Economic impact model of delayed inhibitor development in patients with hemophilia a receiving emicizumab for the prevention of bleeding events

Figures & data

Figure 1. Model structure. Abbreviations. BTB, breakthrough bleeds; FVIII, factor VIII; ITI, immune tolerance induction.

Table 1. Model inputs for 12 month old previously untreated patients with severe hemophilia A receiving emicizumab or FVIII prophylaxis.

Parameter	Base case value	Lower limit	Upper limit	Source
Inhibitors
Proportion of patients who develop inhibitors
Plasma-derived FVIII prophylaxis
Low titer	7%	5.6%	8.4%	Peyvandi et al.^22
High titer	16%	12.8%	19.2%	Peyvandi et al.^22
Recombinant FVIII prophylaxis
Low titer	13%	10.4%	15.6%	Peyvandi et al.^22
High titer	24%	18.8%	28.2%	Peyvandi et al.^22
FVIII prophylaxis, weighted average
Low titer	12.6%	10.1%	15.2%	Assumption^a
High titer	23.5%	18.8%	28.2%	Assumption^a
Emicizumab prophylaxis
Low titer	12.6%	10.1%	15.2%	Assumption^b
High titer	23.5%	18.8%	28.2%	Assumption^b
Proportion of transient inhibitors
Low-titer inhibitors
Plasma-derived FVIII prophylaxis	44%	35.2%	52.8%	Peyvandi et al.^22
Recombinant FVIII prophylaxis	59%	47.2%	70.8%	Peyvandi et al.^22
FVIII prophylaxis, weighted average	58.1%	46.5%	69.7%	Assumption^a
Emicizumab prophylaxis	58.1%	46.5%	69.7%	Assumption^b
High-titer inhibitors
Plasma-derived FVIII prophylaxis	17%	13.6%	20.4%	Peyvandi et al.^22
Recombinant FVIII prophylaxis	7%	5.6%	8.4%	Peyvandi et al.^22
FVIII prophylaxis, weighted average	7.6%	6.1%	9.1%	Assumption^a
Emicizumab prophylaxis	7.6%	6.1%	9.1%	Assumption^b
Breakthrough Bleeds
Annual bleed rate, mean
FVIII prophylaxis	4.8	3.8	5.8	Mahlangu et al.^21
Emicizumab prophylaxis
No inhibitors	1.5	1.2	1.8	Mahlangu et al.^21
Inhibitors	2.9	2.3	3.5	Oldenburg et al.^19
aPCC prophylaxis	10.5	8.4	12.6	Mahlangu et al.^21Antunes et al.^23
ITI Utilization and Efficacy
Proportion of patients undergoing ITI
Low titer inhibitor	25.0%	20.0%	30.0%	Assumption^c
High titer inhibitor	65.0%	52.0%	78.0%	Assumption^c
Proportion of patients using low-dose ITI regimen
FVIII prophylaxis	50.0%	40.0%	60.0%	Assumption
Emicizumab prophylaxis	50.0%	40.0%	60.0%	Assumption
Low-dose ITI regimen efficacy
Successful treatment	69.7%	55.8%	83.6%	Hay et al.^10
Time to success, months	38	30.4	45.6	Hay et al.^10
High-dose ITI regimen efficacy
Successful treatment	69.7%	55.8%	83.6%	Hay et al.^10
Time to success, months	22	17.6	26.4	Hay et al.^10
Medication Unit Costs^d
Emicizumab (Hemlibra)	$99.20/mg			IBM Micromedex^24
Plasma-derived FVIII (Alphanate)^e	$1.16/IU			IBM Micromedex^24
Recombinant FVIII (Advate)^e	$1.64/IU			IBM Micromedex^24
rFVIIa (NovoSeven)	$2.16/μg			IBM Micromedex^24
aPCC (Feiba)	$2.25/IU			IBM Micromedex^24

Abbreviations. aPCC, activated prothrombin complex concentrate; FVIII, factor VIII; ITI, immune tolerance induction; rFVIIa, recombinant factor VIIa.

^a Weighted average calculated using assumed market share of 94% recombinant FVIII and 6% plasma-derived FVIII (assumption based on Genentech market research).

^b Assumed to be equal to FVIII due to absence of evidence for emicizumab.

^c Assumption based on clinical opinion.

^d Costs in 2019 US dollars, based on wholesale acquisition costs from IBM Micromedex (accessed January 7, 2019).

^e Selected as representative agents in the class due to market share at the time the study was conducted.

Table 2. Medication dosing model inputs for 12 month old previously untreated patients with severe hemophilia A receiving emicizumab or FVIII prophylaxis.

	Base case value	Lower limit	Upper limit	Frequency	Source
Prophylaxis
Emicizumab
Loading dose	3 mg/kg			Once weekly × 4 weeks	HEMLIBRA label^18
Maintenance dose	1.5 mg/kg			Once weekly	HEMLIBRA label^18
FVIII, no inhibitors
Initial dose	30 IU/kg	20 IU/kg	40 IU/kg	Once weekly	ADVATE label^25, Clinical opinion
Second dose	30 IU/kg	20 IU/kg	40 IU/kg	Twice weekly	ADVATE label^25, Clinical opinion
Maintenance dose	30 IU/kg	20 IU/kg	40 IU/kg	Every other day	ADVATE label^25, Clinical opinion
FVIII, low-titer inhibitors	50 IU/kg	40 IU/kg	60 IU/kg	Every other day	ADVATE label^25, Clinical opinion
aPCC	85 IU/kg			Every other day	FEIBA label^26
	Base case value	Lower limit	Upper limit	Number of doses	Source
BTB treatment
FVIII, no inhibitors	50 IU/kg	40 IU/kg	60 IU/kg	1	Valentino et al.^2
FVIII, low-titer inhibitors	50 IU/kg	40 IU/kg	60 IU/kg	2	Valentino et al.^2
rFVIIA, high-titer or low-titer failing ITI	110 mcg/kg	100 mcg/kg	120 mcg/kg	1	Young et al.^20
aPCC, high-titer or low-titer failing ITI	85 IU/kg	80 IU/kg	100 IU/kg	2^a	FEIBA label^26

Abbreviations. aPCC, activated prothrombin complex concentrate; BTB, breakthrough bleed; FVIII, factor VIII; ITI, immune tolerance induction; IU/kg, international units per kilogram; rFVIIa, recombinant factor VII activated.

^a Doses given on 2 consecutive days; aPCC dose should not exceed 100 IU/kg over 24 hours due to risk of thrombotic microangiopathy and thrombotic events in patients receiving emicizumab prophylaxis.¹⁸

Table 3. Base case results: modeled 20-year costs and outcomes in 12 month old previously untreated patients with severe hemophilia A receiving emicizumab or FVIII prophylaxis.

	Emicizumab	FVIII	Incremental analysis
Clinical outcomes (Undiscounted)
Number of breakthrough bleeds	32.3	108.9	−76.7
Time to inhibitor development, months	162	4	158
Cost outcomes (Discounted)^a
Total costs	$4,919,058	$6,864,538	−$1,945,480
Prophylaxis	$4,096,105	$6,290,919	−$2,194,815
Bleeds	$89,282	$342,652	−$253,370
ITI	$733,671	$230,967	$502,705
No inhibitors	$2,655,489	$3,082,877	−$427,388
Prophylaxis (FVIII or emicizumab)	$2,614,953	$2,953,162	−$338,209
Bleeds (FVIII)	$40,536	$129,715	−$89,179
Inhibitors	$2,263,569	$3,781,662	−$1,518,093
Prophylaxis (FVIII or emicizumab)	$1,481,151	$1,138,274	$342,877
Bleeds (FVIII)	$23,292	$56,426	−$33,134
ITI (FVIII)	$733,671	$230,967	$502,705
Bypassing agents, prophylaxis	$0	$2,199,483	−$2,199,483
Bypassing agents, bleeds	$25,454	$156,511	−$131,057
Total costs by inhibitor status, unweighted by probability of developing inhibitors
No inhibitors	$4,159,601	$4,829,068	−$669,467
Inhibitors	$8,671,268	$7,909,080	$762,188

The bold values are category subtotals (total costs, no inhibitors, inhibitors).

Abbreviations. FVIII, factor VIII; ITI, immune tolerance induction.

^a Costs presented in 2019 US dollars.

Figure 2. One-way sensitivity analysis: incremental costs. Costs presented in 2019 US dollars. Only 10 most influential parameters are shown. Abbreviations. FVIII, factor VIII; ITI, immune tolerance induction.

Figure 3. Scenario analysis: total discounted cost by time horizon. Costs presented in 2019 US dollars. Abbreviation. FVIII: factor VIII.

Figure 4. Scenario analysis: total discounted costs for switching from FVIII prophylaxis to emicizumab prophylaxis upon inhibitor development. Costs presented in 2019 US dollars. Abbreviation. FVIII, factor VIII.

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