Cost-effectiveness of alemtuzumab and natalizumab for relapsing-remitting multiple sclerosis treatment in Iran: decision analysis based on an indirect comparison

Figures & data

Figure 1. Schematic representation of the Markov model. EDSS, expanded disability status scale; RRMS, relapsing remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.

Table 1. Annual transition probability of moving between EDSS states for patients with RRMS or SPMS (age ≥28 years).

		Disease stage (EDSS) in cycle n + 1
		0	1	2	3	4	5	6	7	8	9
A. RRMS to RRMS Annual transition probability
Disease stage (EDSS) in cycle, n	0	0.69537	0.20294	0.07251	0.02170	0.00422	0.00137	0.00175	0.00011	0.00003	0.00000
	1	0.05826	0.69502	0.15783	0.06088	0.01638	0.00458	0.00643	0.00048	0.00013	0.00001
	2	0.01586	0.12133	0.60789	0.16796	0.04458	0.01849	0.02159	0.00174	0.00052	0.00004
	3	0.00594	0.04960	0.12006	0.54422	0.09109	0.05845	0.11649	0.01030	0.00355	0.00030
	4	0.00165	0.02214	0.06660	0.11519	0.48936	0.10388	0.16811	0.02580	0.00671	0.00056
	5	0.00052	0.00533	0.02942	0.05866	0.08736	0.48696	0.27310	0.03880	0.01883	0.00102
	6	0.00012	0.00133	0.00444	0.02497	0.03069	0.04080	0.74068	0.10897	0.04377	0.00423
	7	0.00001	0.00015	0.00052	0.00247	0.00727	0.00385	0.11684	0.69269	0.16061	0.01559
	8	0.00000	0.00001	0.00004	0.00029	0.00055	0.00050	0.01881	0.05574	0.90340	0.02066
	9	0.00000	0.00000	0.00000	0.00002	0.00004	0.00003	0.00176	0.00568	0.17414	0.81833
B. SPMS to SPMS Annual transition probability
Disease stage (EDSS) in cycle, n	0	0.69537	0.20294	0.07251	0.0217	0.00422	0.00137	0.00175	0.00011	0.00003	0
	1	0	0.75328	0.15783	0.06088	0.01638	0.00458	0.00643	0.00048	0.00013	0.00001
	2	0	0	0.74508	0.16796	0.04458	0.01849	0.02159	0.00174	0.00052	0.00004
	3	0	0	0	0.71982	0.09109	0.05845	0.11649	0.0103	0.00355	0.0003
	4	0	0	0	0	0.69494	0.10388	0.16811	0.0258	0.00671	0.00056
	5	0	0	0	0	0	0.66825	0.2731	0.0388	0.01883	0.00102
	6	0	0	0	0	0	0	0.84303	0.10897	0.04377	0.00423
	7	0	0	0	0	0	0	0	0.8238	0.16061	0.01559
	8	0	0	0	0	0	0	0	0	0.97934	0.02066
	9	0	0	0	0	0	0	0	0	0	1
C. RRMS to SPMS Annual transition probability		0	0.003	0.032	0.117	0.21	0.299	0.237	0.254	0.153	1

Abbreviations: RRMS, relapsing remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; EDSS, expanded disability status scale.

Table 2. The result of network meta-analysis estimating ALM and NTZ effectiveness vs placebo.

Reference (year)	ALM RR for relapse	NTZ RR for relapse	ALM HR for progression	NTZ HR for progression
Hamidi et al.^41 (2018)	0.29 (0.23–0.35)	0.30 (0.24–0.36)	0.36 (0.16–0.74)	0.59 (0.42–0.84)
ICER^31 (2017)	0.28 (0.22–0.35)	0.31 (0.25–0.40)	0.42 (0.25–0.68)	0.56 (0.37–0.74)
Fogarty et al.^42 (2016)	0.31 (0.26–0.36)	0.31 (0.27–0.36)	0.41 (0.27–0.63)	0.46 (0.33–0.63)
Filippini et al.^43 (2013)	0.40 (0.31–0.51)	0.56 (0.47–0.66)	0.35 (0.26–0.48)	0.64 (0.49–0.85)

Abbreviations: ALM, alemtuzumab; NTZ, natalizumab; HR, hazard ratio.

Table 3. Specific health-state utility weights.

Parameter	Mean utility weight (95% CI)	Distribution	Caregiver disutility
EDSS 0	0.870 (0.782–0.958)	Beta	0.002
EDSS 1	0.799 (0.705–0.893)	Beta	0.002
EDSS 2	0.705 (0.611–0.798)	Beta	0.045
EDSS 3	0.574 (0.472–0.675)	Beta	0.045
EDSS 4	0.610 (0.516–0.703)	Beta	0.142
EDSS 5	0.518 (0.426–0.610)	Beta	0.16
EDSS 6	0.458 (0.365–0.551)	Beta	0.173
EDSS 7	0.297 (0.200–0.393)	Beta	0.03
EDSS 8	–0.049 (–0.147–0.05)	normal	0.095
EDSS 9	–0.195 (–0.340– –0.049)	normal	0.095
SPMS	–0.045 (–0.076– –0.014)	normal	NA
Disutility associated with mild or moderate relapse	–0.071 (–0.096– –0.046)	normal	NA
Disutility associated with severe relapse	–0.236 (–0.295– –0.174)	normal	NA
Disutility associated with PML	–0.4 (–0.3– –0.5)	normal	NA
Disutility associated with thyroid dysfunction	–0.11 (0.09–0.13)	normal	NA

Abbreviations: EDSS, expanded disability status scale; PML, progressive multifocal leukoencephalopathy.

Table 4. Summary of base case cost input parameters.

Parameter description	Frequency (per annum)	Unit cost, $		Total cost ($ per annum)
Per prescription drug acquisition costs
ALM	3 (5 in 1st year)	12,620		37,860 (63,100)
NTZ	13	1,373		17,849
Laboratory tests
ALM	Based on guideline	—		121
NTZ	Based on guideline	—		12
Imaging
ALM	1	125		85
NTZ	2 (3 in 1st year)	125		170 (255)
MS-related health-state costs
Cost per patient per relapse	—	166		—
Supportive therapy	—	—		190
Adverse events management costs
ITP	—	238		—
Thyroid disorder	—	25		—
PML	—	190		—
Other medical direct cost
Neurologist visits	2 (4 in EDSS >6)	11		22 (44)
Psychotherapy	2	11		22
Physiotherapy	104	4.7		489
Common prescriptions	—	—		28
ALM premedication	—	—		26
Cost of hospitalization (per day)	—	75		—
Direct non-medical costs
Nursing in EDSS 3–5.5	—	—		2,280
Nursing in EDSS 6–7.5	—	—		3,996
Nursing in EDSS 8–9.5	—	—		7,140
Instruments	—	—		715
Car modification	—	—		1,190
House modification	—	—		3,570
Indirect costs
Absence from work EDSS 1–3.5	10.9	20		2,616
Absence from work EDSS 3–5.5	14.8	20		3,552

Abbreviations: EDSS, expanded disability status scale; PML, progressive multifocal leukoencephalopathy; ITP, immune thrombocytopenia; ALM, alemtuzumab; NTZ, natalizumab.

Table 5. Calculated risk of NTZ-related PML according to risk factors.

	Prior immunosuppressant therapy	Overall risk	Risk up to 24 months of therapy	Risk after 24 months of therapy
Seronegative for JCV	No	∼0.13:1000	∼0.02:1000	∼0.2:1000
	Yes	∼0.37:1000	∼0.06:1000	∼0.85:1000
Seropositive for JCV	No	∼5.10:1000	∼0.90:1000	∼8:1000
	Yes	∼14.7:1000	∼2.50:1000	∼23:1000

Abbreviations: PML, progressive multifocal leukoencephalopathy; NTZ, natalizumab; JCV, John Cunningham virus.

Figure 2. ALM and NTZ cumulative costs and effectiveness (NHS perspective). ALM, alemtuzumab; NTZ, natalizumab; NHS, national health system; QALYs, quality adjusted life years.

Table 6. Base-case results and sensitivity analyses of the effect of key input parameters on ICER.

Scenario	Total cost ($)	Incr. cost ($)	Total effect (QALYs)	Incr. effect (QALYs)	Incr. cost per QALY gained
Base case
NHS perspective
ALM	147,417	–3,162	7.07	0.57	Dominant
NTZ	150,579		6.51
Societal perspective
ALM	163,044	–3,723	6.40	0.63	Dominant
NTZ	166,767		5.77
Sensitivity analyses (NHS perspective)
Cost of NTZ decreased 25%
ALM	147,417	23,037	7.07	0.57	40,761
NTZ	124,380		6.51
Cost of ALM increased 25%
ALM	175,258	24,679	7.07	0.57	43,666
NTZ	150,579		6.51
Reduced time horizon (5 years)
ALM	122,758	55,797	2.38	0.03	2,170,481
NTZ	66,961		2.36
Reduced time horizon (10 years)
ALM	132,795	20,196	4.67	0.19	109,071
NTZ	112,599		4.48
Increased time horizon (30 years)
ALM	155,506	–7,603	7.88	–0.85	Dominant
NTZ	163,109		7.03
Increased time horizon (Life-time)
ALM	158,925	–8,216	8.13	1	Dominant
NTZ	167,141		7.13
Disease progression HR of ALM increased 25%
ALM	148,506	–2,073	6.64	0.13	Dominant
NTZ	150,579		6.51
Disease progression HR of NTZ decreased 25%
ALM	147,417	–8,626	7.07	0.017	Dominant
NTZ	156,043		6.90
ALM re-treatment increased 25%
ALM	150,579	4,099	7.07	0.57	7,280
NTZ	154,678		6.51
No discounting
ALM	183,389	–59,077	10.36	1.01	Dominant
NTZ	242,466		9.35
Using data in Hamidi et al.^41 as clinical effectiveness vs placebo
ALM	146,881	2,456	7.29	1.21	2,030
NTZ	144,425		6.08
Using data in ICER^31 as clinical effectiveness vs placebo
ALM	147,506	1,671	7.03	0.86	1,950
NTZ	145,835		6.17
Using data in Filippini et al.^43 as clinical effectiveness vs placebo
ALM	146,831	4,616	7.32	1.04	3,254
NTZ	142,214		5.91
Using data in Kalincik et al.^44 (assuming the same HR for relapse and disability worsening)
ALM	147,417	–5,544	7.07	0.39	Dominant
NTZ	152,961		6.68

Abbreviations: ALM, alemtuzumab; NTZ, natalizumab; NHS, national health system; QALYs, quality adjusted life years; HR, hazard ratio.

Figure 3. Results for one-way sensitivity analysis. (a) Effect of parameter variation on the incremental cost per QALY in the NHS perspective. (b) Effect of parameter variation on the incremental cost per QALY in the societal perspective. ALM, alemtuzumab; NTZ, natalizumab; NHS, national health system; QALYs, quality adjusted life years.

Figure 4. Incremental cost-effectiveness scatter plot for ALM vs NTZ with a willingness-to-pay line at 1 and 3 GDP/capita.

Figure 5. Cost-effectiveness acceptability curve for ALM vs NTZ.

Hamidi V, Couto E, Ringerike T, et al. A multiple treatment comparison of eleven disease-modifying drugs used for multiple sclerosis. J Clin Med Res 2018;10:88–105

 PubMedGoogle Scholar

Fogarty E, Schmitz S, Tubridy N, et al. Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: systematic review and network meta-analysis. Mult Scler Relat Disord 2016;9:23–30

 PubMed Web of Science ®Google Scholar

Filippini G, Del Giovane C, Vacchi L, et al. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane database Syst Rev 2013;6:CD008933

 PubMed Web of Science ®Google Scholar

Kalincik T, Brown JWL, Robertson N, et al. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study. Lancet Neurol 2017;16:271–81

 PubMed Web of Science ®Google Scholar