Budget impact of prophylactic treatment of rVIII-SingleChain in moderate and severe hemophilia A in Italy

Figures & data

Table 1. Assumptions around epidemiological data.

Description
Age distribution^23
<6 years	4%
6 to <12 years	4%
12 to <18 years	13%
18+ years	79%
Assumed average weight of patients
<6 years	17 kg
6 to <12 years	33 kg
12 to <18 years	57 kg
18+ years	75 kg
Population growth, patients per year^2^,^18–22	13
Total number of patients with hemophilia A (excluding those treated with pdFVIII)^2^,^18–23, n
Year 1	1782
Year 2	1795
Year 3	1808
Proportion of patients on prophylaxis^2^,^23
<6 years	100%
6 to <12 years	100%
12 to <18 years	100%
18+ years	64%
Number of patients receiving prophylactic treatment, n
Year 1	1275
Year 2	1284
Year 3	1294

Table 2. Dosing and price information.

Product	SmPC-based dosing^28–38		Weekly dose considered in the budget impact model (IU/kg)*	Ex-factory list price per unit (€)
	Dose per infusion (prophylaxis [IU/kg])	Infusion frequency (doses/week) or interval
rFVIII product
rVIII-SingleChain (AFSTYLA)^28
<6 years	30–50	2–3	83.0^16	0.74 per IU^39
6 to <12 years
12 to <18 years	20–50
Adults 18+ years
rFVIIIFc (ELOCTA)^29
<6 years	50	Every 3–5 days	96.9^16	0.72 per IU^40
6 to <12 years
12 to <18 years
18+ years
BAX 855 (ADYNOVATE/ADYNOVI)^30
<6 years	Not indicated	–	–	0.72 per IU^41
6 to <12 years
12 to <18 years	40–50	2 (every 3–4 days)	90.0
18+ years
BAY 94-9027 (JIVI)^33
<6 years	Not indicated	–	–	0.70 per IU^42
6 to <12 years
12 to <18 years	45–60	Every 5 days	73.5
18+ years
N8-GP (ESPEROCT)^34
<6 years	Not indicated	–	–	0.72 per IU^43
6 to <12 years
12 to <18 years	50	Every 4 days	87.5
18+ years
BAY 81-8973 (KOVALTRY)^35
<6 years	20–50	2–3 or Every other day	104.3^16	0.69 per IU^44
6 to <12 years
12 to <18 years	20–40	2–3
18+ years
Human cl-rhFVIII (NUWIQ)^35
<6 years	20–40	Every 2–3 days	84.0	0.65 per IU^45
6 to <12 years
12 to <18 years
18+ years
Octocog alfa (ADVATE)^36
<6 years	20–50	3–4	108.6^16	0.65 per IU^46
6 to <12 years	20–40	2–3
12 to <18 years
18+ years
BDDrFVIII (REFACTO AF)^32
<6 years	20–40	Every 2–3 days	84.0	0.69 per IU^47
6 to <12 years
12 to <18 years
18+ years
N8 (NOVOEIGHT)^37
<6 years	25–50 or 25–60^†	Every 2 days or 3 times weekly^†	129.4	0.65 per IU^48
6 to <12 years
12 to <18 years	20–40 or 20–50^†		108.8
18+ years
Non-factor replacement product
Emicizumab (HEMLIBRA)^38
<6 years	Loading dose: 3 mg/kg (first 4 weeks) Maintenance dose: 1.5 mg/kg, 3 mg/kg, or 6 mg/kg^‡ (from week 5 on)	Loading dose: once weekly Maintenance dose: Every week, every 2 weeks, or every 4 weeks^‡	Loading dose: 3 mg/kg (first 4 weeks) Maintenance dose: 1.5 mg/kg (from week 5 on)	77.13 per mg^49
6 to <12 years
12 to <18 years
18+ years

Abbreviations. IU, international unit; SmPC, summary of product characteristics.

*Weekly dose for rVIII-SingleChain, rFVIIIFc, BAY 81-8973 and octocog alfa are taken from real-world data as reported in Olivieri et al. 2022; weekly dose for the remaining products is calculated based on SmPC dosing.

†Recommended dosing for children <12 years is 25–50 IU/kg every 2 days or 25–60 IU/kg 3 times weekly; for adolescents and adults, recommended dosing is 20–40 IU/kg every 2 days or 20–50 IU/kg 3 times weekly.

‡Recommended dosing is 3 mg/kg once weekly for the first 4 weeks, followed by a maintenance dose of either 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks from week 5 on.

Table 3. Efficacy and dosing information for treatment of breakthrough bleeds.

	Median annual bleeding rates (breakthrough bleeds) All age groups	Number of infusions needed to treat a bleed		Dose per infusion to treat a bleed (IU)*
		Age 0 to <12	Age 12+	Age <6	Age 6 to <12	Age 12 to <18	Age 18+
rFVIII products
rVIII-SingleChain (AFSTYLA)	0.00^16	1.20^28	1.29^28	383	743	1,283	1,688
rFVIIIFc (ELOCTA)	0.00^16	1.29^50	1.16^50
BAX 855 (ADYNOVATE/ ADYNOVI)	1.90^30	1.26^30	1.19^30
BAY 94-9027 (JIVI)	1.79^33	1.28^33	1.24^33
N8-GP (ESPEROCT)	1.18^34	1.18^34^,^51	1.18^34
BAY 81-8973 (KOVALTRY)	1.00^16	1.21^35	1.14^35
Human cl-rhFVIII (NUWIQ)	1.20^31	1.37^52	1.14^52
Octocog alfa (ADVATE)	1.00^16	1.24^53	1.30^53
BDDrFVIII (REFACTO AF)	3.80^32	1.04^32	1.04†
N8 (NOVOEIGHT)	3.80^37	1.24^37	1.24^37
Non-factor replacement product
Emicizumab (HEMLIBRA)	0.00^38	Not indicated^38	Not indicated^38	Not indicated	Not indicated	Not indicated	Not indicated

*Calculated according to the formula provided in the European label: Dose (IU) = body weight (kg) × desired factor VIII (FVIII) rise (IU/dl or % of normal) × 0.5 (IU/kg per IU/dl). Required FVIII levels are 20–40% IU/dl for minor bleeding, 30–60% IU/dl for moderate bleeding, and 60–100% IU/dl for major bleeding. The desired FVIII rise used was 45% IU/dl for all rFVIII products and was calculated as the average rise for moderate bleeding.

†No data were available on the number of infusions needed to treat a bleed in adults, therefore it was assumed to be the same as in children.

Table 4. Patient shares of hemophilia A products in considered scenarios.

Product	Year 0^a	Base-case scenario, %^b			Alternative scenario, %^b
		Year 1	Year 2	Year 3	Year 1	Year 2	Year 3
rFVIII
rVIII-SingleChain (AFSTYLA)	8.6	8.6	8.6	8.6	15.0	20.0	25.0
rFVIIIFc (ELOCTA)	13.0	14.0	15.0	16.0	13.0	13.0	13.0
BAX 855 (ADYNOVATE/ADYNOVI)	2.9	3.9	4.5	5.5	3.9	4.5	5.5
BAY 94-9027 (JIVI)	7.0	7.8	8.5	9.5	7.8	8.5	9.5
N8-GP (ESPEROCT)	3.6	4.6	5.5	6.5	4.6	5.5	6.5
BAY 81-8973 (KOVALTRY)	18.5	17.4	15.6	13.6	16.7	13.0	8.0
Human cl-rhFVIII (NUWIQ)	5.5	4.8	3.7	2.5	4.2	3.0	2.0
Octocog alfa (ADVATE)	11.7	10.4	9.2	7.5	9.2	7.0	5.0
BDDrFVIII (REFACTO AF)	12.7	11.0	9.7	8.0	9.1	7.0	5.0
N8 (NOVOEIGHT)	3.5	3.5	2.7	2.3	2.5	1.5	0.5
Non-factor replacement
Emicizumab (HEMLIBRA)	11.0	14.0	17.0	20.0	14.0	17.0	20.0

^aCSL Behring data on file; ^bAssumptions.

Table 5. Annual consumption and annual costs of prophylaxis per patient for products with pooled real-world data.

Products	Age group	Total annual consumption (regular prophylaxis and treatment of breakthrough bleeds) (IU)	Proportion of annual consumption for the treatment of breakthrough bleeds (%)	Annual cost (€)
rFVIII
rVIII-SingleChain (AFSTYLA)	<6 years	73,574	0	54,444
	6 to <12 years	142,819	0	105,686
	12 to <18 years	246,688	0	182,549
	18+ years	324,589	0	240,196
rFVIIIFc (ELOCTA)	<6 years	85,895	0	61,844
	6 to <12 years	166,737	0	120,051
	12 to <18 years	288,001	0	207,360
	18+ years	378,948	0	272,843
BAY 81-8973 (KOVALTRY)	<6 years	92,917	0.5	64,113
	6 to <12 years	180,368	0.5	124,454
	12 to <18 years	311,457	0.5	214,905
	18+ years	409,811	0.5	282,770
Octocog alfa (ADVATE)	<6 years	96,742	0.5	62,882
	6 to <12 years	187,792	0.5	122,065
	12 to <18 years	324,442	0.5	210,887
	18+ years	426,897	0.5	277,483

Abbreviation. IU, international units.

Table 6. Annual consumption and annual costs of prophylaxis per patient for products with data from the European product labels.

Products	Age group	Total annual consumption (regular prophylaxis and treatment of breakthrough bleeds) (IU)	Proportion of annual consumption for the treatment of breakthrough bleeds (%)	Annual cost (€)
rFVIII
BAX 855 (ADYNOVATE/ ADYNOVI)	<6 years	Not indicated	–	Not indicated
	6 to <12 years	Not indicated	–	Not indicated
	12 to <18 years	270,383	1.1	194,676
	18+ years	355,767	1.1	256,152
BAY 94-9027 (JIVI)	<6 years	Not indicated	–	Not indicated
	6 to <12 years	Not indicated	–	Not indicated
	12 to <18 years	221,292	1.3	154,905
	18+ years	291,174	1.3	203,822
N8-GP (ESPEROCT)	<6 years	Not indicated	–	Not indicated
	6 to <12 years	Not indicated	–	Not indicated
	12 to <18 years	261,847	0.7	188,530
	18+ years	344,535	0.7	248,065
Human cl-rhFVIII (NUWIQ)	<6 years	75,091	0.8	48,809
	6 to <12 years	145,764	0.8	94,747
	12 to <18 years	251,419	0.7	163,422
	18+ years	330,815	0.7	215,029
BDDrFVIII (REFACTO AF)	<6 years	75,958	2.0	52,411
	6 to <12 years	147,447	2.0	101,739
	12 to <18 years	254,682	2.0	175,731
	18+ years	335,108	2.0	231,224
N8 (NOVOEIGHT)	<6 years	116,500	1.6	75,725
	6 to <12 years	226,147	1.6	146,996
	12 to <18 years	329,317	1.9	214,056
	18+ years	433,312	1.9	281,653
Non-factor replacement
Emicizumab (HEMLIBRA)	<6 years	1,335	0	102,949
	6 to <12 years	2,591	0	199,842
	12 to <18 years	4,475	0	345,181
	18+ years	5,889	0	454,186

Abbreviation. IU, international units.

Figure 1. Treatment costs of hemophilia A prophylaxis (analysis 1, considering list prices).

Table 7. Cost by product, total cost, and budget impact for prophylaxis, per year, using current list prices.

	Year 1		Year 2		Year 3
	Base-case scenario	Alternative scenario	Base-case scenario	Alternative scenario	Base-case scenario	Alternative scenario
rFVIII
rVIII-SingleChain (AFSTYLA)	23,417,301	40,844,130	23,620,045	54,930,338	23,837,831	69,296,019
rFVIIIFc (ELOCTA)	43,302,492	40,209,456	46,797,214	40,557,585	50,377,281	40,931,541
BAX 855 (ADYNOVATE/ ADYNOVI)	10,757,840	10,757,840	12,503,461	12,503,461	15,392,703	15,392,703
BAY 94-9027 (JIVI)	17,120,155	17,120,155	18,792,704	18,792,704	21,155,750	21,155,750
N8-GP (ESPEROCT)	12,288,146	12,288,146	14,799,549	14,799,549	17,617,067	17,617,067
BAY 81-8973 (KOVALTRY)	55,777,736	53,533,804	50,440,604	42,033,837	44,379,338	26,105,493
Human cl-rhFVIII (NUWIQ)	11,701,525	10,238,834	9,098,036	7,376,786	6,204,018	4,963,214
Octocog alfa (ADVATE)	32,714,306	28,939,579	29,190,126	22,209,878	24,015,698	16,010,466
BDDrFVIII (REFACTO AF)	28,833,601	23,853,252	25,646,129	18,507,516	21,346,471	13,341,544
N8 (NOVOEIGHT)	11,279,356	8,056,683	8,778,627	4,877,015	7,549,626	1,641,223
Non-factor replacement
Emicizumab (HEMLIBRA)	72,083,158	72,083,158	88,287,370	88,287,370	104,825,189	104,825,189
Total cost (€)	319,275,616	317,925,037	327,953,865	324,876,039	336,700,972	331,280,210
Budget impact (€)		−1,350,579		−3,077,826		−5,420,762
Change (%) from the base-case scenario		−0.4%		−0.9%		−1.6%

Figure 2. Treatment costs of hemophilia A prophylaxis (analysis 2, analysis considering regional drug acquisition prices).

Table 8. Cost by product, total cost, and budget impact for prophylaxis, per year, using regional drug acquisition prices.

	Year 1		Year 2		Year 3
	Base-case scenario	Alternative scenario	Base-case scenario	Alternative scenario	Base-case scenario	Alternative scenario
rFVIII
rVIII-SingleChain (AFSTYLA)	18,987,001	33,116,862	19,151,388	44,538,112	19,327,971	56,185,962
rFVIIIFc (ELOCTA)	39,092,527	36,300,204	42,247,485	36,614,487	45,479,490	36,952,085
BAX 855 (ADYNOVATE/ADYNOVI)	8,367,209	8,367,209	9,724,914	9,724,914	11,972,103	11,972,103
BAY 94-9027 (JIVI)	14,674,419	14,674,419	16,108,032	16,108,032	18,133,500	18,133,500
N8-GP (ESPEROCT)	8,021,428	8,021,428	9,660,816	9,660,816	11,500,030	11,500,030
BAY 81-8973 (KOVALTRY)	49,310,752	47,326,986	44,592,418	37,160,348	39,233,908	23,078,769
Human cl-rhFVIII (NUWIQ)	11,341,478	9,923,793	8,818,096	7,149,808	6,013,125	4,810,500
Octocog alfa (ADVATE)	31,707,712	28,049,130	28,291,968	21,526,497	23,276,754	15,517,836
BDDrFVIII (REFACTO AF)	25,908,453	21,433,357	23,044,348	16,629,942	19,180,887	11,988,054
N8 (NOVOEIGHT)	10,585,241	7,560,887	8,238,404	4,576,891	7,085,034	1,540,225
Non-factor replacement
Emicizumab (HEMLIBRA)	51,466,608	51,466,608	63,036,243	63,036,243	74,844,070	74,844,070
Total cost (€)	269,462,830	266,240,884	272,914,113	266,726,092	276,046,871	266,523,134
Budget impact (€)		−3,221,946		−6,188,022		−9,523,736
Change (%) from the base-case scenario		−1.2%		−2.3%		−3.5%

Berntorp E, Dolan G, Hay C, et al. European retrospective study of real-life haemophilia treatment. Haemophilia. 2017;23(1):105–114.

 PubMed Web of Science ®Google Scholar

Abbonizio F, Arcieri R, Associazione Italiana Centri Emofilia (AICE), et al. Registro Nazionale delle Coagulopatie Congenite (Rapporto 2018. (Rapporti ISTISAN 20/14). Roma: istituto Superiore di Sanità; 2020. p. 53.

 Google Scholar

European Medicines Agency. Summary of product characteristics – AFSTYLA; 2019. Available from: https://www.ema.europa.eu/en/documents/product-information/afstyla-epar-product-information_en.pdf.

 Google Scholar

Olivieri M, Simpson M, Yan S, et al. Analysis of pooled real-world data from Germany, Italy, and the United States of rVIII-SingleChain compared with standard- and long-acting FVIII products for prophylaxis of hemophilia A. Curr Med Res Opin. 2022;38(7):1133–1139.

 PubMed Web of Science ®Google Scholar

Gazzetta Ufficiale Serie Generale. 158(191), 17-08-2017. [cited]. Available from: https://www.gazzettaufficiale.it/eli/gu/2017/08/17/191/sg/pdf.

 Google Scholar

European Medicine Agency. Summary of product characteristics – ELOCTA; 2020. Available from: https://www.ema.europa.eu/en/documents/product-information/elocta-epar-product-information_en.pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 157(174), 27-07-2016. Available from: https://www.gazzettaufficiale.it/eli/gu/2016/07/27/174/sg/pdf.

 Google Scholar

European Medicines Agency. Summary of product characteristics – ADYNOVI; 2019. Available from: https://www.ema.europa.eu/documents/product-information/adynovi-epar-product-information_en.pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 161(14), 18-01-2020. Available from: https://www.gazzettaufficiale.it/eli/gu/2020/01/18/14/sg/pdf.

 Google Scholar

European Medicines Agency. Summary of product characteristics – JIVI; 2020. Available from: https://www.ema.europa.eu/documents/product-information/jivi-epar-product-information_en.pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 161(21), 27-01-2020. Available from: https://www.gazzettaufficiale.it/eli/gu/2020/01/27/21/sg/pdf.

 Google Scholar

European Medicines Agency. Summary of product characteristics – ESPEROCT; 2020. Available from: https://www.ema.europa.eu/documents/product-information/esperoct-epar-product-information_en.pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 178(76), 16-07-2020. Available from: https://www.gazzettaufficiale.it/eli/gu/2020/07/16/178/so/24/sg/pdf.

 Google Scholar

European Medicines Agency. Summary of product characteristics – KOVALTRY; 2020. Available from: https://www.ema.europa.eu/en/documents/product-information/kovaltry-epar-product-information_en.pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 163(52), 03-03-2022. Available from: https://www.gazzettaufficiale.it/eli/gu/2022/03/03/52/sg/pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 156(125), 01-06-2015. Available from: https://www.gazzettaufficiale.it/eli/gu/2015/06/01/125/sg/pdf.

 Google Scholar

European Medicines Agency. Summary of product characteristics – ADVATE; 2020. Available from: https://www.ema.europa.eu/documents/product-information/advate-epar-product-information_en.pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 156(198), 27-08-2015. Available from: https://www.gazzettaufficiale.it/eli/gu/2015/08/27/198/sg/pdf.

 Google Scholar

European Medicines Agency. Summary of product characteristics – REFACTO AF. 2019. Available from: https://www.ema.europa.eu/documents/product-information/refacto-af-epar-product-information_en.pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 152(298), 23-12-2011. Available from: https://www.gazzettaufficiale.it/eli/gu/2011/12/23/298/sg/pdf.

 Google Scholar

European Medicines Agency. Summary of product characteristics – NOVOEIGHT; 2020. Available from: https://www.ema.europa.eu/documents/product-information/novoeight-epar-product-information_en.pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 155(190), 18-08-2014. Available from: https://www.gazzettaufficiale.it/eli/gu/2014/08/18/190/sg/pdf.

 Google Scholar

European Medicines Agency. Summary of product characteristics – HEMLIBRA; 2021. Available from: https://www.ema.europa.eu/documents/product-information/hemlibra-epar-product-information_en.pdf.

 Google Scholar

Gazzetta Ufficiale Serie Generale. 161(71), 18-03-2020. Available from: https://www.gazzettaufficiale.it/eli/gu/2020/03/18/71/sg/pdf.

 Google Scholar

Biogen Canada Inc. Product monograph – ELOCTATE; 2016. Available from: https://www.biogen.ca/content/dam/corporate/en_CA/pdfs/products/ELOCTATE/ELOCTATE_PM_E.pdf.

 Google Scholar

Novo Nordisk Canada Inc. Product monograph – ESPEROCT; 2020. Available from: https://www.novonordisk.ca/content/dam/nncorp/ca/en/products/esperoct-product-monograph.pdf.

 Google Scholar

European Medicines Agency. Summary of product characteristics – NUWIQ. 2019. Available from: https://www.ema.europa.eu/documents/product-information/nuwiq-epar-product-information_en.pdf.

 Google Scholar

Octapharma Canada Inc. Product monograph – NUWIQ; 2018. Available from: https://pdf.hres.ca/dpd_pm/00044390.pdf.

 Google Scholar

Shire Pharma Canada ULC. Product monograph – ADVATE; 2018. Available from: https://pdf.hres.ca/dpd_pm/00046596.pdf.

 Google Scholar