Cost-effectiveness of velmanase alfa vs. bone marrow transplantation or no causal therapy in patients with mild to moderate alpha-mannosidosis

Figures & data

Figure 1. DES model representation. Blue rectangles are events that may happen during the lifetime of a patient, each updating quality of life and costs; some events are short-lasting, so they update costs and effects only during the time increment of one month, and some are long-lasting, updating costs and effects on quality of life until the end of a patient’s life. The arrows show the direction of movement of a patient during one model increment. After the pre-defined number of one-month model increments (n = 720), the model stops, total costs and effects are calculated for the current patient, and then another virtual patient enters.

Table 1. Model inputs for events onset.

Input parameter	Treatment option	Base case mean value with variability (months)	References
Time to hearing impairment	No causal therapy	30.00 ± 6.00	[14,15]
	Velmanase alfa	61.30 ± 6.00	[6,14–16]
	BMT	96.00 ± 6.00	[14,15,17]
Time to mental impairment	No causal therapy	60.00 ± 12.00	[14,15]
	Velmanase alfa	60.00 ± 12.00	[14,15]
	BMT	126.00 ± 12.00	[14,15,17]
Time to cerebral atrophy and cerebral demyelination (columnar disease)—fall	No causal therapy	120.00 ± 24.00	[14,15]
	Velmanase alfa	120.00 ± 24.00	[14,15]
	BMT	186.00 ± 24.00	[14,15]
Time to abnormal behavior	No causal therapy	180.00 ± 60.00	[14,15]
	Velmanase alfa	180.00 ± 60.00	[14,15]
	BMT	246.00 ± 60.00	[14,15]
Time to skeletal and muscular abnormalities—fall	No causal therapy	170.00 ± 60.00	[14,15]
	Velmanase alfa	201.30 ± 60.00	[6,14–16]
	BMT	236.00 ± 60.00	[14,15,17]
Time to vision loss	No causal therapy	300.00 ± 80.00	[14,15]
	Velmanase alfa	331.30 ± 80.00	[6,14–16]
	BMT	366.00 ± 80.00	[14,15,17]
Time to hernia	No causal therapy	36.00 ± 18.00	[14,15]
	Velmanase alfa	36.00 ± 18.00	[14,15]
	BMT	36.00 ± 18.00	[14,15]
Time to hepatosplenomegalia	No causal therapy	6.00 ± 2.00	[14,15,17]
	Velmanase alfa	6.00 ± 2.00	[14,15]
	BMT	6.00 ± 2.00	[14,15]
Coarse face	No causal therapy	4.00 ± 2.00	[14,15]
	Velmanase alfa	4.00 ± 2.00	[14,15]
	BMT	4.00 ± 2.00	[14,15]
Otitis media—1st episode	No causal therapy	18.00 ± 6.00	[14,15]
	Velmanase alfa	18.00 ± 6.00	[14,15]
	BMT	18.00 ± 6.00	[14,15]
Otitis media—2nd episode	No causal therapy	24.00 ± 4.00	[14,15]
	Velmanase alfa	24.00 ± 4.00	[14,15]
	BMT	24.00 ± 4.00	[14,15]
Otitis media—3rd episode	No causal therapy	38.00 ± 6.00	[14,15]
	Velmanase alfa	38.00 ± 6.00	[14,15]
	BMT	38.00 ± 6.00	[14,15]
Pneumonia—1st episode	No causal therapy	130.00 ± 24.00	[14,15]
	Velmanase alfa	161.30 ± 24.00	[6,14–16]
	BMT	196.00 ± 24.00	[14,15,17]
Pneumonia—2nd episode	No causal therapy	240.00 ± 60.00	[14,15]
	Velmanase alfa	271.30 ± 60.00	[6,14–16]
	BMT	306.00 ± 60.00	[14,15,17]
Death	No causal therapy	480.00 ± 120.00	[14,15]
	Velmanase alfa	511.30 ± 120.00	[6,14–16]
	BMT	546.00 ± 120.00	[14,15,17]

Table 2. Quality-of-life decrements and costs per episode and sustained.

	QoL decrement per episode	Sustained QoL decrement per month	References for QoL	COSTs per episode (RSD)	COSTs per episode (% of GDP)	Sustained COSTs per month (RDS)	Sustained COSTs per month (% of GDP)	References for COSTs
Hearing impairment	0.027	0.027	[18]	82,422.83	8.98	4,422.83	0.48	[19,20]
Mental impairment	0.048	0.048	[21]	6,880.81	0.75	6,880.81	0.75	[22]
Cerebral atrophy and cerebral demyelination (columnar disease)—fall	0.042	0.042	[23]	7,274.03	0.79	0.00	0.00	[24]
Abnormal behavior	0.104	0.104	[25]	14,558.01	1.59	14,558.01	1.59	[26]
Skeletal and muscular abnormalities—fall	0.042	0.042	[23]	7,274.03	0.79	7,274.03	0.79	[24]
Vision loss	0.244	0.244	[27]	15,498.06	1.69	15,498.06	1.69	[28]
Hernia	0.000	0.000	/	70,643.03	7.70	0.00	0.00	[29]
Hepatosplenomegalia	0.060	0.060	[30]	2,828.78	0.31	2,828.78	0.31	[31]
Coarse face	0.000	0.000	/	0.00	0.00	0.00	0.00	/
Otitis media—1st episode	0.210	0.000	[32]	5,504.65	0.60	0.00	0.00	[33]
Otitis media—2nd episode	0.210	0.000	[32]	5,504.65	0.60	0.00	0.00	[33]
Otitis media—3rd episode	0.210	0.000	[32]	5,504.65	0.60	0.00	0.00	[33]
Pneumonia—1st episode	0.150	0.000	[34]	47,268.61	5.15	0.00	0.00	[35]
Pneumonia—2nd episode	0.150	0.000	[34]	47,268.61	5.15	0.00	0.00	[35]
Death	0.000	0.000	/	0.00	0.00	0.00	0.00	/

QoL: quality of life; GDP: Gross Domestic Product per Capita for Serbia in 2021 was 917,441.90 RSD [36].

Figure 2. ICER for three scenarios. Incremental cost-effectiveness planes for the three scenarios: velmanase alfa vs. no causal therapy, velmanase alfa vs. bone marrow transplantation (BMT), and BMT vs. no causal therapy. Each dot on the graphs is one virtual patient (n = 1000 virtual patients); λ₁, λ₂, and λ₃ are cost-effectiveness thresholds of 1 Gross domestic Product (GDP) per capita per quality adjusted life year (QALY) gained, 3 GDPs per capita per QALY gained and 9 GDPs per capita per QALY gained, respectively. X-axis: difference in effects in QALYs (dE); Y-axis: difference in costs (dT).

Figure 3. ICER CI for three scenarios. Incremental cost-effectiveness planes for the three scenarios: velmanase alfa vs. no causal therapy, velmanase alfa vs. bone marrow transplantation (BMT), and BMT vs. no causal therapy. Blue dots on the graphs within the blue squares represent incremental cost-effectiveness ratio (ICER) with its 99% confidence intervals (CIs); λ₁, λ₂, and λ₃ are cost-effectiveness thresholds of 1 Gross domestic Product (GDP) per capita per quality adjusted life year (QALY) gained, 3 GDPs per capita per QALY gained and 9 GDPs per capita per QALY gained, respectively. X-axis: difference in effects in QALYs (dE); Y-axis: difference in costs (dT).

Figure 4. Tornado diagram for three scenarios. One-way sensitivity analysis for the three scenarios: velmanase alfa vs. no causal therapy, velmanase alfa vs. bone marrow transplantation (BMT), and BMT vs. no causal therapy. X-axis: net monetary benefit (NMB) if the first therapeutic option is used instead of the comparator. Blue bars on the graphs represent the variation range of the NMB if input parameters (shown on the right of the respective bars) are decreased and increased by 50%.

Table 3. Value of main output variables in the base case and PSA (mean ± 99%CI).

Output variables	Base case (RSD)	PSA (RSD)
Scenario 1 (velmanase alfa vs. no causal therapy)
ICER	941,587,152 ± 7,265,674	725,326,217 ± 4,922,928
Net monetary benefit	−365,242,595 ± 2,779,403	−368,742,966 ± 2,468,598
Scenario 2 (velmanase alfa vs. BMT)
ICER	−398,412,755 ± 3,305,129	−422,496,475 ± 3,323,374
Net monetary benefit	−357,498,497 ± 2,912,279	−357,960,242 ± 2,762,547
Scenario 3 (BMT vs. no causal therapy)
ICER	6,032,689 ± 69,063	6,528,187 ± 72,915
Net monetary benefit	−6,785,860 ± 101,332	−6,910,375 ± 99,371

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Data availability statement

The study plan is available at the link: https://osf.io/gs756/. The models used in the study and other materials not contained in the Supplementary File are available to interested readers from the corresponding author, at reasonable request.