Regulatory Decision Summary for Waymade-Trientine

Wilson’s disease is a rare inherited disorder in which excessive amounts of copper accumulate in the body, particularly in the liver, brain, and eyes. If left untreated, it will typically progress to death. The prognosis for patients who receive and are adherent to treatment for Wilson disease is generally good. Patients who cannot tolerate or who respond inadequately to treatment require alternative drug therapies to improve prognosis and quality of life. 

Wilson’s disease typically presents with some combination of liver disease, and neurological and/or psychiatric issues. Clinical features at presentation vary widely. Hepatic symptoms are often present during the initial clinical manifestation of disease, especially if disease manifests in the first decade of life, which occurs in approximately 40-50% of patients with Wilson’s disease. In some cases, hepatic symptoms may precede neurologic manifestations by as many as 10 years. Generally, patients with neurologic symptoms have some degree of liver disease at presentation.

Penicillamine, a copper-chelating agent, is generally recommended as first-line therapy for the treatment of Wilson’s disease. Approximately 30% of patients cannot tolerate penicillamine therapy due to the occurrence of severe adverse reactions, including hypersensitivity reactions, blood dyscrasias, nephritis, drug-induced lupus erythematosis, and various dermatologic manifestations.

Evidence from medical literature to support the efficacy and safety of trientine hydrochloride for the treatment of patients with Wilson’s disease who are intolerant to penicillamine was submitted. Results across the reviewed studies were consistent, and showed that most patients responded well to trientine hydrochloride (trientine) when it was used as a second-line therapy in patients who failed or were unable to tolerate penicillamine as first-line treatment. In patients who presented with hepatic symptoms at baseline but were unable to tolerate penicillamine as first-line therapy, a large retrospective analysis conducted by Weiss demonstrated that 68.9% of patients had improvement in hepatic status following trientine treatment. The same analysis demonstrated that 51.0% of patients with neurologic disease at baseline, and who were unable to tolerate penicillamine as first-line therapy, showed improvement in neurologic disease when treated with trientine as second-line therapy.

In this study, trientine hydrochloride was generally well-tolerated. The most common adverse event reported soon after initiation of trientine treatment was nausea. Skin rash and anemia were also occasionally reported. Iron deficiency has been observed with trientine administration, likely due to its chelating properties. In patients with symptomatic neurologic disease, 15.7% showed signs of neurologic worsening following initiation of trientine as second-line therapy. As such, a Serious Warnings and Precautions box was added to the Product Monograph to highlight the risk of worsening neurologic or neurocognitive functioning, which can be irreversible. This may occur in patients with pre-existing neurologic and/or neuropsychiatric impairment due to Wilson’s disease, and who are treated with trientine. It is thought that most of these patients may have responded adversely to the early increases in serum copper concentrations that are often observed after trientine initiation, due to its action on the mobilisation of copper from central stores. As these patients have sustained damage to the blood-brain barrier from past exposure to excessive serum copper levels, they are vulnerable to adverse neurological effects of temporarily elevated serum copper levels. To manage this potentially irreversible risk, trientine should only be prescribed by physicians experienced in the management of Wilson’s disease, and who are able to carefully gauge the expected benefits and risks of its use for the individual patient.  

A Canadian Risk Management Plan (RMP) for Waymade-Trientine was submitted by Waymade Canada Inc. to Health Canada. An RMP is designed to describe the known and potential safety risks associated with a drug product, present the monitoring scheme and, when needed, describe measures that will be put into place to minimise risks associated with the product. The submitted RMP was not accepted upon initial review, and the Marketed Health Products Directorate (MHPD) requested a revised RMP that will be provided by the sponsor to address the identified concerns.

Overall, the submitted efficacy and safety data demonstrated the utility of trientine in the treatment of patients with Wilson’s disease as second-line therapy in patients intolerant to penicillamine. Although trientine can be associated with some risks, considering the significant health impacts associated with this rare disorder, the benefit-harm-uncertainty profile of this drug is considered favourable.