Cost-effectiveness of Fingolimod, Teriflunomide, 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
`
`Results
`
`Figure 2. INMB of oral drugs vs IM IFN β-1a
`
`Figure 5. Probability each therapy maximizes net monetary benefit
`
`$100,000
`
`$120,000
`
`$160,000
`$140,000
`Willingness-to-pay
`
`$180,000
`
`$200,000
`
`Dimethyl fumarate
`
`Teriflunomide
`
`Fingolimod
`
`IM IFN β-1a
`
`100.0%
`90.0%
`80.0%
`70.0%
`60.0%
`50.0%
`40.0%
`30.0%
`20.0%
`10.0%
`0.0%
`
`Probability of maximizing NMB
`
`$0
`
`$20,000
`
`$40,000
`
`$60,000
`
`$80,000
`
`$100,000
`
`$120,000
`
`$140,000
`
`$160,000
`
`$180,000
`
`Dimethyl fumarate
`
`Willingness-to-pay
`Teriflunomide
`
`Fingolimod
`
`$100,000
`
`$80,000
`
`$60,000
`
`$40,000
`
`$20,000
`
`$0
`
`-$20,000
`
`-$40,000
`
`Incremental net monetary benefit
`
`Figure 3. One-way sensitivity analysis
`
`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 1].
`
`• Compared with IM IFN β-1a, at the WTP of $150,000, INMBs were
`estimated at $36,146, $50,441, and $80,970 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 1].
`
`• Dimethyl fumarate dominated all other drugs over the range of
`WTPs from $0 to $180,000 [Figure 2].
`
` •
`
`Objective
`
`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).
`
`Methods
`
`• A Markov model was developed to simulate the disease progression and
`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.
`
`• 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 $150,000 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.
`
`Fingolimod vs. IM IFN β-1a
`Monthly WAC for FIN
`Monthly WAC for IM IFN β-1a
`Time horizon
`Impact of FIN on utility
`Disutility for IM IFN β-1a
`Annual discontinuation rate for IM IFN β-1a
`Annual discontinuation rate for FIN
`Utility EDSS 6.0-0-7.5
`Discount rate
`Monthly cost of EDSS 6.0-7.5
`-$10,000 $10,000 $30,000 $50,000 $70,000 $90,000
`Incremental net monetary benefit
`
`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 with an
`incremental cost effec0veness ra0o of $5,218.
`
`When monthly cost is below $5,121, fingolimod is cost-effective
`compared with IM IFN beta-1a. However, fingolimod is not cost-
`effective compared with teriflunomide.
`
`Figure 4. INMB vs IM IFN β-1a over time
`
`Key References
`
`1. Scalfari A, Neuhaus A, Degenhardt A, et al. The natural history of multiple sclerosis,
`a geographically based study 10: relapses and long-term disability. Brain
`2010;133:1914-1929.
`2. Hoyert DL, Xu J. Deaths: preliminary data for 2011. Natl Vital Stat Rep
`2012;61:1-65.
`3. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod
`in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401.
`4. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for
`relapsing multiple sclerosis. N Engl J Med 2010;362:402-415.
`5. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide
`for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-1303.
`6. Gold R, Kappos L, Arnold Dl, et al. Placebo-controlled phase 3 study of oral BG-12
`for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-1107.
`7. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial
`of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910.
`8. Kobelt G, Berg J, Atherley D, Hadjimichael O, Jonsson B. Costs and quality of life in
`multiple sclerosis: a cross-sectional study in the USA. Neurology 2006;66:1696–
`1702.
`
`5 years
`
`10 years
`
`20 years
`15 years
`Time horizon
`
`25 years
`
`30 years
`
`Dimethyl fumarate
`
`Teriflunomide
`
`Fingolimod
`
`$180,000
`$160,000
`$140,000
`$120,000
`$100,000
`$80,000
`$60,000
`$40,000
`$20,000
`$0
`
`Incremetnal net monetary benefit
`
`Figure 1. Markov model for disease progression of multiple sclerosis
`
`EDSS 0.0-2.5
`Relapse
`
`EDSS 3.0-5.5
`Relapse
`
`Sensitivity analysis
` One-way sensitivity analyses found model results were robust to
`most parameter variations. The only exception is when the monthly
`cost of fingolimod was beyond $5,121, 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. For all of the three oral therapies versus IM IFN beta-1a,
`INMB increased as the time horizon became longer [Figure 4].
`
`• 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 5].
`
`Table 1. Base case results, compared with IM IFN β-1a (WTP=$150,000)
`
`
`
`Cost
`
`QALY NMB
`
`INMB vs.
`IM IFN β-1a
`
`CER
`
`ICER vs.
` IM IFN β-1a
`
`EDSS 0.0-2.5
`
`EDSS 3.0-5.5
`
`EDSS 6.0-7.5
`
`EDSS 8.0-9.5
`
`EDSS: Expanded Disability Status Scale
`
`EDSS 10.0
`(Death)
`
`IM IFN β-1a
`
`Fingolimod
`
`$322,694 3.34 $177,656
`
`$96,741
`
`$339,457 3.69 $213,802
`
`$36,146
`
`$92,034
`
`$47,523
`
`Teriflunomide
`
`$324,512 3.68 $228,097
`
`$50,441
`
`$88,085
`
`$5,218
`
`All health states may
`progress to death
`
`Dimethyl fumarate $298,875 3.72 $258,626
`
`$80,970
`
`$80,415 Dominant
`
`MYLAN PHARMS. INC. EXHIBIT 1102 PAGE 1
`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
`
`Results
`
`Figure 2. INMB of oral drugs vs IM IFN β-1a
`
`Figure 5. Probability each therapy maximizes net monetary benefit
`
`$100,000
`
`$120,000
`
`$160,000
`$140,000
`Willingness-to-pay
`
`$180,000
`
`$200,000
`
`Dimethyl fumarate
`
`Teriflunomide
`
`Fingolimod
`
`IM IFN β-1a
`
`100.0%
`90.0%
`80.0%
`70.0%
`60.0%
`50.0%
`40.0%
`30.0%
`20.0%
`10.0%
`0.0%
`
`Probability of maximizing NMB
`
`$0
`
`$20,000
`
`$40,000
`
`$60,000
`
`$80,000
`
`$100,000
`
`$120,000
`
`$140,000
`
`$160,000
`
`$180,000
`
`Dimethyl fumarate
`
`Willingness-to-pay
`Teriflunomide
`
`Fingolimod
`
`$100,000
`
`$80,000
`
`$60,000
`
`$40,000
`
`$20,000
`
`$0
`
`-$20,000
`
`-$40,000
`
`Incremental net monetary benefit
`
`Figure 3. One-way sensitivity analysis
`
`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 1].
`
`• Compared with IM IFN β-1a, at the WTP of $150,000, INMBs were
`estimated at $36,146, $50,441, and $80,970 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 1].
`
`• Dimethyl fumarate dominated all other drugs over the range of
`WTPs from $0 to $180,000 [Figure 2].
`
` •
`
`Objective
`
`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).
`
`Methods
`
`• A Markov model was developed to simulate the disease progression and
`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.
`
`• 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 $150,000 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.
`
`Fingolimod vs. IM IFN β-1a
`Monthly WAC for FIN
`Monthly WAC for IM IFN β-1a
`Time horizon
`Impact of FIN on utility
`Disutility for IM IFN β-1a
`Annual discontinuation rate for IM IFN β-1a
`Annual discontinuation rate for FIN
`Utility EDSS 6.0-0-7.5
`Discount rate
`Monthly cost of EDSS 6.0-7.5
`-$10,000 $10,000 $30,000 $50,000 $70,000 $90,000
`Incremental net monetary benefit
`
`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 with an
`incremental cost effec0veness ra0o of $5,218.
`
`When monthly cost is below $5,121, fingolimod is cost-effective
`compared with IM IFN beta-1a. However, fingolimod is not cost-
`effective compared with teriflunomide.
`
`Figure 4. INMB vs IM IFN β-1a over time
`
`Key References
`
`1. Scalfari A, Neuhaus A, Degenhardt A, et al. The natural history of multiple sclerosis,
`a geographically based study 10: relapses and long-term disability. Brain
`2010;133:1914-1929.
`2. Hoyert DL, Xu J. Deaths: preliminary data for 2011. Natl Vital Stat Rep
`2012;61:1-65.
`3. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod
`in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401.
`4. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for
`relapsing multiple sclerosis. N Engl J Med 2010;362:402-415.
`5. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide
`for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-1303.
`6. Gold R, Kappos L, Arnold Dl, et al. Placebo-controlled phase 3 study of oral BG-12
`for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-1107.
`7. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial
`of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910.
`8. Kobelt G, Berg J, Atherley D, Hadjimichael O, Jonsson B. Costs and quality of life in
`multiple sclerosis: a cross-sectional study in the USA. Neurology 2006;66:1696–
`1702.
`
`5 years
`
`10 years
`
`20 years
`15 years
`Time horizon
`
`25 years
`
`30 years
`
`Dimethyl fumarate
`
`Teriflunomide
`
`Fingolimod
`
`$180,000
`$160,000
`$140,000
`$120,000
`$100,000
`$80,000
`$60,000
`$40,000
`$20,000
`$0
`
`Incremetnal net monetary benefit
`
`Figure 1. Markov model for disease progression of multiple sclerosis
`
`EDSS 0.0-2.5
`Relapse
`
`EDSS 3.0-5.5
`Relapse
`
`Sensitivity analysis
` One-way sensitivity analyses found model results were robust to
`most parameter variations. The only exception is when the monthly
`cost of fingolimod was beyond $5,121, 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. For all of the three oral therapies versus IM IFN beta-1a,
`INMB increased as the time horizon became longer [Figure 4].
`
`• 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 5].
`
`Table 1. Base case results, compared with IM IFN β-1a (WTP=$150,000)
`
`
`
`Cost
`
`QALY NMB
`
`INMB vs.
`IM IFN β-1a
`
`CER
`
`ICER vs.
` IM IFN β-1a
`
`EDSS 0.0-2.5
`
`EDSS 3.0-5.5
`
`EDSS 6.0-7.5
`
`EDSS 8.0-9.5
`
`EDSS: Expanded Disability Status Scale
`
`EDSS 10.0
`(Death)
`
`IM IFN β-1a
`
`Fingolimod
`
`$322,694 3.34 $177,656
`
`$96,741
`
`$339,457 3.69 $213,802
`
`$36,146
`
`$92,034
`
`$47,523
`
`Teriflunomide
`
`$324,512 3.68 $228,097
`
`$50,441
`
`$88,085
`
`$5,218
`
`All health states may
`progress to death
`
`Dimethyl fumarate $298,875 3.72 $258,626
`
`$80,970
`
`$80,415 Dominant
`
`MYLAN PHARMS. INC. EXHIBIT 1102 PAGE 1
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