An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Indication: For the treatment of patients with Wilson disease who are intolerant to penicillamine
CADTH recommends that Waymade-Trientine should be reimbursed by public drug plans for the treatment of patients with Wilson disease if certain conditions are met.
Waymade-Trientine should only be covered to treat patients who have previously tried and demonstrated intolerance to d-penicillamine (DPA).
Waymade-Trientine should only be reimbursed if initiated by clinicians experienced in the management of Wilson disease and if the cost of Waymade-Trientine is reduced.
Wilson disease is a rare genetic disease of copper metabolism that can involve the liver, nervous system, brain, or a combination of these. Wilson disease may lead to liver failure, movement disorders, intellectual deterioration, and may ultimately be fatal. Most patients with Wilson disease present between 5 and 35 years of age. Wilson disease has been estimated to affect 1 in 30,000 people.
There is a need for an effective and tolerable copper chelating drug for patients who cannot tolerate DPA and for patients in whom DPA should not be used.
Treatment with Waymade-Trientine is expected to cost approximately $21,900 to $58,400 per adult patient per year, and $14,600 to $58,400 per child or adolescent patient per year.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that trientine hydrochloride be reimbursed for the treatment of of patients with Wilson disease who are intolerant to penicillamine only if the conditions listed in Table 1 are met. As per the product monograph, Health Canada has not authorized trientine hydrochloride for use in children younger than 5 years of age.
One retrospective cohort study of patients with Wilson disease suggested that treatment with trientine hydrochloride had comparable efficacy to d-penicillamine (DPA). Specifically, hepatic improvement scores for all patients were comparable in the first-line treatments group (25 of 38 [65.8%] trientine treatments versus 185 of 295 [62.7%] DPA treatments), as well as the second-line treatments group (31 of 103 [30.1%] trientine treatments versus 12 of 31 [38.7%] DPA treatments). Similarly, neurologic improvement scores for all patients were comparable in the first-line treatments group (11 of 38 [28.9%] trientine treatments versus 77 of 295 [26.1%] DPA treatments) as well as the second-line treatments group (26 of 103 [25.2%] trientine treatments versus 3 of 31 [9.7%] DPA treatments). Further, trientine had improved tolerability compared with DPA. This was demonstrated by a lower number of treatments discontinued due to adverse events with trientine (10 of 141 [7.1%] treatments) versus DPA (94 of 326 [28.8%] treatments). The presented evidence was also considered in light of the lack of an effective option for patients who cannot tolerate DPA, and the high morbidity and mortality associated with the lack of treatment. Given the lack of other options for copper chelating agents, CDEC concluded that trientine met some of the needs identified by patients: specifically, the improved tolerability profile compared to DPA.
The cost-effectiveness of trientine is highly uncertain due to limitations with the economic model and clinical evidence. As such, a base-case cost-effectiveness estimate was unable to be determined in patients with Wilson disease who are intolerant to DPA. CDEC considered exploratory analyses conducted by CADTH where the incremental cost-effectiveness ratio (ICER) was $146,927 per QALY when compared with no treatment and therefore determined that trientine would likely not be considered cost-effective at a $50,000 QALY WTP threshold. Based on these reanalyses, a price reduction would be required for trientine to achieve an ICER of $50,000 per QALY.
Reimbursement Conditions and Reasons.
Issues that may impact the drug plan’s ability to implement a recommendation as identified by CDEC and the drug plans are summarized in Table 2.
Implementation Guidance from CDEC.
Trientine hydrochloride has a Health Canada indication for the treatment of patients with Wilson disease who are intolerant to penicillamine. Trientine hydrochloride is a chelating agent with a polyamine-like structure that chelates copper by forming a stable complex with the 4 constituent nitrogens in a planar ring that is readily excreted in the urine. Trientine hydrochloride is available as 250 mg oral capsules.
To make their recommendation, the Committee considered the following information:
One patient submission from the Canadian Liver Foundation (CLF) was received for this drug. The CLF supports education and research into all forms of liver diseases and is committed to reducing the incidence and impact on Canadians at risk or living with liver diseases. The CLF gathered information through an online survey to which 8 patients and 5 caregivers responded, although additional input was collected from 2 health care professionals.
Patients described the negative impact of Wilson disease on their day-to-day activities, which was reiterated by caregivers, related especially to the ability to work and travel. The emotional and psychological effects of living with and managing Wilson disease results in constant stress and fear as well as psychiatric symptoms such as anxiety and depression, which negatively affect patient and caregiver quality of life. Side effects of current treatments such as fatigue, appetite loss, nausea, and pain were described as completely to somewhat intolerable. The survey respondents felt it was important to have access and choice of treatments for Wilson disease and for choices to be based on known side effects. The following outcomes were identified as being important to patients: reduction of short- and long-term side effects, overall quality of life, long-term disease stability, and adherence. Two patients and 2 caregivers had experience with trientine and relayed the challenges of accessing trientine via the SAP and obtaining private insurance coverage for it. If unable to access trientine, patients may have no choice but to use DPA despite experiencing side effects because they require chelation therapy to live. A benefit of trientine that was highlighted by patients was that it does not require refrigeration, thus making it more portable.
The responses from the 2 health care professionals firmly advocated for better access to medications for their patients with Wilson disease and described the difficulty in accessing trientine for their patients. Moreover, without reimbursement, trientine remains out of reach for many patients with Wilson disease, which is unacceptable in their views because these patients require effective and safe chelation therapy to live.
Two clinical specialists with expertise in the diagnosis and management of Wilson disease in adult and pediatric patients, respectively, contributed to this review. The clinicians advised that not all patients will respond to, or tolerate, DPA or zinc. Further, Canadian patients who require chelation and cannot take DPA due to toxicity or intolerance (estimated to be 20% to 40% of patients) currently have no available chelation treatment options as in the expert’s experience, zinc is inadequate in about 30% of patients and is relatively poorly tolerated. Available treatments have limited effect on acute liver failure, and none can reverse the neurologic or psychiatric manifestations of Wilson disease. A specific unmet need identified by the pediatric clinical expert was the lack of specific drug formulations (e.g., liquid formulations) to meet pediatric needs.
The current use of trientine after DPA treatment is mainly due to access issues. In the clinical expert’s opinion, if trientine were available as a first-line option, it would be preferred by many providers due to twice daily dosing, few adverse events (AEs), good tolerability, and solid efficacy. The clinical experts felt it was inappropriate for trientine to be limited only to patients who do not tolerate or fail DPA or zinc; however, if DPA and/or zinc must be tried before access to trientine is granted, intolerance or lack of efficacy should be based on subjective inability to tolerate the medication (AEs), poor adherence, and/or lack of efficacy based on symptom progression and/or inadequate de-coppering measured by non-ceruloplasmin-bound copper or 24-hour urinary copper excretion. Repeated trials of DPA or zinc should not be required before granting approval for trientine as toxicity with DPA may be worse upon rechallenge and some AEs associated with DPA are irreversible or slow to reverse and may be difficult, if not impossible, to predict. Significant delays in initiating therapy in patients with progressive disease can lead to irreversible impairment and this is particularly true with neurologic symptoms associated with Wilson disease.
The clinical experts advised that any patient with Wilson disease is expected to respond to trientine in terms of reducing overall body copper burden. Both adult and pediatric patients with hepatic-prominent Wilson disease are likely to have their hepatic symptoms respond to chelation therapy, including trientine. In contrast, patients with neurologic disease may have their neurologic symptoms worsen with initiation of any chelator treatment due to too rapid cerebral mobilization of copper.12 Some evidence and anecdotal reports suggest that neurologic worsening occurs more frequently with DPA than trientine, although this has not been rigorously evaluated. The experts felt that patients with advanced and progressive neurologic and/or psychiatric disease would be considered least suitable for trientine treatment, although trientine may still stabilize the disease and prevent further progression. Patients with acute liver failure often require immediate liver transplantation so trientine is unlikely to benefit those presenting with an acute Wilsonian crisis. Patients without symptoms but a confirmed diagnosis of Wilson disease should be treated; however, if the copper burden is not excessive initial treatment with zinc is appropriate rather than chelation therapy.
According to the clinical experts, response to treatment is usually assessed by ceruloplasmin-bound copper, 24-hour urinary copper collection, as well as liver enzymes and function tests in both adult and pediatric patients. It is also important to assess neurologic and hepatic improvement following treatment. While some assessments are subjective, they can usually be supported by objective assessments. Treatment response should be subjectively evaluated (i.e., patient perspective on symptoms) monthly at treatment initiation and then every 6 to 12 months once stable. Objective assessments such as neurologic assessment with or without brain MRI, laboratory improvement (non-ceruloplasmin-bound copper, 24-hour urinary copper excretion, liver enzymes/function) should be evaluated at least annually but may require more frequent testing, especially at treatment initiation. In pediatric patients, response to treatment should be assessed more frequently (e.g., every 3 to 6 months) due to the need for more frequent reassessment of dosage and treatment efficacy because of weight-based dosing.
The clinical experts reiterated that treatment of Wilson disease is lifelong and in all cases if 1 chelator is stopped, an alternative treatment must be started immediately as patients cannot be left untreated. The main reason for treatment discontinuation would be inadequacy of treatment due to either lack of efficacy or tolerability issues. The experts agreed that while a specialist is required to diagnose Wilson disease and should be involved in the care of patients, they do not necessarily have to be the only prescriber of trientine. Once a diagnosis is established, patients can be followed locally because access to a specialty clinic or specialist with experience treating Wilson disease could be problematic for patients.
Responses to Questions From the Drug Programs.
Two pivotal trials submitted by the sponsor were included in the systematic review. No additional trials from the literature search met the inclusion criteria for the systematic review and no indirect comparisons or other relevant evidence were identified. The first included study (Weiss et al., 2013) was a retrospective cohort analysis that evaluated the efficacy and safety of trientine compared to DPA in 405 patients with Wilson disease based on hepatic and neurologic outcomes and treatment discontinuations due to AEs. The analysis included 380 patients who were examined at tertiary care centres in Germany (Heidelberg, Dresden, and Dusseldorf) and Austria (Vienna, Graz, and Linz) and 25 additional patients identified from the EUROWILSON registry who had received trientine monotherapy. There were no patient inclusion criteria stated and no information on the specific time frame of the study or the calendar years over which time the patients were treated. It appears that efficacy outcomes were based on the latest available follow-up evaluation within a 6- to 48-month period. Data on discontinuations and discontinuations due to AEs were collected over a median 13.3-year period, although no range of time was reported. The results of the analysis were reported by number of chelator treatments (i.e., 326 DPA treatments and 141 trientine treatments) rather than by the number of patients, and the researchers categorized the DPA and trientine treatments as first-line or second-line, but how this was determined is unknown. The second study (Study 17-VIN-0021) was an open-label, 2-period, 2-sequence, 2-treatment, crossover, single-dose, fasting bioequivalence study of Waymade-Trientine 250 mg capsules compared to Syprine 250 mg capsules in 44 healthy adult male volunteers. The objective of this study was to compare the rate and extent of absorption of trientine from the 2 formulations to determine if they were bioequivalent. As the purpose of Study 17-VIN-0021 was to assess bioequivalence in healthy volunteers and not the efficacy and safety of trientine in patients with Wilson disease, this study was not reviewed in detail in this report.
According to the clinical experts on the review team, the baseline characteristics of the patients in the Weiss et al., 2013 study are reasonably similar to Canadian patients who would be candidates for trientine, with the possible exception of pediatric patients (< 18 years of age). The median age of included patients at the time of diagnosis of Wilson disease (the only age parameter reported in the study) was 17 to 19 years. Although patients less than 18 years were included, no details on the number or the age of pediatric patients was provided. At initial presentation, about half (207 [51.1%] patients) had only hepatic symptoms, 92 (22.7%) had only neurologic symptoms, 52 (12.8%) had mixed presentation (hepatic and neurologic symptoms), and 54 (13.3%) were asymptomatic, a similar distribution as expected in Canadian clinical practice.
In the Weiss et al., 2013 study, hepatic improvement scores after first-line treatment were comparable for all patients (25 of 38 [65.8%] trientine treatments versus 185 of 295 [62.7%] DPA treatments) and for symptomatic patients (25 of 27 [92.6%] versus 185 of 204 [90.7%], respectively) which were not statistically significantly different. Following second-line treatment, hepatic improvement scores were generally lower than with first-line treatment (i.e., 31 of 103 [30.1%] trientine treatments and 12 of 31 [38.7%] DPA treatments) for all patients and (31 of 45 [68.9%] and 12 of 16 [75.0%], respectively) for symptomatic patients. There were also no statistically significant differences between treatments. For symptomatic patients, stable hepatic disease categorized as unchanged hepatic symptoms was observed in 7.4% of first-line treatments for both groups (i.e., 2 of 27 trientine treatments and 15 of 204 DPA treatments). Stable hepatic disease after second-line therapy was reported in 10 of 24 (22.2%) of trientine treatments and 4 of 16 (25%) of DPA treatments. No statistical comparisons were reported for the number of treatments associated with stable or unchanged hepatic symptoms.
There were no first-line trientine treatments associated with hepatic worsening (i.e., defined as a decline in liver function or progression of chronic liver disease) compared to first-line DPA treatments (i.e., 0 of 38 [0%]) trientine treatments versus 4/295 [1.4%] DPA treatments) for all patients and (0 of 27 (0%) versus 4 of 204 (2.0%), respectively) for symptomatic patients. While second-line trientine treatment was associated with hepatic worsening, there were no second-line DPA treatments associated with hepatic worsening (i.e., 4 of 103 [3.9%] trientine treatments versus 0 of 31 [0%] DPA treatments) for all patients and (4 of 45 [8.9%] versus 0 of 16 [0.0%], respectively) for symptomatic patients. The differences between trientine and DPA treatments for hepatic worsening after either first-line or second-line treatments were not statistically significantly different. Overall, there were 12 treatments with an outcome of liver transplantation (i.e., 3 [2.1%] trientine treatments and 9 [2.7%] DPA treatments).
In the Weiss et al., 2013 study, neurologic improvement scores for first-line treatment were comparable between trientine treatments (11 of 38 [28.9%]) and DPA treatments (77 of 295 [26.1%]) for all patients but were numerically higher for DPA treatments (77 of 114 [67.5%]) versus trientine treatments (11 of 20 [55.0%]) in symptomatic patients, although the differences were not statistically significant. Following second-line therapy for all patients, neurologic improvement rates were comparable to those after first-line therapy for trientine treatments (26 of 103 [25.2%]) but were numerically lower for DPA treatments (3 of 31 [9.7%]). For symptomatic patients, neurologic improvement with second-line therapy after trientine treatments (26 of 51 [51.0%]) was numerically higher than after DPA treatments (3 of 13 [23.1%]). Nonetheless, all comparisons between trientine and DPA treatments for all patients and symptomatic patients for second-line therapy were not statistically significantly different. For symptomatic patients, stable neurologic disease, which was categorized as unchanged neurologic symptoms, was observed in 5 of 20 (25.0%) trientine treatments and 31 of 114 (27.2%) DPA treatments after first-line therapy and 1 of 51 (33.3%) and 9 of 13 (69.2%), respectively, after second-line therapy. No statistical comparisons were reported for stable or unchanged neurologic symptoms.
Rates of neurologic worsening after first-line therapy were statistically significantly higher for trientine treatments compared to DPA treatments for all patients (4 of 38 [10.5%] versus 6 of 295 [2.0%]; P = 0.018) and for symptomatic patients (4 of 20 [20.0%] and 6 of 114 [5.3%]; P = 0.042), respectively. For second-line therapy, rates of neurologic worsening were numerically higher with trientine treatments compared to DPA treatments for all patients (8 of 103 [7.8%] and 1 of 31 [3.4%], respectively) and symptomatic patients (8 of 51 [15.7%] and 1 of 13 [7.3%], respectively); although the differences were not statistically significant.
In the Weiss et al., 2013 study, the only harms outcomes reported were the proportions of chelator treatments with AEs that led to treatment discontinuation. Treatment discontinuations due to AEs were more common with DPA (94 of 326 [28.8%] treatments) compared with trientine (10 of 141 [7.1%] treatments). The difference between DPA and trientine treatments was statistically significant (P = 0.039), as reported in the publication.13 The frequency of AEs was higher with DPA treatments and the most common AEs (≥ 5% frequency in either group) that led to treatment discontinuation were arthralgia (29 of 326 [8.9%] versus 4 of 141 [2.8%]), increase in antinuclear antibodies (22 of 326 [6.7%] versus 1 of 141 [0.7%]), and albuminuria/proteinuria (20 [6.1%] versus not reported) for DPA treatments versus trientine treatments, respectively. Rates of discontinuations for any reason were not statistically significantly different between the chelator treatments (P = 0.360), as reported in the publication.
Key limitations of the Weiss et al., 2013 study pertaining to internal validity are the retrospective design, which is limited by lack of randomization and the non-prospective collection of efficacy and harms outcomes, and the unknown time frame of the study. The analysis was also not blinded which may have introduced bias into the categorization of hepatic and neurologic outcomes and the identification of symptomatic patients, as all were subjectively assessed by the researchers. The reporting of results by number of chelator monotherapy treatments rather than by number of patients complicates the interpretation of baseline characteristics and efficacy and harms outcomes as an individual patient may have been counted more than once in the results. This leads to double data counting which compromises the validity of the dataset. For example, if an individual patient displays a specific characteristic such as hepatic presentation, this will result in more treatments being characterized as having hepatic presentation than if patients were randomly selected and counted only once in the dataset. There were no clear definitions or validation of the efficacy outcomes in terms of reliability, validity, responsiveness, or minimally important differences, which makes interpretation difficult.
Key limitations relating to external validity in the Weiss et al., 2013 study are the lack of data for Canadian patients, lack of evidence on combination use of trientine in combination with zinc which is common in clinical practice, and lack of evidence in pediatric patients. The diagnosis and treatment of Wilson disease can be challenging in children as children may not display the same clinical and laboratory hallmarks of the disease as adults. No information on the dosage and administration schedules of trientine or DPA used in the study were reported so it is not known if the dosage regimens used in the study are in alignment with the Health Canada–approved doses for trientine and DPA. There were also no data available for most efficacy outcomes identified in the review protocol, including outcomes of interest to patients such as health-related quality of life and adherence.
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s analysis:
CADTH reanalyses included: removing copays from consideration, increasing the proportion of patients who require chelation therapy, increasing the proportion of patients who will be eligible for public reimbursement, and assuming 100% adherence.
Based on CADTH reanalyses, the budget impact of reimbursing trientine for patients who are intolerant to DPA is expected to be $5,191,012 in year 1, $5,259,144 in year 2, and $5,327,301 in year 3, for a 3-year total budget impact of $15,777,456 ($14,935,472 when dispensing fees and markups are excluded). This estimate was substantially different from that of the sponsor (3-year total: $3,844,144). CADTH was neither able to account for the offsetting of medications required for the hepatic and neurologic consequences of unstable Wilson disease, nor for the funding previously spent to acquire trientine through the SAP; thus, the actual budgetary impact of reimbursing trientine is likely lower than estimated.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Meeting date: December 15, 2021.
Regrets: One expert committee member did not attend.
Conflicts of interest: None.
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third-party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.
This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
Redactions: Confidential information in this document may be redacted at the request of the sponsor in accordance with the CADTH Drug Reimbursement Review Confidentiality Guidelines.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Indication: For the treatment of patients with Wilson disease who are intolerant to penicillamine.
Sponsor: Waymade PLC
Final recommendation: Reimburse with conditions
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
Your browsing activity is empty.
Activity recording is turned off.
See more...
