Sunday, April 30, 2017

Trientine tetrahydrochloride for treatment of Wilson's disease

Trientine tetrahydrochloride (Cuprior, gmp-orphan SA) has been recommended for approval in Europe for the treatment of Wilson's disease in adults, adolescents, and children aged 5 years and older who are intolerant to d-penicillamine.

The positive opinion, from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP), is for a hybrid medicine: a drug that is similar to an authorized medicine containing the same active substance but that differs in characteristics such as strength, indication, or pharmaceutical form. Hybrid applications rely in part on the results of preclinical tests and clinical trials for a reference product and in part on new data.

Wilson's disease is a rare genetic storage disease caused by a defect in a copper transporter gene, leading to copper accumulation in the liver, brain, eye, and peripheral nerves.

Trientine is a copper-chelating agent that removes copper from the body by forming a stable complex that is eliminated through urinary excretion. Trientine may also inhibit copper absorption from the intestinal tract.

Cuprior is a hybrid of trientine dihydrochloride, which has been on the market in Europe since 1985.  
Cuprior works in the same way as the reference product but, unlike the reference product, the trientine salt in Cuprior (tetrahydrochloride) does not need to be stored in the refrigerator.

Cuprior has had orphan status since 2015. It will be available in 150-mg tablets.

"The benefits with Cuprior are its ability to decrease serum copper levels in patients with Wilson's disease," the EMA said in a statement.
Nausea is the most commonly reported adverse reaction with trientine. Serious iron deficiency anemia and severe colitis may occur during treatment, the agency notes.


  1. Trientine or D-Penicillamine for Wilson Disease? Atif Zaman, MD, MPH reviewing Weiss KH et al. Clin Gastroenterol Hepatol 2013 Aug.

    Monotherapy with either chelation agent was highly efficacious, but D-penicillamine was better in patients with neurologic symptoms.

    In a recent study, zinc monotherapy, an inhibitor of intestinal copper uptake, was not as effective as chelating agents in the treatment of Wilson disease (NEJM JW Gastroenterol May 27 2011). However, information is lacking on which chelating agent is best. D-penicillamine has been in clinical use the longest, but trientine has been shown to have fewer adverse effects.

    To compare the safety and efficacy of these chelator-based therapies for Wilson disease, researchers retrospectively analyzed data from 405 patients, most of whom were treated at tertiary centers in Germany and Austria. Neurologic and hepatic outcomes were assessed periodically up to 48 months, and median follow-up of discontinuation due to adverse events was 13.3 years.

    A total of 467 chelator-based treatments were analyzed; most were D-penicillamine (326). At 48 months, hepatic deterioration was reported in only 4 patients; however, 9 patients on D-penicillamine and 4 patients on trientine underwent liver transplantation. Compared with patients receiving trientine, patients receiving D-penicillamine had less neurologic deterioration (4 of 38 vs. 6 of 295, respectively; P=0.02) but more discontinuations due to adverse events (7.1% vs. 28.8%; P=0.04).


    Long-term follow-up in this large cohort demonstrated similarly high efficacy of each chelating agent. Although more tolerable, trientine appears to be less efficacious in patients with Wilson disease who have neurologic symptoms. In such patients, D-penicillamine should be the drug of choice. Future studies should evaluate the efficacy of combination therapy of trientine plus zinc in patients with Wilson disease who have mostly neurologic symptoms.

  2. D-Penicillamine, Trientine Only Somewhat Effective in Wilson's Disease

    Dr. Heinz led a retrospective international multicenter cohort study of long-term outcomes with the drugs. The study involved 347 patients, some of whom crossed over from one drug to the other at various times (d-penicillamine treatments, n = 326; trientine treatments, n = 141).

    Patients had an established diagnosis of Wilson's disease for at least 6 months and could not have been taking zinc salts long with the drugs, according to study criteria. At baseline, there were no differences in the d-penicillamine or trientine groups by sex, presentation, genotype, age at diagnosis (median, 17.5 to 19.5 years), or proportion with cirrhosis at diagnosis (approximately one third in each group).

    The only significant difference was that d-penicillamine had been used as first-line therapy by 90.2% of the patients in that group, whereas 25.5% of the patients in the trientine group had used trientine as first-line therapy (P < .001), indicating that d-penicillamine was generally used as initial treatment. There were no differences between groups in terms of baseline laboratory parameters. Hepatic outcomes were determined by liver function tests and neurologic outcomes were determined by clinical assessment at 48 months.

    Dr. Weiss reported that with an average follow-up of 16.5 years, both treatments were associated with excellent survival rates and prevented the need for liver transplantation in more than 98% of patients.

    Follow-up at 48 months showed that patients with hepatic symptoms improved, regardless of first- or second-line treatments (no significant differences between drugs). Among patients receiving first-line d-penicillamine (n = 295), symptoms improved in 90.7% and worsened in 2%. Among patients receiving first-line trientine (n = 38), symptoms improved in 92.6% and worsened in 0%. Among patients receiving second-line d-penicillamine (n = 31), symptoms improved in 75% and worsened in 0%. Among patients receiving second-line trientine (n = 103), symptoms improved in 68.9% and worsened in 8.9%.

    The drugs were not as effective in treating neurologic symptoms as they were in treating hepatic symptoms, although d-penicillamine appeared to be more effective than trientine. Neurologic symptoms improved in 67.5% of patients receiving first-line d-penicillamine and in 55.0% receiving first-line trientine (no significant difference between the groups). Neurologic symptoms worsened in 5.3% of the d-penicillamine patients and in 20.0% of the trientine patients (P = .042).

    D-penicillamine was associated with a higher prevalence of adverse events, even after decades of therapy.

    Although the 2 drugs have been used for decades, Dr. Weiss said they had never before been directly compared. Trientine has generally been preferred because of a higher incidence of adverse effects with d-penicillamine; this study supports that preference. But d-penicillamine might be better in terms of the amelioration of neurologic symptoms.