Trientine dihydrochloride (TETA-2HCl) is an established treatment for Wilson disease. We assessed different dissolution profiles of TETA-2HCl capsules on the pharmacokinetics (PK) of trientine (TETA) and on direct copper (Cu) parameters. In this open-label, randomized, two way cross-over study, 24 healthy subjects received two single oral doses of 600mg TETA-2HCl with a washout of at least one week; one dose with a fast and one dose with a slow dissolution profile. Blood and urine samples were collected up to 48h for analysis of plasma TETA and its metabolites, N1-acetyltriethylenetetramine (MAT) and N1-N10-diacetyltriethylenetetramine (DAT), serum Cu, ceruloplasmin (Cp) and urinary Cu excretion (UCE). The effect of dissolution profile on the PK was assessed through the ratio of geometric mean ratios (GMRs) and two-sided 90%-confidence intervals (CI) of the fast vs. slow dissolution profile. The Cmax of TETA was comparable for the two products (GMR 95.81%; CI 83.87-109.46%) while AUC0 - inf was slightly lower for the capsules with fast dissolution profile (GMR 90.65; 90% CI 78.32-104.91%). PK parameters were similar for the metabolites of TETA. Additionally, serum Cu and Cp concentrations remained stable over the 12h period after dosing and were comparable between the two products, as was UCE. The pharmacokinetic profiles of TETA after administration of TETA-2HCl capsules with fast and slow dissolution characteristics were similar. Though the lower 90%-CI for AUC0-inf was outside the formal bioequivalence ranges, differences were small (9%) and not considered clinically relevant. A difference in dissolution profile did not affect copper parameters and tolerability.

Results of the up-titration phase of the UNITED study, an open label, multicenter, prospective study to characterize the pharmacokinetics and pharmacodynamics of trientine dihydrochloride and to investigate the efficacy and safety in Wilson disease patients

SAT-367 UNITED study: results of the up-titration phase of an open label, multicenter, prospective study to characterize the pharmacokinetics and pharmacodynamics of trientine dihydrochloride and to investigate the efficacy and safety in Wilson disease patients

Wilson disease is an inherited disorder of copper metabolism affecting mainly the liver and brain. Trientine dihydrochloride (TETA-2HCl) is approved for the treatment of Wilson disease in patients (≥ 5 years) intolerant to D-penicillamine therapy. This study assessed the long-term outcomes of treatment with TETA-2HCl in Wilson disease patients. In this Phase 2, prospective study, patients continued their treatment of TETA-2HCl 300 mg (200 mg trientine base) for 12 months (July 2015-April 2017) at one center in Germany. Primary outcomes were the safety and efficacy of TETA-2HCl treatment; Biomarkers of copper metabolism; and the course of hepatic and neurologic disease. Overall, 51 patients contributed data. Almost all patients (50 [98.0%]) were considered responders (rating of ≤ 4 at the 12-month visit); Unified Wilson Disease Rating Scale scores improved throughout the study from a mean (standard deviation) of 11.3 (24.31) at Baseline to 8.8 (22.86) at Month 12. Biochemical assessments of liver parameters (transaminases, liver synthesis) as well as markers of copper metabolism (24-h urinary copper, non-ceruloplasmin bound copper (NCC)) showed improved or stable disease throughout the study. Treatment-emergent adverse events were reported in five (9.6%) patients. No patients withdrew from treatment due to adverse events, and no serious adverse events were considered to be treatment-related. This study demonstrated that treatment with TETA-2HCl was effective and well tolerated in hepatic and neurologic disease manifestations. Additionally, improvement in neurological symptoms was reported throughout the trial, suggesting that improvements may be reported for an extended period after initiation of therapy. Trial Registration: NCT02426905.

Wilson’s disease (WD) is a rare autosomal recessive disorder of copper metabolism that primarily affects the liver and brain. In children, the hepatic phenotype of the disease predominates. Low awareness of the neuropsychiatric manifestations of WD in children leads to insufficient diagnosis of neurological forms. Managing children with WD requires a multidisciplinary approach involving hepatologists, geneticists, neurologists, and psychiatrists. This review aims to highlight the latest advances in the study of WD in children, discuss diagnostic challenges, and explore treatment prospects. Key Points. The article reviews recent advancements in understanding the hepatic and neuropsychiatric symptoms of WD in children and describes existing diagnostic and treatment challenges. The ATP7B gene, whose mutations cause WD, plays a key role in copper metabolism. Diagnosis of WD is based on a combination of clinical signs, biochemical tests, and genetic testing. Serum ceruloplasmin levels, urinary copper excretion, and hepatic copper content are primary biomarkers of the disease. WD treatment focuses on reducing copper levels in the body using chelating agents such as D-penicillamine and trientine dihydrochloride. Zinc is used to decrease copper absorption from the gastrointestinal tract. Liver transplantation is considered a treatment option in cases of severe hepatic failure. Conclusions. WD requires early diagnosis and a multidisciplinary approach to patient management. Further research is needed to improve diagnostic and therapeutic strategies, including the development of new biomarkers and gene therapy. The importance of genetic counseling and family screening is emphasized for the timely identification and treatment of the disease. The authoritative information presented in the article contributes to raising awareness of WD in children and improving clinical practice.

This study evaluates the effectiveness and safety of trientine dihydrochloride (TETA 2-HCl) in patients with Wilson disease (WD) following a switch from trientine tetrahydrochloride (TETA 4-HCl). A total of 30 WD patients with stable copper metabolism were identified for treatment with TETA 2-HCl (Cufence™) after prior use of TETA 4-HCl (Cuprior™). Biochemical markers including urinary copper, non-ceruloplasmin bound copper (NCC) and liver function were analyzed at baseline and followed up over 12 months. Safety was assessed based on reported adverse events (AEs). Urinary copper levels and NCC remained stable across all follow-ups, indicating adequate copper metabolism control. Reported AEs during TETA 2-HCl treatment were mostly gastrointestinal discomfort (n = 6). In two patients, progressive elevation of transaminases occurred (despite stable copper metabolism). AEs led to discontinuation of treatment in five cases. Median baseline dose per day was 10.2 mg TETA 4-HCl/kg bodyweight, whereas median baseline dose after therapeutic switch to TETA 2-HCl was 12.8 mg/kg bodyweight. Median daily dose at 12 months did not differ significantly from TETA 2-HCl dose at switching timepoint, with stable biochemical markers and markers of copper metabolism in most (25/30) of the patients. Transitioning from TETA 4-HCl to TETA 2-HCl maintained stable copper parameters and liver function in most of analyzed patients. TETA 2-HCl treatment was generally well tolerated, suggesting that switching medications is safe and effective. In our real-life cohort, adjustment factor of ~1.25× for the switch of TETA 4-HCl to TETA 2-HCl resulted in adequate copper metabolism control.

THU-335 - Quality of life in patients with Wilson disease treated with Trientine dihydrochloride: a prospective study

Exploring the potential of trientine tetrahydrochloride in the treatment of Wilson disease

The UNITED study – Open label, Multicenter, Prospective Study to Characterize the Pharmacokinetics and Pharmacodynamics of Cufence (Trientine Dihydrochloride) and to Investigate the Efficacy and Safety in Wilson’s Disease Patients

Background: Wilson’s disease (WD) is one of the few genetic disorders that can be successfully treated with pharmacological agents. Copper-chelating agents (D-penicillamine and Trientine salts) and zinc salts have been demonstrated to be effective. There are two salts of trientine. Trientine dihydrochloride salt (TETA 2HCL) is unstable at room temperature and requires storage at 2–8 °C. Trientine tetrahydrochloride (TETA 4HCL) is a more stable salt of trientine that can be stored at room temperature. No comparative study between both of the salts of trientine has been performed to date. As the two chemical forms were available in France between 1970 and 2009, we conducted a study to evaluate their efficacy and safety profiles. Methods: This retrospective cohort study was conducted by reviewing data from the national WD registry in France. Forty-three WD patients who received TETA 2HCL or TETA 4HCL monotherapy for at least one year until 2010 were included. The primary endpoints were hepatic and neurological outcomes. Secondary endpoints were the events leading to a discontinuation of medication. Results: Changes in medication were common, leading to the analysis of 57 treatment sequences of TETA 4HCL or TETA 2HCL. The mean duration of treatment sequence was significantly longer in the TETA 4 HCL group (12.6 years) than in the TETA 2HCL group (7.6 years) (p = 0.011). Ten patients experienced both trientine salts: eight stopped TETA 4 HCL (six had a hepatologic phenotype and two had a neurological phenotype) because this treatment was not available anymore (mean duration 7.4 years). Three of these patients already experienced TETA 2 HCL before the sequence. Two patients with a hepatologic phenotype (one had a previous sequence of TETA 4 HCL before) stopped TETA 2 HCL because of cold storage issues (mean duration 42.8 years). The total number of sequences was 57. All of the patients were clinically stable. No difference in efficacy was detected. Both treatments were well tolerated, except for a case of recurrence of lupus erythematosus-like syndrome in the TETA 2HCL group. The major reason for interruption of TETA 4HCL was due to a discontinuation in production of this salt. The reasons for stopping TETA 2HCL were mainly due to adherence issues largely attributed to the cold storage requirement. Conclusions: The two salts of trientine were effective in treating patients with WD. However, interruption of TETA 2HCL was frequent, linked to the cold storage requirement. As adherence to treatment is a key factor in the successful management of WD, physicians need to be even more vigilant in detecting adherence difficulties in patients receiving treatment with TETA 2HCL.

FRI258 - Gender dependent neurological and hepatic improvement in Wilson disease patients treated with Trientine dihydrochloride: post hoc results from a prospective study

Trientine dihydrochloride (TETA-2HCl) has been used for the treatment of Wilson disease for over 30 years. The current study was designed to systematically evaluate existing data to further define the long-term outcome of the efficacy and tolerability of TETA-2HCl in Wilson disease patients. Medical records of 77 Wilson disease patients were reviewed to collect data on hepatic and neurologic symptoms, copper (Cu) homeostasis and adverse events. Data were collected for 48 months after initiation of TETA-2HCl after withdrawal of D-penicillamine treatment. Mean duration of TETA-2HCl treatment was 8 years (range 5 months-32.5 years). Over the course of TETA-2HCl treatment, 35% of patients had no hepatic symptoms whereas in 49.4% of patients, hepatic symptoms improved. They remained unchanged in 10.4% of patients and worsened in 5.2% of patients. No patients progressed to acute hepatic failure or necessity of a liver transplant. During TETA-2HCl treatment, 46.7% of patients had no neurologic symptoms; in 14.3% of patients, neurologic symptoms improved whereas in 36.4% of patients, they remained stable and worsened in 2.6% of patients. During the evaluation period, 12 patients discontinued TETA-2HCl treatment due to: anemia ( N = 1), inadequate hepatic response ( N = 2), switch to zinc treatment ( N = 8) and patient's decision to withdraw from treatment ( N = 1). Treatment-emergent adverse events were reported by 24.7% of the patients of which gastrointestinal disorders (9.1%) and nervous system disorders (5.2%) were most reported. TETA-2HCl is well-tolerated and effective in Wilson disease patients following the withdrawal of treatment with D-penicillamine. ClinicalTrials.govIdentifier : NCT02426905.

BackgroundDisturbances of copper (Cu) homeostasis can lead to hypertrophic cardiac phenotypes (eg, Wilson’s disease). We previously identified abnormal Cu homeostasis in patients with hypertrophic cardiomyopathy (HCM) and, therefore, hypothesised that...

Trientine dihydrochloride for Wilson's disease.

The aim of the study was to investigate the efficacy and safety of trientine-dihydrochloride (TD) in pediatric patients with Wilson disease (WD) and the effect of different weight-based dosages on their clinical and biochemical outcome. We retrospectively reviewed the clinical data of 31 children with WD receiving TD therapy ages under 18 years at the time of diagnosis. Outcome measures included parameters of copper metabolism and liver function tests. To examine the impact of different weight-based dosages, 2 dosage subgroups were analyzed. Group 1 received less than 20 mg/kg TD per day, group 2 more than 20 mg · kg-1 · day-1. Median follow-up was 60 (5-60) months in the total study group. During TD therapy, nonceruloplasmin-bound copper was reduced from mean 1.53 (0.01-6.95) at baseline to 0.62 (0.01-4.57) μmol/l. 24h-urinary copper excretion diminished to 1.85 (0.8-9.6) μmol/day approximating the therapeutic goal of 1.6 μmol/day. Seven of 31 patients (22.6%) required discontinuation of TD treatment, in 4 cases it was because of adverse events (ulcerative colitis, gingival and breast hypertrophy, hirsutism, elevation of transaminases).Investigations about weight-based dosage showed no significant difference of any laboratory parameter between the 2 cohorts. But in terms of clinical safety, adverse effects because of TD were only found in 6.7% of children in group 1 (<20 mg · kg-1 · day-1, median follow-up 60 [9-60] months), whereas in group 2 (>20 mg · kg-1 · day-1, median follow-up 60 [14-60] months), it was 63.6%. TD proves to be an efficacious alternative chelating agent for children with WD. Weight-based dosages above the recommended 20 mg · kg-1 · day-1 may increase the rate of adverse effects in pediatric patients.

Human medicines European public assessment report (EPAR): Cufence, trientine dihydrochloride, Hepatolenticular Degeneration, Date of authorisation: 25/06/2019, Status: Authorised

Orphan designation: trientine dihydrochloride, Treatment of Wilson's disease

Summary of opinion: Cufence,trientine dihydrochloride

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. Radiofrequency ablation (RFA) is currently performed widely for managing HCC. RFA treatment causes damage around the ablation. Trientine dihydrochloride has been used to reduce the copper in liver. The rats were treated with trientine dihydrochloride for 5days before liver RFA. Liver function, copper concentration, inflammation biomarkers and MDA, SOD were analyzed after RFA treatment for 2h, 2 and 5days. The results indicated that trientine dihydrochloride reduced the copper in plasma and liver tissue significantly. And trientine dihydrochloride significantly inhibited RFA-induced inflammatory gene expression in liver. Similar inhibitory effects of trientine dihydrochloride were observed on ROS-induced malondialdehyde production in liver tissues. These results suggest that pre-treatment with the selective copper chelator trientine dihydrochloride can inhibit inflammatory response effectively during and after liver RFA in vivo. Chelation of copper to a lower level before liver RFA may be a novel strategy to prevent or ameliorate inflammatory responses in liver induced by RFA and to protect the parenchyma tissues in liver during and after RFA in HCC patients.

Edema and Cirrhosis Caused by Wilson's Disease