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ISPOR 2019 Presentation CO4

Alemtuzumab Versus Generic Glatiramer Acetate in Patients With Relapsing Forms of : A Cost-Effectiveness Study in the

Viktor Chirikov1, Ingrid Ma2, Namita Joshi1, Dipen Patel1, Alden Smith2, Cindy Giambrone2, Noelle Corneilio1, Nupur Greene2, Lobat Hashemi2

Presented by Lobat Hashemi

1Pharmerit International, Bethesda, MD, USA; 2Sanofi, Cambridge, MA, USA

Chirikov V et al. Value Health 2019;22:168-76.

ISPOR 2019 Disclosures

• Viktor Chirikov, Namita Joshi, Dipen Patel, and Noelle Corneilio: Employees of Pharmerit

• Ingrid Ma, Alden Smith, and Cindy Giambrone: Former employees of Sanofi

• Lobat Hashemi and Nupur Greene: Employees of Sanofi

• The study was funded by Sanofi US

• Editorial and scientific support for this presentation was provided by Darren P Baker, PhD, Ericka M Bueno, PhD, and Colin Mitchell, PhD, of Sanofi. Editorial assistance was supported by Sanofi and provided by Valerie P Zediak, PhD, of Eloquent Scientific Solutions

1 ISPOR 2019 Introduction: Multiple Sclerosis

• Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the , which results in progressive disability1 Common symptoms include6-8: It affects approximately 727,344 • individuals in the United States2 • Depression • Urinary incontinence • Gait abnormality 30/23.5 years ~3:1 • Paresthesia Mean/median Prevalence rate by • Vision problems age of onset3 gender (women:men)3,4 • Cognitive changes

$4 million in total lifetime Relapsing forms of MS (RMS) are the most prevalent type 9,10 of MS, with patients experiencing relapses interspersed with costs per patient periods of disease remission5

1. Zuvich et al. Semin Immunol 2009;21:328-33. 2. Wallin MT et al. Neurology 2019;92:e1029-40. 3. Campbell JD et al. Mult Scler Relat Disord 2014; 4. National MS Society. Who Gets MS? (Epidemiology). Available from: https://www.nationalmssociety.org/What-is-MS/Who-Gets-MS (Accessed on October 24, 2018). 5. Gold R et al. Ther Adv Neurol Disord 2010;3:351-67. 6. Owens GM. Am J Manag Care 2016;22(6suppl):s151-8. 7. Oleen-Burkey M et al. Patient 2012;5:57-69. 8. Zwibel HL, Smrtka J. Am J Manag Care 2011;17(suppl5):S139-45. 9. Adelman G et al. J Med Econ 2013;16:639-47. 10. Owens GM et al. J Manag Care Pharm 2013;19(1supplA):S41-53.

ISPOR 2019 RMS Treatment Landscape – Disease-Modifying Therapies (DMTs)

Cladribine US Not approved (Mayzent, Generic Fingolimod ) (EU) 2022 (Gilenya, SC IFNB-1b Novartis) Ublituximab (Betaseron, (Novantrone, ) Generic) EU 2021 (Lemtrada, Sanofi Dimethyl Generic DMF IM IFNB-1a fumarate Genzyme) (Avonex, (Tysabri, (Ocrevus, (Tecfidera, Ofatumumab Biogen) Biogen) Biogen) Roche)

1993 1996 1998 2001 2004 2007 2010 2013 2014 2015 2016 2017 2018 2019 2020+

SC IFNB-1b Peg-IFNB-1a Glatiramer Glatiramer SC IFNB-1a (Extavia, (Plegridy, acetate acetate (Rebif, Merck) BIIB098/ (Copaxone, Novartis) Biogen) (Synthon) EU ALKS87009 Teva) Generic fingolimod Generic (US) (Aubagio, Sanofi Genzyme) glatiramer acetate (Glatopa, Sandoz) US Injectable DMTs

Oral DMTs Glatiramer acetate TIW (Copaxone, Teva) Evobrutinib 2024 Infused DMTs

DMF=; IFNB-1a= beta-1a; IFNB-1b=interferon beta-1b; IM=intramuscular; Peg=pegylated; SC=subcutaneous; TIW=three times a week.

2 ISPOR 2019 Study Rationale

Timeline of DMT approval

Is Lemtrada 2014 cost effective? 2015

GLATOPA® Generic glatiramer acetate 20 mg, 40 mg • A previous analysis found alemtuzumab to be among the highest-ranked DMTs, but did not  Administered as 2 annual courses by  Administered as 3 evaluate relative cost- effectiveness1 IV infusion times/week self-injected subcutaneously  Course 1 – 5 infusion treatment days • Our analysis also incorporated societal spillover  Course 2 – one year later, 3 infusion  One of the lowest cost effects of RMS to caregivers, which are seldom treatments treatment options for RMS, 2,3 considered in the cost-effectiveness appraisal of  Additional courses as needed given in generic form4 (lower DMTs wholesale acquisition cost  About half of patients with RMS compared with COPAXONE) received no additional treatment through 8 years after their initial 2 courses Lemtrada2,3

1. Fogarty E et al. Mult Scler Relat Disord 2016;9:23-30. 2. Singer et al. Mult Scler 2018;24(2suppl):P913. 3. Comi et al. Mult Scler 2018;24(2suppl);P1235. 4. Hua LH, Cohen JA. Neurol Clin Pract 2016;6:369-76.

Methods Model Overview • A Markov model with annual periods was constructed, similar to a widely used model structure1 • The disability states in the model were defined using steps 0 to 9 of the Kurtzke EDSS State Proportion of Expanded Disability Status Scale (Steps) Patients at (EDSS)2 Baseline in pooled CARE-MS • In each model period, patients were I and II trials allowed to: 0.0 3.71% • Stay in the same disability state 1.0 26.35% • Progress to a higher (worse) disability state 2.0 33.44% • Regress to a lower (better) disability state 3.0 23.93% • Die 4.0 8.54% • Key assumptions on transition 5.0 3.79% probabilities 6.0 0.24%

• Probability of dying was modeled indirectly State Health Worse 7.0 0.00% by multiplying mortality ratio and background mortality 8.0 0.00% • Probability of transitioning depended on 9.0 0.00% the current EDSS health state • Patients could experience a relapse that may or may not have resulted in Schematic representation of the model structure and initial distribution of patients in each EDSS state hospitalization 1. Chilcott J et al. BMJ 2003;326:522. 2. Kurtzke JF. Neurology 1983;33:1444-52.

3 ISPOR 2019 Methods Treatment Efficacy

Projected natural course and manifestation of RMS

Treatment efficacy inputs based on Fogarty et al. 20161 Natural 6-month Annualized Relative confirmed relapse rate, Annualized RMS risk ratios disability RR (95% CI) Relapse X rates for worsening, (RRs) Rate (ARR) relapse HR (95% CI) Alemtuzumab 12mg 0.41 (0.27–0.63) 0.31 (0.26–0.36)

Glatopa 20 mg 0.75 (0.56–0.98) 0.65 (0.59–0.71)

Glatopa 40 mg 0.75 (0.56–0.98) 0.65 (0.55–0.78)

Placebo (BSC) 1.00 (1.00–1.00) 1.00 (1.00–1.00) Natural Hazard Disability rates for Key assumptions on treatment efficacy: ratios Worsening X disability (HRs)  Treatment efficacy may diminish over time (using treatment-waning multipliers) worsening  A proportion of patients could withdraw and switch to best supportive care (BSC)  Patients could experience adverse events (AEs) from treatment or relapse  Each disability state was associated with EDSS-specific disease management cost and disutility  Proportion of patients requiring hospitalization was assumed to be 30.7%

CI=confidence interval. 1. Fogarty E et al. Mult Scler Relat Disord 2016;9:23-30.

ISPOR 2019 Methods Societal Perspective

• Caring for patients with RMS poses economic, psychological, emotional, and quality-of-life burdens on patients, caregivers, and relatives • Model was run from payer and societal perspectives

Payer Impact

Direct care costs Productivity losses Informal care •Ambulatory costs •Short-term absence •Care by friends •Inpatient costs •Reductions in work •Care by family •Tests and services hours and income •Other OTC treatments •Early retirement

Societal Impact

OTC=over the counter.

4 ISPOR 2019 Methods Model Outcomes

Drug-related costs • Acquisition • Administration Payer • Monitoring

RMS-related costs • Relapse costs Calculated model • Disability worsening costs outcomes: • Total cumulative cost AE costs • Total number of quality- adjusted life years (QALYs) Utilities Summed up over time • Incremental cost- (20 years), with effectiveness ratio Indirect costs and discount rate of 3% utilities* • Informal care

Societal • Productivity loss

*For sensitivity analysis only.

ISPOR 2019 Methods Base Case Parameters and Values

Model parameter Value Treatment frequency Glatopa 20 mg and 40 mg 100% every annual cycle Alemtuzumab - Course 1 (Year 1) 100% Course 2 (Year 2) 100% Re-treatment (Year 3) 40.2% Re-treatment (Year 4) 11.4% Re-treatment (Year 5) 1.5% Treatment efficacy for both drugs1 Years 0–5 100% (full efficacy) Years 6–9 75% (lower efficacy) Years 10+ 50% (half efficacy) Withdrawal rate for Glatopa2,3 Years 1–2 10% each year Years 3+ 3% each year Discounting (standard assumption) 3%

1. National Institute for Clinical Excellence. 2014; Technology Appraisal Guidance TA312; 2. Mauskopf J et al. J Med Econ 2016;19:432-42. 3. Tappenden P et al. Value Health 2009;12:657-65.

5 ISPOR 2019 Methods Drug-Related Drug Inputs

Treatment Administration method Annual wholesale Annual Annual monitoring acquisition cost administration costs (derived) (Redbook 2016) cost (derived)

Year 1 Year 2+

Alemtuzumab

Course 1 (Year 1) IV infusion $101,219 $2,038 $6,376 -

Courses 2–5 (Years 2–5) IV infusion $60,731 $1,223 - $5,306 Self-injected Glatopa 20 mg $63,236 $0 $3,642 $3,165 subcutaneously Self-injected Glatopa 40 mg $60,399 $0 $3,642 $3,165 subcutaneously

ISPOR 2019 Methods EDSS State Costs and Utilities1,2

Patient Caregiver Productivity Informal care EDSS state utilities utilities Direct care costs loss cost costs 0 0.92 0.00 $6,719 $6,616 $0 1 0.76 0.00 $7,547 $11,940 $880 2 0.67 0.00 $8,374 $17,006 $2,017 3 0.56 -0.01 $9,202 $22,074 $3,153 4 0.56 -0.01 $10,028 $27,139 $4,292 5 0.49 -0.02 $10,856 $32,206 $5,428 6 0.45 -0.03 $15,801 $32,653 $9,650 7 0.27 -0.05 $20,747 $30,516 $13,871 8 0.00 -0.11 $25,691 $29,671 $18,094 9 -0.23 -0.14 $30,636 $28,826 $22,316

1. Mauskopf J et al. J Med Econ 2016;19:432-42; 2. Palace J et al. Lancet Neurol 2015;14:497-505.

6 ISPOR 2019 Methods AEs

AE selection process1,2:

AEs with at least 5% overall Top 5 AEs selected for the AEs sorted by the magnitude incidence and/or at least 3% comparators (supplemented of the difference between the higher in the drug arm than in with additional AEs considered drug and placebo arms the placebo arm were included significant by clinical experts)

Key assumptions on AEs:

 Incidence of AEs for Glatopa remained constant for all years of the model time horizon  Incidence of AEs for alemtuzumab was constant every year for 9 years due to unique dosing frequency, except infusion-associated reactions (restricted to each year on treatment) . This is a conservative approach, given that AEs with alemtuzumab generally decline over time3,4

1. Mauskopf J et al. J Med Econ 2016;19:432-42. 2. Palace J et al. Lancet Neurol 2015;14:497-505. 3. Havrdova E, et al. Neurology 2017;89:1107-1116. 4. Coles AJ, et al. Neurology 2017;89:1117-26.

ISPOR 2019 Results Base Case: QALYs

• Patients on alemtuzumab had higher 20-year cumulative QALYs (8.98 vs 7.84) versus Glatopa 20 mg and 40 mg – Higher cumulative QALY was mainly due to higher disease-related QALYs (9.02 vs 7.84) despite lower disutility due to AEs (−0.0407 vs −0.0003)

16 14.76 14.67 14.67 AEs QALYs 10 14 9.02 0 9 -0.0003 -0.0003 7.84 7.84 12 8 -0.005 10 7 -0.01 6 8 -0.015 5 6 -0.02 4 4 3 -0.025 2 2 -0.03 1 0 -0.035 Total life-years 0 Disease-related QALYs -0.04 Alemtuzumab Glatopa 20 mg -0.04 -0.045 Glatopa 40 mg

7 ISPOR 2019 Results Base Case: Total 20-Year Costs

• The total discounted 20-year costs were lower for alemtuzumab ($421,996) versus Glatopa 20 mg ($895,661) and Glatopa 40 mg ($867,285)

$700,000 $660,318 $632,126 $600,000

$500,000

$400,000

$300,000 $235,155 $235,155 $226,406 $193,258 $200,000

$100,000 $2,332 $187 $4 $0 Disease-related Treatment-related AEs

Alemtuzumab Glatopa 20 mg Glatopa 40 mg

ISPOR 2019 Results Probabilistic Sensitivity Analysis (PSA) – Payer Perspective

• The PSA confirmed the base-case results that alemtuzumab dominated Glatopa as patients accumulated lower total incremental costs and higher incremental QALYs

Likelihood Probabilistic Probabilistic alemtuzumab is incremental costs, incremental QALY, cost effective at Alemtuzumab mean (95% CI) mean (95% CI) WTP=$50,000

-$476,987 1.1379 vs Glatopa 20 mg 100% (-$579,996 to -$379,029) (0.4230 to 1.8306)

-$447,304 1.1234 vs Glatopa 40 mg 100% (-$540,024 to -$354,026) (0.4213 to 1.8016)

WTP=willingness to pay.

8 ISPOR 2019 Results Base Case: Societal Perspective

• Alemtuzumab generated greater benefit to society by reducing caregiver disutility, informal care, and productivity loss versus Glatopa

Alemtuzumab Glatopa 20 mg Glatopa 40 mg Total cost $773,286 $1,308,371 $1,279,996 Treatment-related and AE costs $228,738 $660,505 $632,130 Direct medical costs $193,258 $235,155 $235,155 (disability and relapse) Productivity loss cost $291,676 $327,829 $327,829 Informal care costs $59,613 $84,882 $84,882 Total QALYs 8.777 7.519 7.519 QALYs due to disease and AEs 8.977 7.845 7.845 QALY loss due to caregiver -0.200 -0.326 -0.326 disutility

Previous Independent Analysis by the Institute for Clinical and Economic ISPOR 2019 Review (ICER) Found Alemtuzumab to Provide the Highest Number of QALYs Gained While Costing Less

Total Costs vs QALYs

• Alemtuzumab was dominant compared with Glatopa

Institute for Clinical and Economic Review, 2017. Multiple Sclerosis: Final Evidence Report. Available from: https://icer-review.org/material/ms-final-report/ (Accessed March 6, 2017).

9 ISPOR 2019 Discussion

• The cost-effectiveness of alemtuzumab was driven not only by treatment efficacy but also by much lower treatment-related costs – Because Glatopa needs to be administered on a chronic or defined periodic basis, the cumulative costs of treatment were higher ($660,318) from a payer perspective – Alemtuzumab’s lower cumulative cost of treatment ($226,406) is due to long-term treatment effects, with only 36.1% of patients requiring re-treatment over 5 years with the 2-course initial administration2,3 – Alemtuzumab generated greater benefit to society by reducing caregiver disutility, informal care, and productivity loss versus Glatopa

• Limitations – AEs of alemtuzumab may be examined more closely due to concerns about high-cost AEs; the results demonstrated only a small impact of AEs on overall cost-effectiveness results, consistent with prior analyses1 – Benefits of patient convenience resulting from 2 initial courses for alemtuzumab instead of chronic treatment were not captured

1. Mauskopf J, et al. J Med Econ 2016;19:432-42. 2. Havrdova E, et al. Neurology 2017;89:1107-16. 3. Coles AJ, et al. Neurology 2017;89:1117-26.

ISPOR 2019

Appendix

10 21

ISPOR 2019 Methods Other Model Inputs

Population Similar EDSS distribution from alemtuzumab clinical trial populations characteristics Treatment withdrawal • Withdrawal rate for all therapies except alemtuzumab was assumed to be constant at 10% rates1,2 for each of the first 2 years followed by 3% for each subsequent year until the end of the time horizon • For alemtuzumab, 100% of patients received alemtuzumab for the first 2 years, followed by occasional re-treatment Treatment waning3 • For Years 0–5, the comparative treatment efficacy was assumed to be unchanged • For Years 6–9, 75% treatment effectiveness was assumed • For Years 10+, 50% treatment effectiveness was assumed Mortality rates4 A weighted average mortality rate was obtained from background all-cause mortality rates for US men and women aged 20–100 for 2010, multiplied by a mortality factor corresponding to EDSS health state Cost (2016 USD)1,5-7 • Medical and formal health care costs, and natural history costs by EDSS state, were obtained from the literature • Wholesale acquisition costs for the treatment were sourced from Redbook • The administration costs for glatiramer acetate 20 mg were zero; alemtuzumab infusion costs were included in accordance with prescribing information and clinical experts Utility8-10 Baseline utility was sourced from the literature. Annual utility loss per relapse = -0.0252 (with hospitalization) and -0.0076 (without hospitalization), multiplied by utility loss values for relapse

1. Mauskopf J et al. J Med Econ 2016;19:432-42. 2. Tappenden P et al. Value Health 2009;12:657-65. 3. National Institute for Health and Care Excellence, 2014. Technology Appraisal Guidance TA312. Available from: https://www.nice.org.uk/guidance/ta312 (Accessed on May 28, 2014). 4. Pokorski RJ. J Insur Med 1997;29:101-6. 5. O’Brien JA et al. BMC Health Serv Res 2003;3:17. 6. Kobelt G et al. SSE/EFI Working Paper Series in Economics and Finance, 2005. Available from: https://ideas.repec.org/p/hhs/hastef/0594.html (Accessed on May 14, 2019). 7. RED BOOK Online (July 2016). Truven Health Analytics. 8. Palace J et al. Lancet Neurol 2015;14:497-505. 9. Guo S et al. Pharmacoeconomics 2014;32:559-72. 10. Prosser LA et al. Value Health 2004;7:554-68.

11 ISPOR 2019 Results Base Case: Relapse

• Patients on alemtuzumab had fewer total relapse events compared with patients on Glatopa (total events: 7.064 vs 9.793)

Relapse Event 8

7 6.787 6.787

6 4.895 5

4 3.006 3.006 3 2.169

2 Total Relapse Relapse Events Total 1

0 Not hospitalized Hospitalized Alemtuzumab Glatopa 20 mg Glatopa 40 mg

ISPOR 2019 Results Probabilistic Sensitivity Analysis (PSA)

The following data parameters were assessed simultaneously:

 6-month disability worsening and relapse rate efficacy ratios (at upper and lower 95% CI values)  Alemtuzumab acquisition costs (±10%)  Relapse management costs (±20%)  Model time horizon  Treatment withdrawal rate

12 ISPOR 2019 Results PSA – Payer Perspective

• The PSA confirmed the base-case results that alemtuzumab dominated Glatopa as patients accumulated lower total incremental costs and higher incremental QALYs • Alemtuzumab dominated even in a scenario where natural history data was sourced from the London, Ontario, dataset

Likelihood Probabilistic Probabilistic alemtuzumab is Alemtuzumab incremental costs, incremental QALY, cost effective at vs Glatopa 20 mg mean (95% CI) mean (95% CI) WTP=$50,000

PSA 1: using British -$476,987 1.1379 100% Columbia dataset (-$579,996, -$379,029) (0.4230, 1.8306)

PSA 2: using London, -$212,222 0.9442 100% Ontario, dataset (-$260,900, -$165,772) (0.3635, 1.5248)

ISPOR 2019 Results PSA vs Glatopa 20 mg

Cost-Effectiveness Plane 0 -0.500 0.000 0.500 1.000 1.500 2.000 2.500

-100,000

-200,000

-300,000

Cost -400,000

-500,000 Incremental Incremental -600,000

-700,000

-800,000 Probabilistic results (Lemtrada vs Glatopa 20 mg® (glatiramer acetate))

Incremental QALY

13 ISPOR 2019 Methods Data Sources

• The two widely used data sources for natural history in RMS include: London, Ontario (LO), natural history database and British Columbia Multiple Sclerosis (BCMS) longitudinal observation cohort

Key differences between LO and BCMS cohort1,2

LO cohort BCMS cohort Cohort size N=1099 N=2837

Data period 1972–1984 1980–1995 EDSS Censors improvements in EDSS Allows EDSS state improvement assessment state, not allowing RMS regression using “real-time” assessment

• Leads to more rapid EDSS progression  Therefore, BCMS cohort was used for the analysis • Underestimates the time spent in an EDSS (LO dataset was used in a separate sensitivity analysis) state and the cumulative QALYs

1. Palace J et al. BMJ Open. 2014;4:e004073; 2. Palace J et al. Lancet Neurol 2015;14:497-505.

ISPOR 2019 Discussion

• In the analysis which modeled a long-time horizon of 20 years to reflect the RMS disability accumulating over an extended period, alemtuzumab was a cost-effective treatment option for RMS when compared with Glatopa 20 mg and 40 mg • Using a validated British Columbia cohort as a source of the RMS natural history can more accurately capture patient experience by accounting for possible disease regression to a better EDSS state

14 ISPOR 2019 Limitations

• AEs of alemtuzumab may be examined more closely due to concerns about high-cost AEs; the results demonstrated only a small impact of AEs on overall cost-effectiveness results, consistent with prior analyses1,2

• Benefits of patient convenience resulting from 2 initial courses of alemtuzumab instead of chronic treatment were not captured

1. Mauskopf J et al. J Med Econ 2016;19:432-42; 2. Palace J et al. Lancet Neurol 2015;14:497-505.

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