INTRODUCTION

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare disease in which protein aggregates (amyloids) are abnormally deposited within tissues and organs, primarily causing destruction of multiple peripheral nerves, including damage and death of autonomic nerves [1, 2]. TTR-FAP is the most severe and disabling hereditary peripheral neuropathy occurring in adults, caused by mutations in the transthyretin (TTR) gene [3, 4].

The progression of TTR-FAP is relentless, with death occurring approximately 10 years from symptoms onset, depending on multiple factors, such as endemic region and genotype [1].

Identification of TTR-FAP is difficult, primarily because it is extremely rare and therefore not generally considered in medical evaluations. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration [1, 2]. The global TTR-FAP prevalence is difficult to determine, in part, due to underdiagnoses. Available estimates indicate that there are approximately 5,000 to 10,000 people living with TTR-FAP worldwide [5]. In Poland, only a few patients have been diagnosed with this type of amyloidosis [6, 7].

Because TTR-FAP has a progressive, irreversible disease course, early diagnosis and treatment are critical. Targeted therapy is essential in the first instance to prevent further production of amyloid deposits [2]. Current treatment options for patients with TTR amyloidosis in Poland are limited. For patients with early stage of TTR-FAP and a diagnosis confirmed by genetic testing and biopsy, liver transplant and symptomatic treatment is the actual standard of care [8].

Vyndaqel® (tafamidis meglumine) is a new, specific stabilizer of transthyretin, recommended as first line therapy by the EU Consensus Treatment Guidelines [2]. Drug received marketing authorization in Europe for the treatment of TTR amyloidosis in adult patients with stage 1 (walking unaided) symptomatic polyneuropathy to delay peripheral neurological impairment [9]. Tafamidis binds non-cooperatively to the two thyroxine binding sites on the native tetrameric form of transthyretin preventing dissociation into monomers. The inhibition of transthyretin tetramer dissociation forms the rationale for the use of tafamidis to slow disease progression [8, 9].

The objective of this project was to conduct economic analysis (cost-utility analysis, CUA) of tafamidis as a support of standard of care (TAF+SOC) for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment. The analyses were conducted in accordance with the Polish Agency for Health Technology Assessment and Tariffs (AOTMiT) recommendations [10].

MATERIALS AND METHODS

The decision problem was formulated in accordance with the PICOS scheme (population, intervention, comparator, outcomes, and study design) and drug programme assumptions:

Population: transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy (walking unaided);

Intervention: tafamidis, administered in combination with standard of care (TAF+SOC); one soft capsule containing 20 mg of tafamidis meglumine per day, orally;

Comparator: standard of care (SOC);

Outcome: quality adjusted life years (QALY);

Study design: head-to-head randomized controlled trials (RCT) conducted in parallel groups (experimental data); observational, post-marketing studies, registries
(real-world data).

The exchange rate of Polish National Bank (2018-11-22) was 1€ = 4.3064 PLN.

Analytical technique

To assess the profitability of transthyretin familial amyloid polyneuropathy treatment using tafamidis (Vyndaqel®) in combination with standard of care compared to SOC alone, a cost-utility analysis was performed using the Markov decision model constructed in MS Excel (Microsoft Corp., Redmond, WA). As the measure of effectiveness, QALY was used and the result was presented as incremental cost-utility ratio (ICUR). ICUR expresses the cost of gaining one additional unit of QALY in case of replacing SOC with TAF+SOC.

Perspective and time horizon

CUA analysis was conducted from the perspective of the public payer for health services (Polish National Health Fund, PNHF) and from the patient’s and PNHF perspective. All calculations were performed in lifetime horizon (50-year).

Model structure

In the Markov decision model, the following states, which are important from economic or clinical point of view, were taken into consideration: “stages of disease”, “liver transplantation”, “stages of disease post-transplant” and “death” (Figure 1). The criteria of division into three stages were proposed by Coutinho 1980 [11] and correspond with the severity of TTR-FAP. All patients entered the model in the “stage 1” and were treated with TAF+SOC or SOC. After the end of the cycle, they could stay in present stage, move to the next stage, undergo liver transplantation, or die. Disease progression (transition to next stage) was based on the results of NIS-LL scale. For each stage there was an analogous stage after transplantation. The length of the model cycle was equal six months. A discount rate of 5% for costs and 3.5% for benefits was used.

Assumption and model parameters

Data on clinical effectiveness were taken from publications identified as part of the systematic review [12]. The baseline value of NIS-LL, together with the probability of disease progression, came from the Fx-005 study (Coelho 2012) [13] and from THAOS registry [14] (Table 1). The probability of transplant was based on expert opinion, assumed to be 50% in stage 1 TTR-FAP, due to many contraindications to such surgery. In accordance with expert opinion, patients in stage 2 and 3 do not receive transplantation. The probability of re-transplant was determined based on the study by Yamamoto 2007 [14], where 5 patients out of 86 (5.8%) had second transplant. The probability of death due to the surgery was 3%, based on the data presented by Herlenius 2004 [16]. The mortality of patients was calculated based on the study by Okamoto 2009 [17].

Systematic search did not reveal any utility weights for TTR-FAP with respect to disease stage. Therefore, the data from THAOS registry [12], collected through the EQ-5D questionnaire, were used (Table 1). The influence of liver transplantation on quality of life was determined based on the Ratcliffe 2002 [18]. It was assumed that the utility decrease due to the transplantation was equal 0.2 in first six months after the surgery.

Following direct medical costs were included in the analysis: tafamidis, standard of care, liver transplantation, diagnosis and monitoring. The costs of adverse events were not included, as there are similar in both groups. All costs were calculated based on national drug and procedure tariffs, drug costs databases, and expert opinion (Table 2).

In Table 1 (clinical data) and Table 2 (cost data) main parameters used in the model were presented.

Sensitivity Analysis

One-way sensitivity analysis was performed to identify the impact of changing key drivers of model outcomes. The results of the cost-utility analysis were evaluated in relation to the changes in the cost and clinical parameters. For the above the parameters were analyzed by extreme value analysis, which assesses the impact of extreme parameters' adoption, and thus assumes pessimistic and optimistic scenarios.

RESULTS

Base Case Results

Results of a cost-utility analysis of TAF were presented in Table 3. The incremental cost-utility ratio (ICUR) for the comparison of TAF+SOC with SOC was determined from the following formula:

The cost of gaining an additional QALY by replacing SOC with TAF+SOC is equal 1,012,424 PLN/ 1,012,631 PLN (235,098 €/ 235,146 €) from PNHF/PNHF+patient’s perspective. The cost-utility analysis proved that scheme TAF+SOC is more expensive but more effective (2.87 QALY) than standard of care alone, in the treatment of adult patients with TTR-FAP.

The obtained results were above the acceptability threshold in Poland (~134,514 PLN (31 236 €)).

Sensitivity Analysis Results

The tornado diagrams illustrate the parameters of interest, with corresponding values producing a low and high incremental cost-effectiveness estimate (Figure 2, Figure 3). The highest influence on economic analysis results from both perspectives (the change of ICUR value by at least 10%) had the discount rates for costs and effects, utility weights in stage 1 and 3, and care costs in stage 1.

DISCUSSION

Transthyretin familial amyloid polyneuropathy is a rapidly progressing disease that leads to cachexia, severe infection and death. The impairment caused by the disease, even after liver transplantation, is usually irreversible [3]. As the disease progresses, the ability of patients to work, their health status and quality of life decline, while healthcare resource use and the burden on caregivers increase [20]. Patients with end-stage TTR-FAP are severely disabled and malnourished. They suffer from cachexia, urinary and fecal incontinence, are bedridden or bound to a wheelchair and unable to care for themselves [21].

The aim of this publication was to summarize the results of the conducted evaluation of the cost-effectiveness of tafamidis and SOC for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment.

It should be emphasized that rare diseases, such as the analysed one, have been recognized as a priority area in public health in the European Union and given fundamental importance in European Union programs for health and scientific research [22]. The assessment of a medical technology in reference to orphan drugs is a challenging issue in view of the high cost of the therapy, frequent lack of comparative medicines and the small quantity of scientific reports due to the difficulties of conducting reliable studies on a small population.

Tafamidis (Vyndaqel®) is an oral, disease-modifying agent that kinetically stabilizes TTR, received marketing authorization in Europe for stage 1 (walking unaided) TTR-FAP allowing to slow progression of the neuropathy [9].

In the analyzed indication tafamidis is on the list of orphan medicinal products admitted to marketing authorization in Europe [23]. So, it’s intended for a very small group of patients, and the proposed indication is classified as a group of ultra-rare diseases. Poland is one of the countries where the Vyndaqel® is not financed by public payer in patients with TTR-FAP (tafamidis is currently reimbursed in 15 European countries) [8]. At present, patients from the analysed population receive only standard of care; there is no active pharmacological treatment in this group of patients.

This publication is based on results of economic analysis [24] verified by AOTMiT as part of the reimbursement process. In addition, in November 2018 tafamidis received a positive reimbursement decision in Poland for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment [25]. However, at the time of preparing the presented analyses, tafamidis was not yet on the reimbursed drugs list.

To assess the cost-effectiveness of tafamidis with SOC compared to SOC a decision model was prepared in MS Excel. The Markov model was designed to estimate costs and outcomes, in terms of QALY, from the perspective of the PNHS over time horizons up to 50 years. The economic model predicted a gain of 2.87 QALY from 8.61 QALY in the SOC arm to 11.47 with TAF+SOC. Results of the cost-utility analysis proved that a therapy with TAF+SOC is more expensive and more effective than SOC alone. In the absence of special criteria for the assessment of drugs used for rare diseases, this means that TAF is unlikely to represent good value for money when considered against the current standards (SOC) applied to interventions in the polish health service.

To our knowledge, this is the first cost-effectiveness analysis on this topic. We utilized rigorous methodology, systematically screened the international literature, and appraised and summarized the evidence. Such knowledge might be valuable when making decisions regarding the refund of new effective therapeutic options such as tafamidis in TTR-FAP.

CONCLUSIONS

At the current marketed price tafamidis is not cost-effective. This is common situation for orphan drugs. Tafamidis therapy does not offer an economically beneficial treatment option, despite high clinical value for TTR-FAP patients. The high cost of the therapy is reflected in the result of the cost-utility analysis, in which an ICUR was 1.01 mln PLN from both study perspectives and exceeded the willingness-to-pay value in Poland (134 514 PLN (31 236 €)/ QALY).

Acknowledgements

This study was supported by a grant from Pfizer Polska Sp. z o.o., Warsaw, Poland.

ABBREVIATIONS

TTR-FAP - transthyretin familial amyloid polyneuropathy

NIS-LL - the Neuropathy Impairment Score of the Lower Limb

CUA - cost-utility analysis

AOTMiT - Polish Agency for Health Technology Assessment and Tariffs

TAF – tafamidis

SOC – standard of care

QALY - quality adjusted life years

RCT - randomized controlled trials

ICUR – incremental cost-utility ratio

PNHF - Polish National Health Fund

Charts and Figures:

Figure 1. Simplified structure of the model

Table 1. Summary of model parameters - clinical data

Table 2. Summary of model parameters - cost data

Notes: TAF – tafamidis; SOC – standard of care; PNHF - Polish National Health Fund; * with the exception of the cost of Vyndaqel^®

Table 3. Results of economic analysis

Notes: SOC – standard of care; ICUR - incremental cost-utility ratio

Figure 2 Tornado diagram for PNHF

Figure 3 Tornado diagram for PNHF+patient’s