is a randomized, parallel-group, open-label, multicenter study enrolling symptomatic and asymptomatic patients with Wilson disease. Eligible participants must be treatment-naive or naive to chelator therapy. Symptomatic patients who have received zinc salts for no more than 28 days may also qualify. Following an approximately 4-week screening period, participants will be randomly assigned to 48 weeks of TETA 4HCl or DPA, stratified by clinical phenotype (neurological or non-neurological) and by treatment status at screening (chelator-naive or prior zinc salts).2
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In response to questions from NeurologyLive®, Orphalan provided additional detail on the trial’s assessments, design rationale, and the treatment gap it is intended to address.
Because Wilson disease can present with prominent neurological involvement, safety monitoring is a priority for the study, Orphalan explained. Participants will undergo regular neurological assessments to track changes from baseline, using tools the company said are designed to complement a movement disorder specialist’s clinical examination, including the Global Assessment Scale for WD (GAS for WD) and the Unified Wilson Disease Rating Scale (UWDRS).
For efficacy, Orphalan noted that TRADITiONAL is designed as a noninferiority trial, with the primary end point centered on bioavailable serum copper. Per the company, investigators will measure non-ceruloplasmin–bound copper by speciation (NCC-Sp), an assay that uses liquid chromatography coupled with inductively coupled plasma mass spectrometry (LC-ICP-MS) to quantify total serum copper and separate protein-bound copper fractions, allowing the non-ceruloplasmin–bound portion to be isolated and measured directly.
Orphalan told NeurologyLive that TRADITiONAL is notable in that head-to-head comparisons of DPA and trientine in newly diagnosed patients with Wilson disease have not previously been conducted. The company said its investigational once-daily TETA 4HCl formulation, tested directly against the current standard-of-care chelator, distinguishes this trial from prior Wilson disease research in this population.
The study is international and multicenter, having launched first at the University of Colorado Anschutz School of Medicine in Denver, according to Orphalan. In the US, sites also include Yale University and the University of Michigan, alongside additional sites in Saudi Arabia, China, and Pakistan. The company said referrals for screening and potential enrollment at the US sites are welcomed from clinical practices and other medical institutions nationwide. Additional trial details are available at
The trial is intended to determine whether a once-daily chelation regimen can provide an alternative to D-penicillamine while potentially reducing treatment burden. Patient-reported treatment satisfaction will be assessed alongside clinical efficacy, safety, and tolerability.
Wilson disease is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic variants in ATP7B, which impair copper excretion. Copper subsequently accumulates in tissues, particularly the liver and brain, and can produce hepatic, neurologic, and psychiatric manifestations; without effective lifelong treatment, the disease can be fatal.
Per Orphalan, chelators work by binding to absorbed copper, forming a stable complex that is eliminated through urinary excretion. The company noted that DPA is currently the only approved first-line chelator therapy for Wilson disease, but that its use can be limited by tolerability issues and adverse events.
Existing Wilson disease therapies also require lifelong treatment with multiple daily doses and strict separation from food or other substances that can impair absorption, Orphalan said, resulting in a demanding regimen that often contributes to poor or suboptimal adherence. The company said the clinical consequences of nonadherence can be severe, and even fatal in some cases, and that a significant unmet need remains for first-line treatment options that offer improved tolerability and simpler dosing to reduce treatment burden and support long-term adherence.
For context, copper-chelating therapy promotes removal of excess copper, whereas zinc salts reduce intestinal copper absorption. The comparison to D-penicillamine in TRADITiONAL is clinically relevant because the study focuses on initial therapy rather than switching patients who are already stable on another regimen.
