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Supplementary Materials

Cost-effectiveness of Secukinumab Compared to Other Biologics in the Treatment of Ankylosing

Spondylitis in Finland

Timo Purmonen1, Kari Puolakka2, Dinesh Mishra3, Praveen Gunda3, Janne Martikainen4

1. Novartis Finland Oy, Finland

2. Rheumatologist, Chief of Department, South Karelia Central Hospital, Lappeenranta,

Finland

3. Novartis Product Lifecycle Services-NBS, Novartis Healthcare Private Limited, Hyderabad,

India

4. Professor of Pharmacoeconomics, School of Pharmacy, University of Eastern Finland,

Kuopio, Finland

Correspondence to: Timo Purmonen ([email protected])

1

Table S1: Population inputs to define baseline characteristics

Input Mean SD

Percentage male 69.5% N/A

Age (years) 42.37 N/A

Weight (kg) 78.20 16.882Notes: MEASURE 1 and MEASURE 2 study pooled trial data (data not published).Abbreviations: N/A = not applicable; SD = standard deviation.

2

Table S2: Drug dosing, mode of administration, and number of doses in each treatment period

Number of Doses

Administration Drug Dose First 3 Months Months 4-6 Subsequent 3-month Periods

Subcutaneous Secukinumab 150 mg 7.00 3.00 3.00

Certolizumab pegol 200 mg 10.00 6.00 6.52

Etanercept 50 mg 13.00 13.00 13.04

Adalimumab 40 mg 7.00 6.00 6.52

Golimumab 50 mg 3.00 3.00 3.00

Intravenous Infliximab 100 mg 3.00 2.00 1.63

Notes: Dosing information derived from Finnish Medicinal products and prices database 1 and product specific details from Summary of Product Characteristics (SPC).2-7

3

Table S3: Annual treatment-specific biologic withdrawal rates

Administration Drug Year 1 Year 2+

Subcutaneous Secukinumab 15.3% 1.6%

Certolizumab pegol 12.6% 11.0%

Etanercept 25.1% 25.1%

Adalimumab 13.0% 9.3%

Golimumab 15.1% 6.2%

Intravenous Infliximab 2.1% 15.7%

Notes: This withdrawal rates are calculated from clinical trial based on the total patients entering a given treatment arm (N) and then assessing the number of patients dropping out (n) due to reasons such as lack of efficacy/adverse events or loss to follow up at a given time point (Withdrawal rate = n/N at time t). To assess the withdrawal rate this drop out was assessed at 1 year (or closest time point available and then converted to annual rate). For withdrawal rate beyond 1st year, it was assessed at a time point >1 year and converted to annual rate. Secukinumab from MEASURE 1 and MEASURE 2 Clinical Study Report (data not published); Certolizumab pegol from Sieper et al. 2015;8 Etanercept from Dougados et al. 20129 and Navarro-Sarabia et al. 2011;10 Adalimumab from van der Heijde et al. 200611 and Sieper et al. 2012;12; Infliximab from van der Heijde et al. 200613 and Braun et al. 2008;14 Golimumab from Deodhar et al 2015.15

4

Table S4: Medical support costsParameters First 3 months Subsequent 3-

month PeriodsCost per test

Medical visit

Specialist 2.00 0.25 € 314.04 [a]

Laboratory test

Full blood count 2.00 0.50 € 2.57 [a]

C-reactive protein 2 0.5 € 1.50 [a]

Erythrocyte sedimentation rate (ESR) 2.00 0.25 € 4.07 [a]

Liver function test 2.00 0.50 € 3.21 [a]

Creatinine test 1.00 0.25 € 1.39 [a]

Chest radiograph 1.00 0.00 € 35.49 [a]

Tuberculosis (TB) Heaf test 1.00 0.00 € 50.00 [b]

Notes: Frequency for laboratory tests is based on local expert opinion. For cost:16

[a] Kapiainen S, Väisänen A, Haula T. Terveyden- ja sosiaalihuollon yksikkökustannukset Suomessa vuonna 2011. (Social- and health care unit costs in Finland in 2011). Report of National Institute for Health and Welfare, Helsinki, 2014. http://www.julkari.fi/ handle/10024/114683. Unit costs indexed to year 2016 value.[b] The Finnish society for rheumatology (test 6173)

5

Table S5: Adverse event rates per 3 months

Administration Adverse Event Serious Infection Malignancy

Subcutaneous Secukinumab 0.16% 0.0015%

Certolizumab pegol 0.67% 0.0000%

Etanercept 0.00% 0.0000%

Adalimumab 0.35% 0.1249%

Golimumab 0.19% 0.0309%

Intravenous Infliximab 0.52% 0.1278%

Notes: Adverse event data for different treatments were obtained from clinical trials as mentioned below.Secukinumab from MEASURE 1 and MEASURE 2 trial (unpublished data); Certolizumab pegol from Sieper et al. 20158

Etanercept from Braun et al 201117

Adalimumab from Burmester et al. 201318

Infliximab from Braun et al. 2008 14 and van der Heijde et al. 200513

Golimumab from Deodhar et al 201515

6

Table S6: Adverse event related costs

Adverse event Cost per event

Tuberculosis € 14,445*[a]

Other serious infection € 3,013.10 [a]

Malignancy € 24,832.00 [b]

Notes: *Care consisting of 14 days hospital care and monthly 1 year follow up in specialized health care unit. [a] Kapiainen et al 2014;16 [b] Torkki et al 2017.19 Unit costs indexed to year 2016 value.

7

Table S7: Utility weight inputs used in the model to calculate QALYs

Parameter MEASURE 1 / 2 Data* McLeod et al. 2007 [20]

Intercept 0.9610 0.8772

BASFI coefficient -0.0330 -0.0323

BASDAI coefficient -0.0442 -0.0384

Male coefficient -0.0111 -0.0279

Age coefficient -0.0005 0.0017

Notes: Secukinumab from Novartis Data on File 2015a: MEASURE 1 Clinical Study Report and MEASURE 2 Clinical Study Report (unpublished data)*Utilities calculated from MEASURE 1 and MEASURE 2 pooled trial data (data not published)For base-case analysis, utilities calculated from MEAURE 1 and 2 trials are included. For alternative scenario analysis, utilities obtained from McLeod et al. 200720 are included.Abbreviations: BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index

8

Table S8: Disease-specific and adverse event related mortality inputs considered in the analysis

Input Relative Risk

Disease specific mortalityMale 1.63Female 1.38

Adverse EventTuberculosis 1.65Other serious infection 1.65Malignancy

1 year 1.412 years 1.41

Notes: Disease-specific mortality data obtained from Bakland et al. 201121

Mortality data for adverse event obtained from Abuabara et al. 201022

9

Table S9: Sensitivity analysis inputs for biologic-naive base-case population

Parameter Base case

Lower Bound

Upper Bound

Standard Error Distribution used in probabilistic

sensitivity analysis

Discount rate - costs 3.00% 0.0% 5.0% Not variedDiscount rate - outcomes 3.00% 0.0% 5.0% Not variedBaseline BASDAI 6.75 5.40 8.10 Not variedBaseline BASFI 6.38 5.10 7.65 Not variedBaseline BASDAI responders: SEC 6.23 4.98 7.47 Not variedBaseline BASDAI responders: CER P

6.23 4.98 7.47 Not varied

Baseline BASDAI responders: ETN 6.23 4.98 7.47 Not variedBaseline BASDAI responders: ADA

6.23 4.98 7.47 Not varied

Baseline BASDAI responders: INF 6.23 4.98 7.47 Not variedBaseline BASDAI responders: GOL 6.23 4.98 7.47 Not variedBaseline BASDAI non-responders: SEC

6.90 5.52 8.28 Not varied

Baseline BASDAI non-responders: CER P

6.90 5.52 8.28 Not varied

Baseline BASDAI non-responders: ETN

6.90 5.52 8.28 Not varied

Baseline BASDAI non-responders: ADA

6.90 5.52 8.28 Not varied

Baseline BASDAI non-responders: INF

6.90 5.52 8.28 Not varied

Baseline BASDAI non-responders: GOL

6.90 5.52 8.28 Not varied

Baseline BASFI responders: SEC 5.69 4.55 6.83 Not variedBaseline BASFI responders: CER P 5.69 4.55 6.83 Not variedBaseline BASFI responders: ETN 5.69 4.55 6.83 Not variedBaseline BASFI responders: ADA 5.69 4.55 6.83 Not variedBaseline BASFI responders: INF 5.69 4.55 6.83 Not variedBaseline BASFI responders: GOL 5.69 4.55 6.83 Not variedBaseline BASFI non-responders: SEC

6.83 5.47 8.20 Not varied

Baseline BASFI non-responders: CER P

6.83 5.47 8.20 Not varied

Baseline BASFI non-responders: ETN

6.83 5.47 8.20 Not varied

Baseline BASFI non-responders: ADA

6.83 5.47 8.20 Not varied

Baseline BASFI non-responders: INF

6.83 5.47 8.20 Not varied

Baseline BASFI non-responders: GOL

6.83 5.47 8.20 Not varied

Annual rate of MSASSS change 1.440 1.152 1.728 0.133 Normal

10

Parameter Base case

Lower Bound

Upper Bound



for MSASSS≥10 - SECAnnual rate of MSASSS change for MSASSS≥10 - TNFs

1.440 1.152 1.7280.133

Normal

BASFI change with 1 unit change in MSASSS

0.057 0.046 0.0680.005

Normal

Treatment effect on progression - SEC

0.153 0.122 0.1840.044

Normal

Treatment effect on progression - TNFs

0.420 0.336 0.5040.122

Normal

Relative risk BASDAI response: Second line

1.00 0.80 1.20 - Not varied

Relative risk Δ BASDAI: Second line

1.00 0.80 1.20 - Not varied

Relative risk Δ BASFI: Second line 1.00 0.80 1.20 - Not variedDiscontinuation year 1: SEC 15.3% 12.3% 18.4% 0.031 NormalDiscontinuation year 1: CER P 12.6% 10.1% 15.1% 0.025 NormalDiscontinuation year 1: ETN 25.1% 20.1% 30.2% 0.050 NormalDiscontinuation year 1: ADA 13.0% 10.4% 15.7% 0.026 NormalDiscontinuation year 1: INF 2.1% 1.7% 2.6% 0.004 NormalDiscontinuation year 1: GOL 15.1% 12.1% 18.1% 0.030 NormalDiscontinuation year 2: SEC 1.6% 1.3% 2.0% 0.003 NormalDiscontinuation year 2: CER P 11.0% 8.8% 13.2% 0.022 NormalDiscontinuation year 2: ETN 25.1% 20.1% 30.2% 0.050 NormalDiscontinuation year 2: ADA 9.3% 7.5% 11.2% 0.019 NormalDiscontinuation year 2: INF 15.7% 12.6% 18.9% 0.031 NormalDiscontinuation year 2: GOL 6.2% 4.9% 7.4% 0.012 NormalDrug acquisition cost: SEC €584.43 €467.54 €701.32 - Not variedDrug acquisition cost: CER P €483.07 €386.45 €579.68 - Not variedDrug acquisition cost: ETN €260.04 €208.03 €312.04 - Not variedDrug acquisition cost: ADA €527.41 €421.93 €632.89 - Not variedDrug acquisition cost: INF €436.06 €348.85 €523.27 - Not variedDrug acquisition cost: GOL €

1,086.93€869.54 €

1,304.32 -

Not varied

SC administration training €51.47 €41.18 €61.76 10.29 NormalIV administration €382.00 €305.60 €458.40 76.40 NormalDisease related cost intercept €

1,508.99€

1,207.19

€1,810.7

9 0.165

Log-normal

BASFI coefficient 0.21 0.17 0.26 0.038 NormalTuberculosis cost €14,445.

00€11,556.

00€17,334.

00 2889.000Gamma

Other serious infection cost €3,013.10

€2,410.48

€3,615.72 602.60

Gamma

11

Parameter Base case

Lower Bound

Upper Bound



Malignancy cost €24,832.00

€19,865.60

€29,798.40 4966.400

Gamma

GP visit cost €118.06 €94.45 €141.67 23.612 GammaSpecialist visit cost €314.04 €251.23 €376.85 62.808 GammaFull blood count cost €2.57 €2.06 €3.08 0.514 GammaErythrocyte sedimentation rate cost

€4.07 €3.26 €4.880.814

Gamma

Liver function test cost €3.21 €2.57 €3.85 0.642 GammaC-reactive protein cost €1.50 €1.20 €1.80 0.300 GammaChest radiograph cost €35.49 €28.39 €42.59 7.098 GammaTuberculosis Heaf test cost €50.00 €40.00 €60.00 10.000 GammaCreatinine test cost €1.39 €1.11 €1.67 0.278 GammaSerious infection probability: SEC 0.16% 0.13% 0.20% 0.000327 BetaSerious infection probability: CER P

0.67% 0.54% 0.81%0.001345

Beta

Serious infection probability: ETN 0.00% 0.00% 0.00% 0.000000 BetaSerious infection probability: ADA 0.35% 0.28% 0.42% 0.000699 BetaSerious infection probability: INF 0.52% 0.41% 0.62% 0.001036 BetaSerious infection probability: GOL 0.19% 0.15% 0.23% 0.000377 BetaMalignancy probability: SEC 0.00% 0.00% 0.00% 0.000003 BetaMalignancy probability: CER P 0.00% 0.00% 0.00% 0.000000 BetaMalignancy probability: ETN 0.00% 0.00% 0.00% 0.000000 BetaMalignancy probability: ADA 0.12% 0.10% 0.15% 0.000250 BetaMalignancy probability: INF 0.13% 0.10% 0.15% 0.000256 BetaMalignancy probability: GOL 0.03% 0.02% 0.04% 0.000062 BetaAS mortality relative risk - males 1.63 1.30 1.96 0.326000 Log-normalAS mortality relative risk - females

1.38 1.10 1.660.276000

Log-normal

Tuberculosis mortality relative risk

1.65 1.32 1.98 - Not varied

Other serious infection mortality relative risk

1.65 1.32 1.98 - Not varied

Malignancy relative risk: Year 1 1.41 1.13 1.69 - Not variedMalignancy relative risk: Year 2 1.41 1.13 1.69 - Not variedUtility intercept 0.961 0.77 1.15 0.192 NormalUtility BASFI coefficient -0.0330 -0.0264 -0.0396 0.007 NormalUtility BASDAI coefficient -0.0442 -0.0354 -0.0530 0.009 NormalUtility male coefficient -0.0111 -0.0089 -0.0133 0.002 NormalUtility age coefficient -0.0005 -0.0004 -0.0006 0.0001 NormalSerious infection disutility: Year 1 -0.1560 -0.1248 -0.1872 0.031 NormalSerious infection disutility: Year 2 0.0000 0.0000 0.0000 0.000 NormalSerious infection disutility: Years 0.0000 0.0000 0.0000 0.000 Normal

12

Parameter Base case

Lower Bound

Upper Bound



3+Malignancy disutility -0.0174 -0.0139 -0.0209 0.003 Normal

Log Odds SEBASDAI 50 at 3 months: SEC 41.53% 15.21% 73.77% 0.702 NormalBASDAI 50 at 3 months: CER P 44.20% 19.27% 72.44% 0.612 NormalBASDAI 50 at 3 months: ETN 36.80% 14.92% 65.89% 0.612 NormalBASDAI 50 at 3 months: ADA 48.85% 38.43% 59.37% 0.217 NormalBASDAI 50 at 3 months: INF 44.20% 19.27% 72.44% 0.612 NormalBASDAI 50 at 3 months: GOL 47.20% 28.39% 66.85% 0.415 Normal

SE3-month responder BASDAI change: SEC -4.602 -2.982 -6.222 0.449

Normal

3-month responder BASDAI change: CER P -5.569 -4.010 -7.127 0.453

Normal

3-month responder BASDAI change: ETN -4.474 -2.743 -6.206 0.453

Normal

3-month responder BASDAI change: ADA -4.562 -3.970 -5.155 0.175

Normal

3-month responder BASDAI change: INF -7.941 -5.836 -10.046 0.612

Normal

3-month responder BASDAI change: GOL -5.316 -4.004 -6.629 0.407

Normal

3-month non-responder BASDAI change: SEC -1.007 -0.652 -1.361 0.449

Normal

3-month non-responder BASDAI change: CER P -1.275 -0.886 -1.575 0.453

Normal

3-month non-responder BASDAI change: ETN -1.025 -0.608 -1.375 0.453

Normal

3-month non-responder BASDAI change: ADA -0.806 -0.837 -1.087 0.175

Normal

3-month non-responder BASDAI change: INF -1.819 -1.290 -2.220 0.612

Normal

3-month non-responder BASDAI change: GOL -1.368 -0.906 -1.500 0.407

Normal

3-month responder BASFI change: SEC -3.748 -2.294 -5.202 0.444

Normal

3-month responder BASFI change: CER P -3.594 -2.211 -4.978 0.409

Normal

3-month responder BASFI change: ETN -3.444 -1.914 -4.975 0.409

Normal

3-month responder BASFI change: ADA -3.145 -2.622 -3.668 0.164

Normal

3-month responder BASFI change: INF -3.965 -2.119 -5.811 0.546

Normal

13

Parameter Base case

Lower Bound

Upper Bound



3-month responder BASFI change: GOL -4.072 -2.816 -5.327 0.362

Normal

3-month non-responder BASFI change: SEC -1.174 -0.718 -1.629 0.444

Normal

3-month non-responder BASFI change: CER P -0.886 -0.651 -1.465 0.409

Normal

3-month non-responder BASFI change: ETN -0.849 -0.555 -1.442 0.409

Normal

3-month non-responder BASFI change: ADA -0.775 -0.778 -1.089 0.164

Normal

3-month non-responder BASFI change: INF -0.977 -0.624 -1.710 0.546

Normal

3-month non-responder BASFI change: GOL -0.712 -0.781 -1.477 0.362

Normal

14

Abbreviations: ADA = adalimumab; ETN = etanercept; CER P = certolizumab pegol; INF = infliximab; GOL = golimumab; SEC = secukinumab; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index.Table S10: Disaggregated costs contributing to total costs for each treatment

COSTS SEC CER P ETN ADA INF GOLTotal cost 279,872

€309,257

€305,883

€312,139

€316,291

€309,551

€Drug cost for patients on primary drug 41,895 € 40,857 € 19,314 € 49,523 € 39,410 € 54,937 €

Drug cost post discontinuation126,594

€147,722

€160,795

€141,268

€147,138

€138,122

€Background disease cost for patients on primary drug 13,533 € 7,831 € 3,659 € 12,936 € 9,344 € 10,630 €

Background disease cost post discontinuation 84,839 € 98,794 €107,896

€ 94,414 € 98,414 € 92,298 €

Administration cost for patients on primary drug 51 € 51 € 51 € 51 € 7,828 € 51 €

Administration costs post discontinuation 5,035 € 5,872 € 6,392 € 5,615 € 5,849 € 5,491 €

Monitoring cost for patients on primary drug 2,536 € 1,693 € 1,128 € 1,851 € 1,623 € 2,059 €

Monitoring cost post discontinuation 4,040 € 4,714 € 5,131 € 4,508 € 4,695 € 4,407 €Serious infection for patients on primary drug 148 € 330 € 0 € 199 € 237 € 127 €

Serious infection post discontinuation 630 € 734 € 800 € 702 € 732 € 687 €

Malignancy cost for patients on primary drug 8 € 0 € 0 € 442 € 366 € 128 €

Malignancy cost post discontinuation 564 € 658 € 717 € 630 € 656 € 616 €

15

Table S11: Probabilistic sensitivity analysis results*

Outcome SEC CER P ETN ETN biosimilar

ADA ADA biosimilar

INF GOL

Total cost Mean (Euros)

279,716 309,764 305,961 301,284 312,321 297,383 317,998 309,938

Total QALYs Mean (years)

13.279 12.818 12.355 12.095 12.676 12.584 12.825 12.786

NMB Mean (Euros)

118,668 74,786 67,718 61,568 67,965 80,124 66,762 82,370

Max NMB 95.0% 1.0% 0,0% 0.0% 0.0% 0.10% 0.0% 4.0%*Derived at Willingness-to-Pay threshold of €30,000.Abbreviations: ADA = adalimumab; ETN = etanercept; CER P = certolizumab pegol; INF = infliximab; GOL = golimumab; SEC = secukinumab; NMB = net monetary benefit; SD = standard deviation; QALY = quality-adjusted life-year.

Alternative scenario analysis: Detailed results

Table S12: Population: Biologic-naïve and biologic-experienced population

Administration Treatment Total costs (€)

QALYs ICERSEC vs others

Subcutaneous Secukinumab 288,539 11.9

Certolizumab pegol

312,325 11.6 SEC Dominates

Etanercept 308,761 11.2 SEC Dominates

Etanercept biosimilar

303,837 11. 2 SEC Dominates

Adalimumab 314,395 11.4 SEC Dominates

Adalimumab biosimilar 302,283 € 11.4

SEC Dominates

Golimumab 312,577 11.8 SEC Dominates

Intravenous Infliximab 317,944 11.6 SEC Dominates

Table S13: Utility from McLeod et al20




16

Certolizumab pegol






Adalimumab biosimilar




Table S14: Disutility included*




Certolizumab pegol










* Despite including disutilities, there was not major difference in result compared to baseline due to very minor impact.

Table S15: BASFI rebound assumption: Initial gain




Certolizumab pegol






17





Table S16: Indirect cost included




Certolizumab pegol




300,075 12.1 $261,487



297,282 12.5 $440,467



Table S17: Disease related cost excluded




Certolizumab pegol










18

Figure S1: One-way sensitivity analysis: Secukinumab 150 mg (biologic-naïve population)

Secukinumab versus certolizumab pegol

0 € 10,000 € 20,000 € 30,000 € 40,000 € 50,000 € 60,000 € 70,000 € 80,000 € 90,000 € 100,000 €

BASDAI 50 at 3 months: SEC

Baseline BASFI non-responders: CER P

Baseline BASFI non-responders: SEC

3-month responder BASFI change: SEC

3-month responder BASDAI change: SEC

Discount rate - outcomes

Discount rate - costs

Drug acquisition cost: CER P

Baseline BASFI responders: SEC

Baseline BASDAI responders: SEC

Incremental Net Monetary Benefit

High NMB

Low NMB

Secukinumab versus etanercept

0 € 20,000 € 40,000 € 60,000 € 80,000 € 100,000 € 120,000 €










Drug acquisition cost: SEC


High NMB

Low NMB

Secukinumab versus etanercept biosimilar

0 € 20,000 € 40,000 € 60,000 € 80,000 € 100,000 € 120,000 €











Incremental Net Monetory Benefit

High NMB

Low NMB

19

Secukinumab versus adalimumab

0 € 20,000 € 40,000 € 60,000 € 80,000 € 100,000 € 120,000 €








Drug acquisition cost: ADA




High NMB

Low NMB

Secukinumab versus adalimumab biosimilar

0 € 10,000 € 20,000 € 30,000 € 40,000 € 50,000 € 60,000 € 70,000 € 80,000 € 90,000 € 100,000 €











Incremental Net Monetory Benefit

High NMB

Low NMB

Secukinumab versus infliximab

0 € 20,000 € 40,000 € 60,000 € 80,000 € 100,000 € 120,000 €


Baseline BASFI non-responders: INF








Drug acquisition cost: INF


High NMB

Low NMB

20

Secukinumab versus golimumab

-10,000 € 0 € 10,000 € 20,000 € 30,000 € 40,000 € 50,000 € 60,000 € 70,000 € 80,000 € 90,000 €


Baseline BASFI non-responders: GOL



Drug acquisition cost: GOL







High NMB

Low NMB

Abbreviations: ADA = adalimumab; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index; CER P = certolizumab pegol; ETN = etanercept; GOL = golimumab; INF = infliximab; NMB = Net monetary benefit; SEC = secukinumab.

21

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