Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom

Figures & data

Table 1. Baseline patient characteristics for the MSBase cohorts after matching.

Patient characteristic^a	Index DMT (starting or switching to)			Absolute standardized differences
	Natalizumab (n = 721)	Fingolimod (n = 721)	BRACETD (n = 721)	Natalizumab vs fingolimod	Natalizumab vs BRACETD	Fingolimod vs BRACETD
Age, mean (SD), years	36.0 (9.3)	36.0 (9.7)	35.7 (9.4)	0.002	0.031	0.032
Sex, female, n (%)	535 (74.2)	514 (71.3)	519 (72.0)	0.065	0.050	0.015
Country, n (%)				0.047	0.066	0.014
Italy	104 (14.4)	97 (13.5)	184 (25.5)
Czech Republic	92 (12.8)	145 (20.1)	167 (41.3)
Turkey	37 (16.8)	131 (18.2)	52 (7.2)
Spain	68 (9.4)	100 (13.9)	88 (12.2)
Australia	134 (18.6)	118 (16.4)	70 (9.7)
Other	286 (39.7)	130 (18.0)	160 (22.2)
EDSS score, median (IQR)	2.5 (2.0, 3.5)	2.5 (2.0, 4.0)	2.5 (1.5, 4.0)	0.125	0.005	0.110
Disease duration, mean (SD), years	7.3 (7.2)	7.4 (7.1)	7.0 (7.1)	0.016	0.042	0.058
On-treatment proportion of disease duration, mean (SD)	0.4 (0.3)	0.4 (0.3)	0.4 (0.3)	0.014	0.012	0.025
Prior treatment with DMT, n (%)	550 (76.3)	553 (76.7)	549 (76.1)	0.010	0.003	0.013
Pre-index DMT, n (%)^b				0.012	0.015	0.026
DMT naive	171 (23.7)	168 (23.3)	172 (23.9)
Interferon beta-1b SC^c	104 (14.4)	109 (15.1)	89 (12.3)
Interferon beta-1a SC	162 (22.5)	148 (20.5)	191 (26.5)
Interferon beta-1a IM	106 (14.7)	94 (13.0)	142 (19.7)
Glatiramer acetate	140 (19.4)	156 (21.6)	92 (12.8)
Teriflunomide	12 (1.7)	19 (2.6)	11 (1.5)
Dimethyl fumarate	26 (3.6)	27 (3.7)	24 (3.3)
Total relapse onsets in the prior 12 months, mean (SD)	2.2 (0.5)	2.3 (0.6)	2.2 (0.5)	0.121	0.019	0.144
Total relapse onsets in the prior 24 months, mean (SD)	2.8 (1.0)	2.9 (1.0)	2.7 (1.0)	0.120	0.043	0.160
Total steroid-treated relapse onsets in the prior 12 months, mean (SD)	1.5 (0.9)	1.5 (1.0)	1.4 (0.9)	0.030	0.028	0.056
Total steroid-treated relapse onsets in the prior 24 months, mean (SD)	1.8 (1.2)	1.9 (1.3)	1.8 (1.3)	0.033	0.032	0.063

Abbreviations. BRACETD, interferon-based therapies, glatiramer acetate, teriflunomide, and dimethyl fumarate; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; IM, intramuscular; IQR, interquartile range; SC, subcutaneous; SD, standard deviation.

^a The baseline patient characteristics prior to matching for the MSBase cohorts are presented in Table S1 (Supplementary Material).

^b The percentage distribution of therapies after the index date for the BRACETD treatment group is presented in Table S2 (Supplementary Material).

^c The MSBase data did not distinguish between the use of interferon beta-1b SC (Betaferon^® or Extavia^®); as such, the matching algorithm did not distinguish between the 2 options.

Figure 1. Patient selection flow chart for MSBase analysis. Abbreviations. BRACETD, interferon-based therapies, glatiramer acetate, teriflunomide, and dimethyl fumarate; EDSS, Expanded Disability Status Scale; RES, rapidly evolving severe; RRMS, relapsing-remitting multiple sclerosis. ^aRequires ≥2 relapses in the previous 12 months; a minimum treatment persistence of 3 months after treatment initiation; ≥3 months of data following therapy initiation, disability quantified with EDSS recorded at time of therapy initiation and at least 1 subsequent on-treatment EDSS record. ^bAll variables included in the propensity score matching algorithm (Table 1 in the main text) were required for inclusion in the analysis. ^cFor patients contributing multiple episodes within the same treatment group, the first episode was selected. For patients contributing multiple episodes to different groups, the smaller group was prioritized to maximize statistical power.

Figure 2. Model structure diagram for cost-effectiveness analysis. Abbreviations. EDSS, Expanded Disability Status Scale; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis. Note: EDSS changes of more than one level are permitted. ^aDeath is reachable from all health states. Image modified under the Creative Commons 4.0 License and credited to Spelman, T., Herring, W.L., Zhang, Y. et al. Comparative Effectiveness and Cost-Effectiveness of Natalizumab and Fingolimod in Patients with Inadequate Response to Disease-Modifying Therapies in Relapsing-Remitting Multiple Sclerosis in the United Kingdom. PharmacoEconomics. 2022;40:323–339. https://doi.org/10.1007/s40273-021-01106-6.

Table 2. Treatment-specific comparative effectiveness outcomes, costs, discontinuation rates, and adverse event outcomes used in the cost-effectiveness model.

	Natalizumab	Fingolimod
Comparative effectiveness outcomes (reference = BRACETD)^a
Mean years of follow-up (SD)	3.01 (2.26)	2.85 (1.93)
Rate ratio for ARR (95% CI)	0.46 (0.42-0.53)	0.72 (0.65-0.80)
Hazard ratio for CDW6M (95% CI)	1.01 (0.76-1.34)	0.84 (0.63-1.12)
Hazard ratio CDI6M (95% CI)	1.46 (1.16-1.85)	1.17 (0.91-1.50)
EDSS transition matrix for RRMS	See Table S8	See Table S9
ARRs by EDSS for RRMS	See Table S8	See Table S9
Treatment costs per year^b
Acquisition (all years)	£14,740.45	£19,175.63
Administration (year 1)	£3,348.52	£491.11
Administration (years 2+)	£3,348.52	£0.00
Monitoring (year 1)	£404.71	£762.34
Monitoring (years 2+)	£383.60	£411.93
Treatment discontinuation^c
Discontinuation per year	6.3%	10.3%
AE outcomes per year on treatment (weighted average including PML)^d
Costs	£149.05	£898.27
QALY decrement	0.0063	0.0073

Abbreviations. AE, adverse event; ARR, annualized relapse rate; BRACETD, interferon-based therapies, glatiramer acetate, teriflunomide, and dimethyl fumarate; CDI6M, 6-month–confirmed disability improvement; CDW6M, 6-month–confirmed disability worsening; CI, confidence interval; EDSS, Expanded Disability Status Scale; OWSA, one-way sensitivity analysis; PML, progressive multifocal leukoencephalopathy; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life-year; RRMS, relapsing-remitting multiple sclerosis; SD, standard deviation.

^a Detailed comparative effectiveness outcomes, including uncertainty parameters and distributions for the OWSA and PSA, are presented in Figure 3 and in Tables S4–S10 (Supplementary Material).

^b Acquisition costs (from UK list prices⁴¹) were varied in the OWSA only, while administration and monitoring costs (from resource utilization frequencies and standard UK unit costs^{42–44,67,68}) were varied in the PSA and OWSA. See Table S12 (Supplementary Material) for the specific resources used and their unit costs. For all costs, a gamma distribution was used with the standard errors assumed to be 10% of the means.

^c Discontinuation probabilities (derived from pivotal clinical trials for natalizumab³³ and fingolimod^31,32) were varied in the OWSA and the PSA using a beta distribution (sample sizes for beta distribution: N = 627 for natalizumab; N = 856 for fingolimod).

^d Source information, uncertainty parameters, and sampling distributions for AE incidence rates, AE costs per event, and AE QALY decrements per event are provided in Table S13 (Supplementary Material).

Table 3. Direct costs and utility values associated with MS management and relapses.

EDSS score^c	Direct costs^a		Utility values/decrement^b
	RRMS	SPMS	RRMS	SPMS
MS Management	Annual costs		Utility values
0	£504.55	£621.96	0.908	0.888
1.0	£917.73	£1,131.27	0.797	0.777
2.0	£4,770.43	£5,880.46	0.705	0.685
3.0	£3,781.73	£4,661.71	0.583	0.563
4.0	£3,594.10	£4,430.42	0.615	0.595
5.0	£5,017.36	£6,184.85	0.579	0.559
6.0	£9,933.61	£12,245.07	0.490	0.470
7.0	£15,943.92	£19,653.94	0.407	0.387
8.0	£28,745.04	£35,433.77	0.167	0.147
9.0	£35,736.87	£44,052.54	−0.101	−0.121
Relapses	Cost per event		Utility decrement per event
All EDSS scores	£438.49	£438.49	0.013	0.013

Source: 2015 UK MS Burden-of-Illness Survey^4,5 (inflated from 2016 to 2021 Great British Pounds using the consumer price index for health⁶⁷).

Abbreviations. EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; OWSA, one-way sensitivity analysis; PSA, probabilistic sensitivity analysis; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.

^a Direct management and relapse costs by EDSS for both RRMS and SPMS were varied for the PSA and the OWSA using a gamma distribution with standard errors assumed to be 20.0% of the means.

^b Utility values by EDSS for RRMS and SPMS without relapse were varied for the PSA and the OWSA using a lognormal distribution (as differences from 1 to allow for negative utility values), with standard errors assumed to be 20% of the means. Relapse utility decrements were varied for the PSA and the OWSA using a beta distribution, with standard errors assumed to be 20% of the means.

Figure 3. Comparative effectiveness analysis results for natalizumab and fingolimod compared with BRACETD. Abbreviations. ARR, annualized relapse rate; BRACETD, interferon-based therapies, glatiramer acetate, teriflunomide, and dimethyl fumarate; CDI6M, 6-month–confirmed disability improvement; CDW6M, 6-month–confirmed disability worsening; CI, confidence interval; DMT, disease-modifying therapy; HR, hazard ratio; RR, rate ratio. Note: The comparison of natalizumab with fingolimod is presented for context only and is not used in the cost-effectiveness model.

Table 4. Base-case natalizumab versus fingolimod cost-effectiveness analysis results.

Outcomes per patient	Natalizumab	Fingolimod	Incremental (%)
Expected health outcomes
Time on treatment (years)	5.61	4.43	1.179 (26.6)
Number of relapses (undiscounted)	26.26	28.42	−2.165 (−7.6)
LYs	20.50	20.60	−0.107 (−0.5)
QALYs	7.86	7.56	0.302 (4.0)
Expected cost outcomes
Direct, treatment-related	£92,502	£89,525	£2,977 (3.3)
Direct, MS management	£392,857	£409,133	−£16,276 (−4.0)
Direct, relapses	£6,145	£6,844	−£699 (−10.2)
Direct, adverse events	£836	£3,979	−£3,143 (−79.0)
Total direct costs	£492,341	£509,482	−£17,141 (−3.4)
Cost-effectiveness outcomes
Incremental cost per QALY gained	−£56,725	Natalizumab dominates fingolimod
NMB at £30,000 per QALY gained	£26,206

Abbreviations. CE, cost-effectiveness; LY, life-year; MS, multiple sclerosis; NMB, net monetary benefit; QALY, quality-adjusted life-year.

Figure 4. One-way and probabilistic sensitivity analysis results for cost-effectiveness analysis. Abbreviations. EDSS, Expanded Disability Status Scale; NMB, net monetary benefit; OWSA, one-way sensitivity analysis; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life-year; SPMS, secondary progressive multiple sclerosis; WTP, willingness to pay. Note: OWSA results are presented in panel a using the NMB outcome with a WTP threshold of £30,000 per QALY gained. Results of the PSA are presented in panel b.

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Data availability statement

The clinical data analyzed for this study were obtained under a license agreement with MSBase (www.msbase.org). However, no patient-level data were disclosed as part of the study. Therefore, all data relevant to the study have been presented in the article and supplementary materials.