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

Daniel M, Keller, PhD

April 08, 2011

April 8, 2011 (Berlin, Germany) — Two longstanding chelator drugs are effective in treating the hepatic manifestations of Wilson's disease, including improving survival while staving off the need for liver transplantation. The drugs, d-penicillamine and trientine, were less effective in reversing the neurologic symptoms of the disease, according to a study presented here at the European Association for the Study of the Liver (EASL) 46th Annual Meeting.

Wilson's disease is a rare genetic storage disease caused by a defect in a copper transporter gene, resulting in copper accumulation in the liver, brain, eye, and peripheral nerves, Karl Heinz Weiss, MD, consultant hepatologist at University Hospital Heidelberg in Germany, told meeting attendees. If not treated, the disease can be debilitating and life-threatening. D-penicillamine and trientine are the first-line treatments recommended in current guidelines, but optimal regimens still need to be defined, he said.

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.

"What's new in this study is that we did report such a worsening of neurologic symptoms under therapy with trientine, and even at a higher frequency than general opinion thought this worsening should or would occur," Dr. Weiss told Medscape Medical News. He said both drugs are effective, and there is no clear choice between them. "But there are open questions remaining about the optimal treatment regimen concerning neurologic patients," he noted.

Because of the relatively small sample sizes, the investigators could not analyze the results in terms of the duration of disease or body burden of copper.

A possible confounding factor in interpreting the results is that patients could have been on either drug at one time or another. Additionally, patients might have received zinc salts for treatment during the course of their disease, further confounding the results.

"For the time being, I think we're stuck with these drugs," Dr. Weiss said. He suggested performing studies to optimize their use and possibly to test them in combination with zinc because of their different mechanisms of action, but using a chelator with a cation might defeat the purpose.

The practice implications of the findings are that "worsening or nonimprovement of neurological symptoms occurred with trientine . . . [but] this is the first study to show in a large collection [of patients] that trientine has fewer side effects than d-penicillamine and is equally effective for hepatic patients," he said.

Despite the limitations of the study, including its retrospective design, it reflects the way patients are actually treated. "It refers to real patients in a real clinical practice," said Daniele Prati, MD, director of the Department of Transfusion Medicine and Hematology at the Ospedale Alessandro Manzoni in Lecco, Italy, and a member of the EASL Scientific Committee. "The message is that the overall management of this disease with these 2 drugs is satisfactory."

Patrizia Burra, MD, PhD, head of the multivisceral transplant unit and chief of the Cell Therapy Regional Centre for Metabolic Liver Diseases at Padua University Hospital, Italy, noted that research is needed on genetic and other risk factors for patients who develop neurologic symptoms, "because they respond very badly to drugs once . . . the brain has been affected by the copper."

Better drugs are needed that will prevent neurologic symptoms, which can affect the brain, eye, and peripheral nerves, Dr. Burra emphasized.

The study received no outside funding. Dr. Weiss, Dr. Prati, and Dr. Burra have disclosed no relevant financial relationships. Neither Dr. Prati nor Dr. Burra were involved in this study.

European Association for the Study of the Liver (EASL) 46th Annual Meeting. Presented March 31, 2011.