`Dimethyl Fumarate and Intramuscular Interferon
`Beta-1a in Relapsing-remitting Multiple Sclerosis
`
`
`Xinke Zhang, MS, Joel W. Hay, PhD
`
`University of Southern California, Los Angeles, CA, USA
`Email: xinkezha@usc.edu
`
`To compare the cost-effectiveness of fingolimod, teriflunomide, dimethyl fumarate and IM IFN β-1a as first-line therapies in treatment of patients
`with relapsing-remitting multiple sclerosis (RRMS).
`
`Objective
`
`Methods
`• A Markov model was developed to evaluate the cost-effectiveness
`of disease-modifying drugs from a US societal perspective. Time
`horizon in base case was 5 years [Figure 1].
`
`• Model parameters were obtained from randomized controlled
`trials, natural history studies of multiple sclerosis, cross-sectional
`surveys and federal supply schedule drug prices [Table 1].
`
`• Outcomes included quality-adjusted life years (QALYs),
`incremental net monetary benefit (INMB) and incremental cost-
`effectiveness ratio (ICER). The societal willingness-to-pay (WTP)
`threshold was assumed to be $100,000 per QALY.
`
`• Costs were reported in 2012 US dollars and both costs and
`outcomes were discounted at 3% annual rate in base case.
`
`• One-way sensitivity analyses and probabilistic sensitivity analyses
`were conducted to test the robustness of the model results.
`
`Figure 1. Markov model for disease progression of MS
`
`EDSS
`0.0-2.5
`Relapse
`
`EDSS
`3.0-5.5
`Relapse
`
`EDSS
`0.0-2.5
`
`EDSS
`3.0-5.5
`
`EDSS
`6.0-7.5
`
`EDSS
`8.0-9.5
`
`EDSS 10.0
`(Death)
`
`EDSS: Expanded Disability Status Scale
`
`All health states
`may progress to
`death
`
`0.005760
`0.007194
`0.005760
`
`0.001684
`0.002348
`0.003121
`0.004457
`0.400
`0.160
`0.330
`
`0.700
`1.353
`0.700
`0.620
`0.580
`
`0.720
`0.510
`0.410
`0.103
`0.118
`0.265
`0.310
`0.083
`0.5:0.5
`
`0.899
`0.821
`0.769
`0.491
`-0.094
`-0.115
`0
`0
`0.01
`0
`
`Table 1. Parameters and range in one-way sensitivity analysis
`Parameters
`Base Case
`One-way SA Range
`Monthly probability of disease progression (SM)
`EDSS 0.0-2.5
`EDSS 3.0-5.5
`EDSS 6.0-7.5
`Monthly probability of progressing to death
`EDSS 0.0-2.5
`EDSS 3.0-5.5
`EDSS 6.0-7.5
`EDSS 8.0-9.5
`Annual relapse rate for SM
`Annual relapse rate for FIN
`Annual relapse rate for IM IFNβ-1a
`HR of disease progression
`FIN vs. SM
`IM IFNβ-1a vs. FIN
`TER vs. SM
`DF vs. SM
`NAT vs. SM
`HR of annual relapse rate
`TER vs. SM
`DF vs. SM
`NAT vs. SM
`Annual discontinuation rate for FIN
`Annual discontinuation rate for IM IFNβ-1a
`Discontinuation rate for TER, 2yr
`Discontinuation rate for DF, 2yr
`Discontinuation rate for NAT, 2yr
`Assignment ratio between NAT and SM
`Utilities estimates
`Utility EDSS 0.0-0-2.5
`Utility EDSS 3.0-0-5.5
`Utility EDSS 6.0-0-7.5
`Utility EDSS 8.0-0-9.5
`Disutility for Relapse
`Disutility for IM IFNβ-1a
`impact of FIN on utility
`Impact of TER on utility
`Impact of DF on utility
`impact of NAT on utility
`Monthly costs, 2012 US dollar
`$4,164
` $ 4,996
` $ 3,331
`WAC for FIN
`$3,835
` $ 4,602
` $ 3,068
`WAC for IM IFNβ-1a
`$3,320
` $ 3,984
` $ 2,656
`WAC for NAT
`$3,704
` $ 4,444
` $ 2,963
`WAC for TER
`$3,346
` $ 4,015
` $ 2,676
`WAC for DF
`$1,730
` $ 2,076
` $ 1,384
`Cost of EDSS 0.0-2.5
`$3,691
` $ 4,430
` $ 2,953
`Cost of EDSS 3.0-5.5
`$5,395
` $ 6,475
` $ 4,316
`Cost of EDSS 6.0-7.5
`$10,791
` $12,949
` $ 8,633
`Cost of EDSS 8.0-9.5
`$5,008
` $ 6,009
` $ 4,006
`Cost of relapse
`Discount Rate
`0.05
`0
`0.03
`Time Horizon
`10 years
`2 years
`5 years
`SM: Symptom management; FIN: Fingolimod; TER: Teriflunomide; DF: Dimethyl fumarate; NAT: Natalizumab; WAC: Wholesale average cost
`a ±20% unless indicated
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`0.128
`0.264
`
`0.560
`1.083
`0.560
`0.496
`
`0.576
`0.408
`
`0.082
`0.095
`0.212
`0.248
`
`0 : 1
`
`0.719
`0.657
`0.615
`0.393
`-0.075
`-0.092
`-0.03
`-0.03
`-0.03
`
`0.192
`0.396
`
`0.840
`1.624
`0.840
`0.744
`
`0.864
`0.612
`
`0.123
`0.142
`0.318
`0.372
`
`1 : 0
`
`1
`1
`0.923
`0.589
`-0.113
`-0.138
`0.03
`0.03
`0.03
`
`sources
`
`1
`1
`1
`
`2
`2
`2
`2
`3
`4
`4
`
`3
`4
`5
`6
`7
`
`5
`6
`7
`4
`4
`5
`6
`7
`
`8
`8
`8
`8
`9
`8
`10,11
`12
`13
`14
`
`15
`15
`15
`15
`15
`9
`9
`9
`9
`16
`
`
`
`Results
`
`Base case
`• The 5 years’ total costs per patient were estimated at $322,694,
`$339,457, $324,512 and $298,875 for IM IFN β-1a, fingolimod,
`teriflunomide, and dimethyl fumarate, respectively. The accumulated
`QALYs associated with each drug were 3.34, 3.69, 3.68 and 3.72,
`respectively [Table 2].
`
`Figure 2. Incremental net monetary benefit of oral drugs vs IM IFN β-1a
`
`$100,000
`
`$80,000
`
`$60,000
`
`$40,000
`
`$20,000
`
`$0
`
`$20,000
`
`$40,000
`
`$60,000
`
`$80,000
`
`$100,000
`
`$120,000
`
`$140,000
`
`$160,000
`
`$180,000
`
`Willingness-to-pay
`
`Dimethyl fumarate
`
`Teriflunomide
`
`Fingolimod
`
`$0
`
`-$20,000
`
`-$40,000
`
`Incremental net monetary benefit
`
`Figure 3. One-way sensitivity analysis
`Fingolimod vs. IM IFN β-1a
`Monthly WAC for FIN
`Monthly WAC for IM IFNβ-1a
`Impact of FIN on utility
`Time Horizon
`Disutility for IM IFNβ-1a
`Annual discontinuation rate for IM IFNβ-1a
`Annual discontinuation rate for FIN
`Monthly cost of EDSS 6.0-7.5
`Utility EDSS 6.0-0-7.5
`Discount Rate
`-$20 -$10 $0 $10 $20 $30 $40 $50 $60 $70
`Thousands
`Incremental net monetary benefit
`Figure 4. Probability that each therapy maximizes net monetary benefit
`100.0%
`90.0%
`80.0%
`70.0%
`60.0%
`50.0%
`40.0%
`30.0%
`20.0%
`10.0%
`0.0%
`
`$160,000
`$140,000
`Willingness-to-pay
`
`$180,000
`
`$200,000
`
`$100,000
`
`$120,000
`
`Probability of being the optimal therapy
`
`• Compared with IM IFN β-1a, at the WTP of $100,000, INMBs were
`estimated at $18,510, $33,021, and $61,290 for fingolimod,
`teriflunomide, and dimethyl fumarate, respectively. Compared with IM
`IFN β-1a, ICERs were $47,523 and $5,218 for fingolimod and
`teriflunomide, respectively [Table 2].
`
`• Dimethyl fumarate dominated all other drugs over the range of WTPs
`from $0 to $180,000 [Figure 2].
`
`Sensitivity analysis
` One-way sensitivity analyses found model results were robust to
`most parameter variations. When the monthly cost of fingolimod was
`beyond $4,654 or the monthly cost of IM IFN β-1a was below $3,304,
`then fingolimod would no longer be cost-effective compared with IM
`IFN β-1a [Figure 3]. Other one-way sensitivity analysis comparison
`figures are available on request.
`
` •
`
`• Probabilistic sensitivity analysis showed that for more than 90% of
`the simulations, dimethyl fumarate was the optimal therapy across all
`willingness-to-pay values [Figure 4].
`
`Table 2. Base case results, compared with IM IFN β-1a (WTP=$100,000)
`
`
`
`Cost QALY NMB
`
`INMB vs.
`IM IFN β-1a
`
`CER
`
`ICER vs.
` IM IFN β-1a
`
`IM IFN β-1a
`
`Fingolimod
`
`$322,694 3.34 $10,873
`
`$96,741
`
`$339,457 3.69 $29,382
`
`$18,510
`
`$92,034
`
`$47,523
`
`Teriflunomide
`
`$324,512 3.68 $43,894
`
`$33,021
`
`$88,085
`
`$5,218
`
`Dimethyl fumarate $298,875 3.72 $72,792
`
`$61,920
`
`$80,415
`
`Dominant
`
`Dimethyl fumarate
`
`Teriflunomide
`
`Fingolimod
`
`IM IFN β-1a
`
`Conclusion
`The oral therapies were favored in the cost-effectiveness analysis. Of the four disease-modifying drugs, dimethyl fumarate was the dominant
`therapy to manage RRMS. Apart from dimethyl fumarate, teriflunomide was the most cost effective therapy compared with IM IFN beta-1a.
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