Cost-utility analysis of tafamidis for the treatment of adult patients with transthyretin familial amyloid polyneuropathy in Poland


Authors

Name Affiliation
Ewa Borowiack
NUEVO HTA s.c.
Magdalena Marzec
NUEVO HTA s.c.
Joanna Jarosz
NUEVO HTA s.c.
Katarzyna Snarska
PFIZER POLAND
Małgorzata Konopka-Pliszka
PFIZER POLAND
contributed: 2019-01-09
final review: 2019-03-12
published: 2019-04-24
Abstract

Background: The aim of this publication was to evaluate the cost-effectiveness of oral tafamidis (TAF) versus placebo (both used with standard of care, SOC) for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy in order to delay peripheral neurologic impairment.

Methods: The Markov model constructed in TreeAge Pro with 50-year time horizon was used in the cost-utility analysis (CUA). Quality adjusted life years (QALY) were used as the measure of effectiveness. CUA was conducted from the perspective of the public payer for health services (Polish National Health Fund, PNHF) and from the patient’s and PNHF’s perspective. For both perspectives only direct medical costs were included. Utility weights were obtained from the literature.

Results: 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.

Conclusion: Introduction of tafamidis to the regimen occurred to be more effective and more expensive than standard of care alone. The use of TAF resulted in almost 3 additional QALY compared with SOC, in lifetime horizon.



Keywords: tafamidis, transthyretin familial amyloid polyneuropathy, cost-utility


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

Parameter

Value

Reference

Tafamidis + SOC

Standard of care
(SOC)

NIS-LL baseline value

8.40

8.40

Coelho 2012 [13]

NIS-LL progression after transplantation, stage I

0.190

0.190

THAOS registry [14]

NIS-LL progression after transplantation, stage II

0.190

0.190

NIS-LL progression after transplantation, stage III

0.190

0.190

Probability of death during liver transplant

0.030

0.030

Herlenius 2004 [16]

Probability of death, stage 1

0.003

0.023

Okamoto 2009 [17]

Probability of death, stage 2

0.027

0.027

Probability of death, stage 3

0.065

0.065

Probability of receiving a second transplant

0.058

0.058

Yamamoto 2007 [15]

Probability of transplantation, stage 1

0.500

0.500

Expert opinion

Probability of transplantation, stage 2

0.000

0.000

Probability of transplantation, stage 3

0.000

0.000

Threshold value of NIS-LL, stage 1/stage 2

46.000

46.000

Coutinho 1980 [11]

Threshold value of NIS-LL, stage 2/stage 3

63.000

63.000

Decrease in utility after transplantation

0.200

0.200

Ratcliffe 2002 [18]

Utility stage 1

0.800

0.800

THAOS registry [19]

Utility stage 2

0.600

0.600

Utility stage 3

0.160

0.160

Utility stage 1 after transplantation

0.800

0.800

Utility stage 2 after transplantation

0.600

0.600

Utility stage 3 after transplantation

0.160

0.160

 

Table 2. Summary of model parameters - cost data

Parameter

Value

Reference

Stage 1

Stage 2

Stage 3

SOC cost, PNHF + patient’s perspective

3,113.12 PLN
(723
)

3,113.12 PLN
(723
)

1,938.74 PLN
(450
)

National drug tariff, drug costs databases,
expert opinion

SOC cost, PNHF perspective

3,015.68 PLN
(700
)

3,015.68 PLN
(700
)

1,842.05 PLN
(428
)

TAF cost, PNHF + patient’s perspective*

4,219.12 PLN
(980
)

3,113.12 PLN
(723
)

1,938.74 PLN
(450
)

National drug tariff, national procedures

TAF cost, PNHF perspective*

4,121.68 PLN
(957
)

3,015.68 PLN
(700
)

1,842.05 PLN
(428
)

SOC cost after transplantation,
PNHF + patient’s perspective

3,113.12 PLN
(723
)

3,113.12 PLN
(723
)

1,938.74 PLN
(450
)

SOC cost after transplantation,
PNHF perspective

3,015.68 PLN
(700
)

3,015.68 PLN
(700
)

1,842.05 PLN
(428
)

Cost of liver transplantation

204,476.00 PLN (47,482 )

Post-liver transplantation cost – first year, PNHF + patient’s perspective

33,407.61 PLN (7,758 )

Post-liver transplantation cost – first year, PNHF perspective

33,293.31 PLN (7,731 )

Post-liver transplantation cost – subsequent years, PNHF + patient’s perspective

33,153.26 PLN (7,699 )

Post-liver transplantation cost – subsequent years, PNHF perspective

33,046.50 PLN (7,674 )








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

Parameters

PNHF perspective

PNHF + patient’s perspective

Tafamidis + SOC

SOC alone

Tafamidis + SOC

SOC alone

Total costs [PLN/ ]

3,443,376 / 799,595

542,004 / 125,860

3,447,241 / 800,493

545,277 / 126,620

Incremental cost [PLN/ ]

2,901,372 / 673,735

2,901,964 / 673872

Total health effects [QALY]

11.47

8.61

11.47

8.61

Incremental health effects [QALY]

2.87

2.87

ICUR

1,012,424 (235,098 )

1,012,631 (235,146 )

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



Figure 2 Tornado diagram for PNHF


 


Figure 3 Tornado diagram for PNHF+patient’s



References

1.      Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet Journal of Rare Diseases 2013; 8: 31. doi: 10.1186/1750-1172-8-31.

2.      Adams D, Suhr OB, Hund E, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol 2016; 29 (suppl 1): S14–S26. doi: 10.1097/WCO.0000000000000289.

3.      Adams D, Théaudin M, Cauquil C, et al. FAP neuropathy and emerging treatments. Curr Neurol Neurosci Rep. 2014; 14 (3): 435. doi: 10.1007/s11910-013-0435-3.

4.      Adams D, Cauquil C, Labeyrie C. Familial amyloid polyneuropathy. Curr Opin Neurol 2017; 30: 481-489. doi:10.1097/WCO.0000000000000476.

5.      Schmidt H, Cruz MW, Botteman MF, et al. Global epidemiology of transthyretin hereditary amyloid polyneuropathy: a systematic review. Amyloid 2017; 24 (supp1):111-112. doi: 10.1080/13506129.2017.1292903.

6.      Lipowska M. Diagnostyka i leczenie neuropatii amyloidowych. III Warszawskie Dni chorób nerwowo–mięśniowych: od objawu do leczenia. Warszawa, 25-26 maja 2018 r. http://www.chnm.pl/pdf/5b.2.ttr%20fap%20iii%20warszawskie%20dni.pdf

7.      Lipowska M, Rowczenio D, Gilbertson J, et al. Transthyretin-related Familial Amyloid Polyneuropathy (TTR-FAP) caused by a very rare, de novo mutation in a Polish patient. Orphanet Journal of Rare Diseases 2015, 10 (Suppl 1): P25. http://www.ojrd.com/content/10/S1/P25.

8.      NUEVO HTA. Analiza problemu decyzyjnego: Tafamidis (Vyndaqel®, kapsułki 20 mg) w leczeniu amyloidozy transtyretynowej u dorosłych pacjentów w 1. stopniu (stadium) objawowej polineuropatii. Kraków 2018. http://bipold.aotm.gov.pl/assets/files/zlecenia_mz/2018/172/AW/172_AW_1_OT_4331_33_2018_VYNDAQEL.pdf

9.      Summary of Product Characteristics: Vyndaqel 20 mg soft capsules, Date of first authorisation: 16 November 2011. Date of latest renewal: 22 July 2016.

10.  Agencja Oceny Technologii Medycznych i Taryfikacji. Wytyczne przeprowadzania Oceny Technologii Medycznych (HTA). Załącznik do Zarządzenia nr 40/2016 Prezesa Agencji Oceny Technologii Medycznych i Taryfikacji z dnia 13 września 2016 r. w sprawie wytycznych oceny świadczeń opieki zdrowotnej.

11.  Coutinho P, Lima JL, Barbosa AR. Forty years of experience with type I amyloid neuropathy. Review of 483 cases (in: Glenner GG, Costa PP, Freitas F. Amyloid and Amyloidosis, Exerpta Medica, Amsterdam 1980)

12.  NUEVO HTA. Analiza efektywności klinicznej: Tafamidis (Vyndaqel®, kapsułki 20 mg) w leczeniu amyloidozy transtyretynowej u dorosłych pacjentów w 1. stopniu (stadium) objawowej polineuropatii. Kraków 2018. http://bipold.aotm.gov.pl/assets/files/zlecenia_mz/2018/172/AW/172_AW_2_OT_4331_33_2018_VYNDAQEL.pdf

13.  Coelho T, Maia L, Da Silva A, et al.. Tafamidis for transthyretin familial amyloid polyneuropathy: A randomized, controlled trial. Neurology 2012; 79 (8): 785-792. doi: 10.1212/WNL.0b013e3182661eb1.

14.  Stewart M, Keohane D, Short S, et al. Positive Real-World Effectiveness of Tafamidis for Delaying Disease Progression in Transthyretin Familial Amyloid Polyneuropathy. Poster presented at the XXII World Congress of Neurology (CN 2015), October 31 Novomber 5, 2015 Santiago, Chile (poster).

15.  Yamamoto S, Wilczek HE, Nowak G, et al. Liver Transplantation for Familial Amyloidotic Polyneuropathy (FAP): A Single-Center Experience Over 16 years. American Journal of Transplantation 2007, 7:2597-604.

16.  Herlenius G, Wilczek HE, Larsson M, et al. Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry, Transplantation 2004, 77(1):64-71.

17.  Okamoto S, Wixner J, Obayashi K, et al. Liver transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients' survival, Liver Transplantation 2009, 15 (10): 1229-1235.

18.  Ratcliffe J, Longworth L, Young T, et al. Assessing health-related quality of life pre- and post-liver transplantation: a prospective multicenter study, Liver Transplantation 2002, 8 (3): 263-270.

19.  Plante-Bordeneuve V, Suhr OB, Maurer MS, et al. The Transthyretin Amyloidosis Outcomes Survey (THAOS) registry: design and methodology. Current Medical Research & Opinion, 2013, 29(1):77-84.

20.  Stewart M, Shaffer S, Murphy B, et al. Characterizing the High Disease Burden of Transthyretin Amyloidosis for Patients and Caregivers. 2018; Neurol Ther, pp 1-16. doi: 10.1007/s40120-018-0106-z.

21.  Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011 Dec;10(12):1086-97. doi: 10.1016/S1474-4422(11)70246-0.

22.  Libura M, Władusiuk M, Małowicka M, et al. Choroby rzadkie w Polsce - stan obecny i perspektywy. Warszawa, styczeń 2016.

23.  http://www.orpha.net/orphacom/cahiers/docs/GB/list_of_orphan_drugs_in_europe.pdf

24.  NUEVO HTA. Analiza ekonomiczna: Tafamidis (Vyndaqel®, kapsułki 20 mg) w leczeniu amyloidozy transtyretynowej u dorosłych pacjentów w 1. stopniu (stadium) objawowej polineuropatii. Kraków 2018. http://bipold.aotm.gov.pl/assets/files/zlecenia_mz/2018/172/AW/172_AW_3_OT_4331_33_2018_VYNDAQEL.pdf

25.  Rekomendacja nr 108/2018 z dnia 9 listopada 2018 r. Prezesa Agencji Oceny Technologii Medycznych i Taryfikacji w sprawie objęcia refundacją produktu leczniczego Vyndaqel (tafamidis) we wskazaniu: „Leczenie rodzinnej transtyretynowej polineuropatii amyloidowej (TTR-FAP) (ICD 10 E85.1)”.


 

 



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