Cost burden of breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria receiving ravulizumab versus eculizumab

Figures & data

Figure 1. BTH in patients with PNH cost model design schematic. BTH, breakthrough hemolysis; CAC, complement-amplifying condition; C_x, cost for treating each episode; PNH, paroxysmal nocturnal hemoglobinuria; p_x, proportion of episodes.

Table 1. Expected management strategy in response to BTH according to a survey of 10 clinical experts in the treatment of PNH.

Strategy	Frequency of management strategy (%)
	BTH due to elevated free C5		BTH due to pregnancy		BTH due to non-pregnancy CAC
	First event	Subsequent event	First event	Subsequent event	First event	Subsequent event
Patients treated with eculizumab
Increase dose to 1200 mg (one time)^a	4	13	67	0	20	20
Increase dose to 1200 mg (ongoing)^a	95	32	88	12	33	33
Increase dose to 1500 mg (ongoing)^a	0	0	0	4	0	0
Dosing every 12 days (one time)^a	16	50	33	0	20	40
Dosing every 12 days (ongoing)^a	5	18	60	14	0	33
Dosing every 9 days (ongoing)^a	0	0	0	10	0	0
Patients treated with ravulizumab^b
Single additional dose	10	10	10	10	10	10
Dosing every 7 weeks^c	10	10	10	10	10	10

BTH, breakthrough hemolysis; CAC, complement-amplifying conditions; PNH, paroxysmal nocturnal hemoglobinuria.

^aCompared with standard dose of eculizumab 900 every 14 days.

^bThere was no commercial use of ravulizumab at the time the survey was conducted; this information was based solely on the clinical trials of ravulizumab and on the experience of the surveyed clinicians who participated in the trials.

^cCompared with standard dosing of 3300 mg every 8 weeks.

Table 2. Additional medical management requirements for an episode of BTH according to a survey of 10 clinical experts in the treatment of PNH^a.

Strategy	Frequency of management strategy/number of units used per treated episode^b
	BTH due to elevated free C5		BTH due to pregnancy		BTH due to non-pregnancy CAC
	First event	Subsequent event	First event	Subsequent event	First event	Subsequent event
Blood transfusions (unit = number of transfusions)	35%/1.5	30%/1.5	20%/1.5	20%/1.5	15%/1.5	15%/1.5
General ward days (unit = days)	15%/1	15%/1	25%/4	10%/4	23%/3	23%/3
Intensive care days (unit = days)	1%/1	1%/1	13%/1	10%/1	1%/1	1%/1
Dialysis (unit = days)	4%/7	4%/7	0%	0%	4%/7	4%/7

AST, aspartate aminotransferase; BTH, breakthrough hemolysis; CAC, complement-amplifying conditions; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal hemoglobinuria; ULN, upper limit of normal.

^aThe definition of BTH was conservatively based on objective criteria such as elevated serum LDH levels (>1000 U/L, ≥1.5× ULN), increase in transfusion requirements, elevated serum AST levels (>90 IU/L), reduced hemoglobin levels, sub-therapeutic levels of eculizumab (<499 μg/ml), and recurrence of PNH symptoms.

^bOutcomes directly requested in clinical expert survey; average values used.

Table 3. Costs attributed to medical management of BTH in patients with PNH.

Item	Unit cost (US$)	Source
Eculizumab per mg	$21.74^a	Soliris WAC, Micromedex Red Book [18]
Ravulizumab per mg	$21.35^b	United States Securities and Exchange Commission [19]
Blood transfusion	$1188.29	CMS 2018 HCPCS code payment [20]
General ward day	$1049.00	HCCI 2016 Report [21]
Intensive care day	$4300.00	Halpern et al. 2015 [22]
Dialysis per year	$90,971.00^c	2018 US Renal Data System Annual Data Report [23]
Home infusion administration	$250.00	Alexion data on file. Work productivity study 2018 [24]
Clinic infusion administration	$661.00	Alexion data on file. Work productivity study 2018 [24]

BTH, breakthrough hemolysis; CMS, Centers for Medicaid and Medicare; HCCI, Health Care Cost institute; HCPCS, Healthcare Common Procedure Coding System; PNH, paroxysmal nocturnal hemoglobinuria; WAC, wholesale acquisition cost.

^aBased on a price of $6523 per 300 mg vial; 900 mg dose [18].

^bBased on a price of $6404 per 300 mg vial; for an average patient based on a 3300 mg dose [19].

^cCost per year was converted to a daily cost and applied only to the period during which a patient received dialysis.

Figure 2. Characteristics of BTH in patients with PNH reported in articles discovered in a targeted literature review. BTH, breakthrough hemolysis; CAC, complement-amplifying condition; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal hemoglobinuria.

Table 4. Costs associated with an episode of BTH by cause.

	Patients treated with eculizumab	Patients treated with ravulizumab
BTH due to elevated free C5
First episode One-time costs Ongoing costs per year	$1590 $152,895	$7884 $6584
Subsequent episode One-time costs Ongoing costs per year	$3033 $64,608	$7795 $6584
BTH due to pregnancy
First episode One-time costs Ongoing costs per year	$6344 $186,107	$7610 $5989
Subsequent episode One-time costs Ongoing costs per year	$781 $69,366	$7231 $5989
BTH due to non-pregnancy CAC
First episode One-time costs Ongoing costs per year	$5350 $51,716	$7170 $5989
Subsequent episode One-time costs Ongoing costs per year	$3162 $78,225	$7170 $5989

BTH, breakthrough hemolysis; CAC, complement-amplifying conditions.

Note: One-time costs for ravulizumab are higher than for eculizumab due to the dosing difference. The maintenance dose is 3300 mg for ravulizumab versus 900 mg for eculizumab.

Table 5. Annual resource implications of BTH given episode frequency and resources used per episode

	Patients treated with eculizumab			Patients treated with ravulizumab
	1 patient	Cohort of 10	Cohort of 20	1 patient	Cohort of 10	Cohort of 20
BTH due to elevated free C5 Number of BTH episodes Number of blood transfusions Number of hospital days Number with one-time change in dose or schedule Number with ongoing change in dose or schedule	0.05 0.02 0.01 0.01 0.04	0.48 0.25 0.08 0.12 0.45	0.96 0.50 0.15 0.25 0.90	0.00 0.00 0.00 0.00 0.00	0.00 0.00 0.00 0.00 0.00	0.00 0.00 0.00 0.00 0.00
BTH due to pregnancy Number of BTH episodes Number of blood transfusions Number of hospital days Number with one-time change in dose or schedule Number with ongoing change in dose or schedule	0.07 0.02 0.07 0.06 0.09	0.68 0.20 0.71 0.60 0.93	1.36 0.41 1.42 1.20 1.85	0.00 0.00 0.00 0.00 0.00	0.02 0.01 0.02 0.00 0.00	0.04 0.01 0.05 0.01 0.00
BTH due to non-pregnancy CAC Number of BTH episodes Number of blood transfusions Number of hospital days Number with one-time change in dose or schedule Number with ongoing change in dose or schedule	0.01 0.00 0.01 0.00 0.00	0.07 0.02 0.05 0.05 0.03	0.15 0.03 0.10 0.10 0.06	0.04 0.01 0.03 0.01 0.00	0.38 0.09 0.27 0.08 0.00	0.76 0.17 0.53 0.15 0.00

BTH, breakthrough hemolysis; CAC, complement-amplifying conditions.

Table 6. Annual costs of BTH for patients with PNH.

Annual costs (US$)	Patients treated with eculizumab			Patients treated with ravulizumab			Incremental difference in annual cost of BTH for patients treated with ravulizumab versus eculizumab
	1 patient	Cohort of 10	Cohort of 20	1 patient	Cohort of 10	Cohort of 20	1 patient	Cohort of 10	Cohort of 20
Due to elevated free C5	$3267	$32,667	$65,334	$0	$0	$0	−$3267	−$32,667	−$65,334
Due to pregnancy	$5907	$59,070	$118,139	$21	$212	$424	−$5886	−$58,858	−$117,715
Due to non-pregnancy CAC	$206	$2056	$4113	$386	$3863	$7725	$181	$1806	$3612
Total (pregnancy included)	$9379	$93,793	$187,587	$407	$4075	$8149	−$8972	−$89,719	−$179,437
Total (pregnancy excluded)	$3472	$34,724	$69,447	$386	$3863	$7725	−$3086	−$30,861	−$61,722

BTH, breakthrough hemolysis; CAC, complement-amplifying conditions; PNH, paroxysmal nocturnal hemoglobinuria.

Note: Cost of treating CAC episodes is higher for ravulizumab due to distribution suggesting small increases in CAC episodes relative to eculizumab, which is outweighed by the overall increase in BTH episodes and cost associated with eculizumab.

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