A Systematic Review of Efficacy and Safety of Plasma-Derived von Willebrand Factor/Factor VIII Concentrate (Voncento) in von Willebrand Disease

Keywords

blood products - factor VIII - systematic review - von Willebrand disease - von Willebrand factor

Introduction

Visual Summary. This review demonstrates the long-term effectiveness and safety of this plasma-derived VWF/FVIII across all ages, types of VWD and treatment settings.

The therapeutic goal in von Willebrand disease (VWD) patient management is to treat or prevent bleeding events by correcting the deficiency of von Willebrand factor (VWF) and factor VIII (FVIII) plasma levels.[1] [2] Depending on VWD type and bleeding pattern, therapeutic strategies can be summarized in two main categories: non-factor replacement (antifibrinolytics and 1-deamino-8-D-arginine vasopressin [DDAVP]) and VWF-replacement therapy (RT). Different VWF RT regimens may be applied, including on-demand (OD) treatment for nonsurgical bleeds (NSBs), long-term prophylaxis (LTP; also referred to as continuous prophylaxis), and prophylaxis for surgical procedures (SP).[2] [3] [4] Treatment of heavy menstrual bleeding (HMB) is considered an NSB and treatment regimens are tailored to individual need, falling within OD treatment or intermittent prophylaxis, also known as short-term prophylaxis or nonsurgical intermittent prophylaxis.[2]

Plasma-derived human coagulation FVIII/human VWF (Voncento/Biostate, CSL Behring, Marburg, Germany; herein referred to as pdVWF/FVIII) is a highly purified, low-volume concentrate with an average VWF Ristocetin cofactor/FVIII clotting activity (VWF:RCo/FVIII:C) ratio of 2.4:1.[5] [6] pdVWF/FVIII was first marketed in Australia (international birth date August 7, 2000), and later in the European Union (EU birth date August 12, 2013). The same product has been marketed under various names (Voncento, Biostate, Aleviate, TBSF High Purity Factor VIII/VWF Concentrate) and is currently authorized in approximately 40 countries worldwide. pdVWF/FVIII is indicated in all age groups for prophylaxis and treatment of hemorrhage or surgical bleeding in patients with VWD when DDAVP treatment alone is ineffective or contraindicated, as well as prophylaxis and treatment of bleeds in patients with hemophilia A.[5] Clinical trial design in a rare disease setting, such as VWD, is limited by low prevalence and population heterogeneity, which hinders the conduction of classically designed randomized clinical trials.[7] This systematic review was conducted to evaluate the data available regarding the efficacy, consumption, and safety of pdVWF/FVIII for the treatment of patients of all ages with all VWD types, and includes novel reporting of pharmacovigilance data for the first time in this product's lifetime.

Methods

Search Strategy

An electronic search was conducted in the following databases on May 31, 2023: MEDLINE (1946 to present) and MEDLINE In-Process Citations, through Pubmed.com interface; Cochrane Library, including the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR). Search terms were designed to identify publications reporting studies in patients with inherited VWD of all ages treated with pdVWF/FVIII (Voncento/Biostate); the full search strategy is described in [Supplementary Methods] (available in the online version) and [Supplementary Tables S1] to [S5] (available in the online version).

Data Extraction

Data were extracted into preprepared data tables to prevent reporting bias and to allow comparisons for all available outcomes of interest. Once data extraction was complete, comparable results were combined to form the summary tables within this review. To enable comparison between studies, where pdVWF/FVIII dosing was quoted as FVIII:C IU/kg, the VWF:RCo IU/kg dose was estimated using the VWF:RCo/FVIII:C ratio of 2.4:1[5]; the original FVIII:C dosing was also reported. Finally, outcomes for hemostatic efficacy and safety were pooled across studies to produce an overall estimate of hemostatic efficacy for OD, LTP, and SP where data were comparable.

Pharmacovigilance Data

Pharmacovigilance data including spontaneous reports, reports from postmarketing trials, regulatory agencies, and cases identified from a review of the worldwide scientific literature were analyzed for the period up to May 31, 2023. Only adverse events (AEs) with suspected causal relationship between product and occurrence (adverse drug reactions [ADRs]) were included in the pharmacovigilance data analysis. ADRs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 26.0, and the events were classified as serious or nonserious according to regulatory definition; further details provided in [Supplementary Methods] (available in the online version).

Only reports associated with the specific pdVWF/FVIII product (Voncento/Biostate) were included.[5] No distinctions were made between ADRs reported for the indications of VWD or hemophilia A; therefore, all ADRs for pdVWF/FVIII (Voncento/Biostate) were reported.

Results

Systematic Review

The literature search identified 119 individual records, of which 108 were included in full-text screening and 31 were identified in the grey literature review ([Fig. 1]). Further screening removed records superseded by subsequent publication updates, resulting in 11 unique publications from eight study cohorts for qualitative data analysis.

Fig. 1 PRISMA flowchart presenting the results of the systematic literature review.

Of the 11 included publications, five were interventional studies, including three from the SWIFT study program (Studies with von Willebrand factor/Factor VIII),[6] [8] [9] [10] [11] four were prospective observational studies from the OPALE (Observatoire des patients présentant une Maladie de Willebrand et traités par Voncento) study cohort,[12] [13] [14] [15] and two were retrospective observational studies[16] [17] (summarized in [Supplementary Results] and [Supplementary Table S6] [available in the online version]). Population characteristics, which included pediatric and adolescent patients, are presented in [Table 1]. All VWD types were represented, with cases of severe type 3 VWD included in all studies where reported (data unavailable for postmarketing study CS-12-83, [Table 1]).

Table 1 Population characteristics of studies reporting pdVWF/FVIII data

Study name and identifiers				SWIFT-VWD	SWIFTLY-VWD	SWIFT-VWDext	CSL-12-83	OPALE
Primary reference	Dunkley et al (2010) [10]	Howman et al (2011) [16]	Shortt et al (2007) [17]	Lissitchkov et al (2017) [6]	Auerswald et al (2020) [8]	Lissitchkov et al (2020) [9]	EudraCT 2013-003305-25 [11]	Rugeri et al (2021) [13]	Harroche et al (2021) [15]	Rugeri et al (2022) [14]	d'Oiron et al (2022) [12]
Substudy cohort	All ages, all regimens	Pediatric	Surgery	Adolescents and adults	Pediatric	Extension	Postmarketing	Surgery	Pediatric	Long-term prophylaxis	On-demand
Patient number, N	20[a]	43	43	22[b]	17	19	25	66	19	23	29
Age, y	[c]				NR	[d]
Mean (range)/(SD)	–	–	52.0 (19.0–80.0)	33.6 (15.2)	5.2 (3.4)	32.7 (18.5)	35.8 (19.1)	–	(1.0–12)	–
Median (range)	–	10 (0.42–17.5)	–	30.5 (15.0–68.0)	5 (0.0–11.0)	30 (6.0–70.0)	–	45 (4.0–86)	–	16 (1.0–85)	43 (4.0–76.0)
Female sex, n (%)	9 (45)	18 (42)	22 (51)	12 (55)	10 (59)	7 (37)	12 (48)	44 (67)	5 (26)	12 (52)	11 (38)
VWD type, n (%)
1	5 (25)	21 (49)	26 (60)	5 (23)	0	2 (11)	NR	23 (35)	(27)	–	6 (21)
2A	2 (10)	4 (9)	8 (19)	4 (18)	7 (41)	4 (21)		13 (20)	(17)	1 (4)	5 (17)
2B	0	6 (14)	4 (9)	0	–	–		5 (8)	(13)	6 (26)	2 (7)
2M	6 (30)	4 (9)	0	0	–	–		10 (15)	(14)	–	4 (14)
2N	0	1 (2)	0	0	–	–		6 (9)	(5)	–	1 (3)
3	6 (30)	7 (17)	5 (12)	13 (59)	10 (59)	13 (68)		6 (9)	(15)	16 (70)	6 (21)
NA	1 (5)	–	–	–	–	–		3 (4)	(9)	–	5 (17)
Severe VWD, n (%)	NR	NR	NR	22 (100)[e]	17 (100)	19 (100)	25 (100)[f]	NR	NR	NR	NR

Abbreviations: dL, deciliter; IU, international unit; NA, not available; NR, not reported; VWD, von Willebrand disease; VWF, von Willebrand factor.

^a Baseline characteristics available for only 20 patients.

^b Baseline characteristics for the overall safety population, including patients from the three different arms of interest: arm 1 with n = 1 (prophylaxis-treated patient), arm 2 with n = 21 (on-demand treated patients), and arm 3 with n = 8 (prophylaxis-treated patients, previously treated in arm 2 and were qualified for a switch to a prophylaxis regimen).

^c Mean age (range) only reported per VWD type: type 1 52 (30–85) years; type 2A 64 (59–70) years; type 2M 44 (27–67) years; type 2 unknown 82 (NR) years; type 3 40 (3–65) years.

^d Reported per age range: 6 to <12 (n = 3), 12 to <18 (n = 2); ≥18 (n = 14); one patient in the on-demand arm did not experience any bleeding events during the study and was therefore excluded from all analyses.

^e Severe disease defined as VWF:RCo plasma levels <15 IU/dL or documented history of levels <10 IU/dL.

^f Severe disease defined as VWF:RCo plasma levels <20%.

Hemostatic Efficacy Outcomes

Hemostatic efficacy outcomes for OD, LTP, and SP treatment regimens are summarized in [Table 2] and [Supplementary Table S7] (available in the online version). Eight publications evaluated pdVWF/FVIII for OD treatment of bleeding events ([Table 2]). All eight publications reported hemostatic efficacy, with minor differences between rating categories and efficacy assessment. Overall, efficacy was rated as excellent/good for the control of NSB events in 66 to 100% of treated bleeds ([Table 2]). Hemostatic efficacy scores were pooled from 799 treated bleeds from 127 patients across eight studies ([Fig. 2A]), where 96% of bleeds (N = 761) were resolved with excellent/good efficacy and 3% (N = 24) had moderate efficacy; data unavailable for 1% (N = 6).[6] [8] [9] [10] [12] [15] [16] [18]

Table 2 Hemostatic efficacy for on-demand treatment of bleedings, long-term prophylaxis, and surgical prophylaxis with pdVWF/FVIII

On-demand treatment of bleeds
Study name and identifiers			SWIFT-VWD		SWIFTLY-VWD	SWIFT-VWDext	CSL-12-83		OPALE
Primary reference	Dunkley et al (2010)[10]	Howman et al (2011)[16]	Lissitchkov et al (2017)[6]		Auerswald et al (2020)[8]	Lissitchkov et al (2020)[9]	EudraCT 2013-003305-25[11]		Harroche et al (2021)[15]	d'Oiron et al (2022)[12]
Substudy cohort	All ages	Pediatric	Adolescents and adults		Pediatric	Extension	Postmarketing		Pediatric	All ages
Patient number, N	5	24	20[a]		12	7	11		19	29
Number of bleeds, n	9	72	407[b]		80[b]	77[b]	69[b]		23	62
Hemostatic efficacy, n (%)
Overall	N = 6[c]		[d]		[d]	[d]	[d]
Excellent	4 (66)	68 (94)	374 (92)		36 (45)	35 (46)	22 (32)		23 (100)	57 (92)
Good	–		25 (6)		44 (55)	41 (53)	36 (52)
Moderate	1 (17)	4 (6)	7 (2)		–	1 (1)	11 (16)		–	–
NA	1 (17)	–	0		–	–	–		–	5 (8)
Long-term prophylaxis
Study name and identifiers			SWIFT-VWD		SWIFTLY-VWD	SWIFT-VWDext	CSL-12-83		OPALE
Primary reference	Dunkley et al (2010) [10]	Howman et al (2011) [16]	Lissitchkov et al (2017) [6]		Auerswald et al (2020) [8]	Lissitchkov et al (2020) [9]	EudraCT 2013-003305-25[11]		Harroche et al (2021) [15]	Rugeri et al (2022) [14]
			CP arm	CP-Switch arm
Patient number, N	4	2	1	8	4	10	14		7	23
Prophylactic efficacy rating, n (%)	[e]	NR	NR	NR	NR	NR	NR
Excellent/good	4 (100)								7 (100)	19 (100)[f]
Moderate/poor	–								–	–
NA	–								–	–
Number of treated breakthrough bleeds, n	[g]	NR	1	10	73[h]	96[h]	72[h]		NR	NR
Hemostatic efficacy in breakthrough bleeds, n (%)				[i]	[i]	[i]	[i]
Excellent/good	[g]		1 (100)	10 (100)	73 (100)	94 (98)	64 (89)
Moderate/none	–		–	–	–	2 (2)	8 (11)
Surgical prophylaxis
Study name and identifiers				SWIFT-VWD		SWIFTLY-VWD	CSL-12-83		OPALE
Primary reference	Dunkley et al (2010) [10]	Howman et al (2011) [16]	Shortt et al (2007) [17]	Lissitchkov et al (2017) [6]		Auerswald et al (2020) [8]	Postmarketing		Harroche et al (2021) [15]	Rugeri et al (2021) [13]
				OD arm	LTP-Switch arm	OD arm	OD arm	LTP arm
Patient number, N	19	31	43	4	2	3	11	14	9	66
Number of procedures, n	29	42	58	4	2	8	9	4	10	100
Procedure type, n (%)	[j]	[j]		[j]	[j]	[k]
Major surgery	10 (34)	10 (24)	22 (38)	–	–	–	NR	NR	2 (20)	31 (31)
Minor surgery	19 (66)	32 (76)	23 (40)	4 (100)	2 (100)	8 (100)			7 (70)	42 (42)
Dental procedures	–	–	13 (22)	–	–	–			1 (10)	27 (27)
Prophylaxis hemostatic efficacy rating, n (%)
Overall	N = 25[l]			[m]	[n]	[n]
Excellent	25 (100)	38 (90)	45 (78)	4 (100)	2 (100)	7 (87)	4 (44)	3 (75)	9 (100)	65 (99)
Good			13 (22)	–	–	1 (13)	5 (56)	–
Moderate	–	4 (10)	–	–	–	–	–	–	–	1 (1)
NA	–	–	–	–	–	–	–	1 (25)	–	–
Per procedure type (excellent/good rating, %)	[o]						NR	NR
Major	10 (100)	9 (90)	22 (100)	–	–	–			“Good to excellent”	100
Minor	15 (100)	29 (91)	23 (100	4 (100)	2 (100)	8 (100)				99[p]
Dental procedure	–	–	13 (100)	–	–	–
Blood loss during surgical procedures, n (%)	N = 20[q]	N = 23[r]	NR					N = 3[s]	NR	NR
Less than expected	17 (85)	20 (87)		1 (25)	1 (50)	–	1 (11)	1 (25)
Equivalent to expected				3 (75)	1 (50)	8 (100)	8 (89)	2 (50)
NA	–	–		–	–	–	–	1 (25)

Abbreviations: ABR, annualized bleeding rate; LTP, long-term prophylaxis; NA, not available; NR, not reported.

Note: Not all bleeding event details were reported or categorized, hence n numbers within categorized data may vary from total number of bleeds.

^a On-demand efficacy population included 21 study participants. Exclusion of one patient due to the absence of evaluable nonsurgical bleeding event.

^b Regarding number of treated bleeding events requiring pdVWF/FVIII administration as assessed by the investigator; all N are quoted directly from published papers.

^c Overall hemostatic efficacy assessment was done by the investigator at the posttreatment visit 24 hours after the final dose. Only six of the nine nonsurgical bleeds were assessed, although overall hemostatic efficacy rating was only reported for five bleeding events.

^d Investigator evaluated clinical response efficacy in every 3-month visit. Reported the overall hemostatic efficacy assessment according to investigator.

^e Hemostatic efficacy assessment was done each 3 months during the 12-month period. Data report the overall clinical response of investigator throughout the treatment period.

^f Data available for 19 patients.

^g Reported 22 breakthrough bleeds during prophylaxis, although not explicit number of treated bleeds. Authors mention that overall efficacy in the management of bleeding events was excellent although all patients experienced at least one episode of spontaneous bleeding during the study period.

^h Number of bleeding events assessed by the investigator.

ⁱ Reported investigator hemostatic efficacy assessment per treated nonsurgical bleeding event.

^j Dental procedures/extractions were classified as minor surgery.

^k Minor surgical procedure was defined as surgery involving little risk to the life of the subject.

^l Overall hemostatic efficacy assessment at the posttreatment visit 24 hours after the final dose. Of the total 29 procedures, only 25 were assessed by the investigator.

^m Post-surgery overall assessment.

ⁿ Overall hemostatic efficacy assessment at the moment of discharge.

^o All major surgeries (n = 10) were assessed for hemostatic efficacy, while only 15 minor surgeries were evaluated.

^p One moderate outcome reported for minor surgery which included dental procedures.

^q Approximately 85% of the surgery treatment events had assessments of blood loss by the surgeon: minor surgeries (n/N = 10/12); major surgery (n/N = 7/8).

^r Approximately 87% of the surgical events were assessed for blood loss by the surgeon: minor surgeries (n/N = 15/16); major surgery (n/N = 5/7).

^s Assessment reported for only three procedures.

Fig. 2 Pooled hemostatic efficacy for on-demand treatment of bleeds (A), treatment of breakthrough bleeds during long-term prophylaxis (B), and during surgical prophylaxis (C) (N, %). (A) Pooled data from 127 patients and 799 treated bleeds with hemostatic efficacy ratings across eight studies.[6] [8] [9] [10] [12] [15] [16] [18] (B) Pooled data from 37 patients and 252 treated bleeds across nine studies.[6] [8] [9] [10] [13] [14] [15] [16] [18] (C) Pooled data from 202 patients undergoing a total of 266 procedures across eight studies (including moderate and mild severity).[6] [8] [10] [14] [15] [16] [17] [18] Data from included studies which did not report hemostatic efficacy are not represented in this figure.

Six studies reported consumption data for pdVWF/FVIII for OD treatment of bleeding events ([Supplementary Table S8], available in the online version).[6] [8] [9] [10] [11] [16] Reporting of OD treatment regimen varied, with number of infusions per patient, infusions per event number of NSBs, and dose per infusion.

Eight studies evaluated the efficacy of pdVWF/FVIII for LTP treatment ([Table 2]). Prophylactic efficacy was reported as excellent/good in 98 to 100% of patients in four publications,[10] [14] [15] and 89% of patients in a fifth ([Table 2]).[18] The OPALE study reported hemostatic efficacy according to VWD type, where excellent/good effectiveness was reported in 100% of patients (N = 23) with types 2A (N = 1), 2B (N = 5), and 3 (N = 16) where these data were available.[14] Pooled hemostatic efficacy scores for treatment of breakthrough bleeds were pooled from 252 treated bleeds from 37 patients across nine studies ([Fig. 2B]), where 96% of bleeds (N = 242) were resolved with excellent/good efficacy and 4% (N = 10) had moderate efficacy.[6] [8] [9] [10] [13] [14] [15] [16] [18] Three studies reported consumption data for pdVWF/FVIII for LTP treatment,[6] [10] [11] and LTP regimen was reported in six of eight studies reporting LTP outcomes.[6] [8] [9] [10] [14] [18] Dosing was reported as mean VWF:RCo IU per infusion, weekly dose, and median dose to treat NSB events ([Supplementary Table S8], available in the online version).

One case of intermittent prophylaxis was reported[6]; therefore, no efficacy data are presented for intermittent prophylaxis (case discussed in [Supplementary Results], available in the online version).

Eight studies evaluated the efficacy of pdVWF/FVIII for SP. There were variations between studies in surgical procedure category classification and hemostatic efficacy evaluation ([Supplementary Table S7], available in the online version). The proportion of procedures for which the overall hemostatic efficacy was rated as excellent/good ranged from 75 to 100% ([Table 2]). Hemostatic efficacy was reported according to VWD type in one study, in which hemostatic efficacy was excellent/good in 100% of cases in all types studied (types 1 [N = 32], 2A, [N = 13], 2B [N = 4], and 3 [N = 9]).[17] Pooled hemostatic efficacy scores for 266 procedures in 202 patients are shown in [Fig. 2C], where 97.4% of bleeds (N = 221) were resolved with excellent/good efficacy and 2.2% (N = 5) had moderate efficacy; data unavailable for 0.4% (N = 1).[6] [8] [10] [14] [15] [16] [17] [18] Five publications reported consumption data for pdVWF/FVIII for SP,[10] [11] [13] [16] [17] although reporting of loading doses, duration of treatment, and use of adjunctive therapy varied ([Supplementary Table S8], available in the online version). Mean preoperative loading doses were adapted according to surgical procedure severity, with a higher mean dose in major procedures compared to minor (69.6–175.2 IU VWF:RCo/kg and 79.2–96 IU VWF:RCo/kg, respectively; [Supplementary Table S8] [available in the online version]).[10] [16] [17] Use of adjunctive therapies in surgical events, such as tranexamic acid (TXA) or other antifibrinolytics, was reported in four studies.[10] [13] [16] [17]

Safety Outcomes

Safety outcomes for OD, LTP, and SP treatment regimens are summarized in [Table 3]. There were differences in safety evaluation between studies, such as variation in patient follow-up time and reporting of AEs.

Table 3 Safety outcomes for on-demand treatment of bleedings, long-term prophylaxis, and surgical prophylaxis with pdVWF/FVIII

On-demand treatment of bleeds
Study name and identifiers			SWIFT-VWD		SWIFTLY-VWD	SWIFT-VWDext	CSL-12-83		OPALE
Primary reference	Dunkley et al (2010)[10]	Howman et al (2011)[16]	Lissitchkov et al (2017)[6]		Auerswald et al (2020)[8]	Lissitchkov et al (2020)[9]	EudraCT 2013-003305-25[11]		Harroche et al (2021)[15]	d'Oiron et al (2022)[12]
Patient number, N	5	24	21		12	7	11		3	29
Time of exposure, days	[a]	NR	NR		8 (1–36)	NR	NR		NR	NR
Patients with any AE, n (%)	NR	NR	13 (62)		9 (69)	7 (100)	7 (64)		NR	0
Treatment-related			NR		1	NR	0
Patients with any SAE, n (%)	NR	NR	NR		0	3 (43)	1 (9)		NR	0
Treatment-related			0		0	NR	0
Patients with treatment discontinuation due to AE, n (%)			0		0	0	NR		NR	0
Patients with AE of interest, n (%)							NR		NR	0
Severe hypersensitivity reactions	NR	0	0		0	0
Thrombotic events	0	0	0		0	0
Long-term prophylaxis
Study name and identifiers			SWIFT-VWD		SWIFTLY-VWD	SWIFT-VWDext	CSL-12-83	OPALE
Primary reference	Dunkley et al (2010) [10]	Howman et al (2011) [16]	Lissitchkov et al (2017) [6]		Auerswald et al (2020) [8]	Lissitchkov et al (2020) [9]	EudraCT 2013-003305-25 [11]	Rugeri et al (2021) [13]	Harroche et al (2021) [15]	Rugeri et al (2022) [14]
			LTP arm	LTP-Switch arm
Patient number, N	4	2	1	8	4	10	14	12	7	23
Time of exposure, days, median (range)	[b]	NR	NR	NR	129 (55–197)	NR	NR	NR	NR	NR
Patients with any AE, n (%)	NR	NR	1 (100)	3 (38)	3 (75)	7 (70)	12 (86)	1 (8)	NR	0
Treatment-related			17	2	1	NR	1 (7)	0		0
Patients with any SAE, n (%)			0	1 (12)	0	0	1 (7)	NR		0
Treatment-related			NR	0	NR	NR	NR			0
Patients with treatment discontinuation due to AE, n (%)	NR	NR	0	0	0	0	NR	NR	NR	0
Patients with AE of interest, n (%)	NR		NR	NR			NR	NR	NR	NR
Severe hypersensitivity reactions		0			0	0		NR	NR	0
Thrombotic events	0	0	0	0	0	0		0	NR	0
Surgical prophylaxis
Study name and identifiers				SWIFT-VWD	OPALE
Primary reference	Dunkley et al (2010) [10]	Howman et al (2011) [16]	Shortt et al (2007) [17]	Lissitchkov et al (2017) [6]	Harroche et al (2021) [15]	Rugeri et al (2021) [13]
Patient number, N	19	31	43	4	9	66
Time of exposure, days, median (range)	[c]	3 (1–24)	NR	NR	NR	1 (1–8)
Patients with any AE, n (%)	NR	NR	NR	NR	NR	6[d]
Treatment-related			0			NR
Patients with any SAE, n (%)			NR
Treatment-related			0
Patients with treatment discontinuation due to AE, n (%)	NR	NR	NR	NR	NR	NR
Patients with AE of interest, n (%)
Severe hypersensitivity reactions		0
Thrombotic events	0	0		0		1

Abbreviations: AE, adverse event; NR, not reported; SAE, serious adverse event.

^a Reported median exposure (range): 2 (1–10) days.

^b Only reported median (range) treatment duration: 62 (53–197) days.

^c Reported median (range) exposure: 7.5 (3–24) and 2 (1–8) days in major and minor procedures, respectively.

^d 6 AEs reported, not N patients.

Seven publications reported safety outcomes for OD treatment of bleedings, eight reported safety outcomes for LTP, and five for SP ([Table 3]). The incidence of AEs and serious AEs (SAEs) varied from 0 to 100% and 0 to 43% of treated patients, respectively ([Table 3]). In studies reporting these data, no patient discontinued treatment due to an AE and no thromboembolic events (TEEs) were reported during patient follow-up.

Eight studies reporting LTP evaluated the safety of pdVWF/FVIII for prophylactic treatment ([Table 3]), where reported AE incidence ranged from 0 to 100% of patients. No patient discontinued LTP treatment due to an AE and no TEEs were reported during patient follow-up.

Five study reports evaluated the safety of pdVWF/FVIII for SP ([Table 3]). Six AEs were reported in the OPALE surgery study population of 66 patients.[13] No treatment-related AE or SAE was reported during follow-up in the study from Shortt et al.[17] From three studies that reported TEE incidence, only one case of deep vein thrombosis (DVT) was reported, occurring 10 days after the last infusion of pdVWF/FVIII and classified by the investigator as unrelated to treatment (case discussed in [Supplemental Results] [available in the online version]).[13]

Pooled safety data for OD treatment of bleedings, LTP, and SP are summarized in [Table 4]. Approximately one-third of patients treated with pdVWF/FVIII with OD or LTP regimen had an AE (33 and 35%, respectively), although a quarter of AEs were considered treatment-related with LTP (27%) and only 1% of AEs were treatment related for OD ([Table 4]). The AE rate was much lower in SP (4%). Patients with any SAE was low for all regimens, where 4, 3, and 0% of patients experienced SAEs with OD, LTP, and SP regimens, respectively. No SAEs were considered treatment-related. No hypersensitivity reactions were reported across 350 patients included in the pooled clinical trial safety data, and only one thrombotic event occurred with SP regimen.

Table 4 Pooled safety data for on-demand treatment of bleedings, long-term prophylaxis, and surgical prophylaxis with pdVWF/FVIII

Pooled safety data	On-demand	Long-term prophylaxis	Surgical prophylaxis
Patient number, N	109	78	163
Patients with any AE, n (%)	36 (33)	27 (35)	6 (4)
Treatment-related	1 (1)	21 (27)	0
Patients with any SAE, n (%)	4 (4)	2 (3)	0
Treatment-related	0	0
Patients with AE of interest, n (%)	0	0
Severe hypersensitivity reactions			0
Thrombotic events			1 (1)[a]

Abbreviations: AE, adverse event; SAE, serious adverse event.

^a DVT deemed unrelated to treatment, case report included in [Supplementary Results] (available in the online version).

Pharmacovigilance Data

Pharmacovigilance Data Reported in Clinical Trials

The clinical trial program for pdVWF/FVIII included 246 patients with hemophilia A or VWD ([Table 5]). A total of 34 SAEs were reported in 24 cases; including cases from trials reported within this review. Five case reports from clinical trial populations described a total of five AEs (all serious) specifically pertaining to development of inhibitors; all were FVIII inhibitors. Four of these cases were reported within hemophilia A clinical trial populations.[19] [20] The fifth case was a patient with type 3 VWD with a low responding inhibitor noted after 4 years of prophylaxis; this patient was excluded from the dosing and efficacy analyses of the study.[16]

Table 5 Pharmacovigilance surveillance data

Pharmacovigilance data reported in postmarketing surveillance
Total clinical trial population ( N ) [a]	246
Reported cases ( N )	24
Serious adverse events ( N )	34
Anti-FVIII inhibitors ( N )	5
Hemophilia A patients (n)	4
VWD patients (n)	1[b]
Thromboembolic events (TEE; N )	1
Incidence of TEEs in study population (%)	0.41
Ischemic stroke (n)	1[c]
Hypersensitivity and/or anaphylaxis	0
Incidence of hypersensitivity in study population (%)	0.00
Transmission of infectious agents ( N )	2[d]
Incidence of transmission of infectious agents in study population (%)	0.82
Pharmacovigilance data reported in postmarketing surveillance
Doses of pdVWF/FVIII administered
IU VWF	3,300,753,000
IU FVIII	1,375,313,750
Single-dose exposures	916,875
Patient years[e]	5,877
Reported cases (N)	241[f]
Adverse drug reactions (ADRs; N)	494
Case reports specific to Voncento/Biostate (n)	158
ADRs specific to Voncento/Biostate ( n )	392
Anti-FVIII/VWF inhibitors
Reported cases ( N )[g]	9
Anti-FVIII/VWF inhibitors ADRs ( N ) [h]	11
Proportion of inhibitor ADRs relative to total ADRs (%)	2.8
Nonserious ADRs (n)	1
Serious ADRs (n)	10
Anti-FVIII inhibitors (n)	10
Serious ADRs	9
Nonserious ADRs	1
Anti-VWF inhibitors (n)	1
Serious ADRs	1
Nonserious ADRs	0
Thromboembolic events (TEE)
Reported cases ( N )	5
TEE ADRs ( N )	5
Proportion of TEE ADRs relative to total ADRs (%)	1.28
Nonserious ADRs (n)	0
Serious ADRs (n)	5
Deep vein thrombosis	2
Pelvic venous thrombosis	1
Pulmonary embolism	2
Hypersensitivity reactions
Reported cases ( N )	34
Hypersensitivity ADRs ( N )	62
Proportion of hypersensitivity ADRs relative to total ADRs (%)	15.82
Nonserious ADRs (n)	28
Serious ADRs (n)	34
Anaphylaxis (n)	7
Transmission of infectious agents (TIA)
Reported cases ( N )	1
TIA ADRs ( N )	1
Proportion of TIA ADRs relative to total ADRs (%)	0.26
Viral infection (n)	1

Abbreviations: ADR, adverse drug reaction; FVIII, factor VIII; SLR, systematic literature review; VWD, von Willebrand disease VWF; von Willebrand factor.

^a Includes hemophilia A and VWD.

^b Type 3 VWD.

^c Not a case from a clinical trial within this SLR and not related to the use of pdVWF/FVIII.

^d Epstein–Barr virus infection and comprised a total of two AEs in one patient, not confirmed to be associated with pdVWF/FVIII complex.

^e Using 1,500 IU FVIII/3,600 IU VWF as standard dose per single administration.

^f Includes remaining 83 cases with 102 ADRs pertaining to Human Factor VIII VWF (generic) that were excluded.

^g Hemophilia A and VWD indication was not available.

^h In one case, two serious ADRs of both FVIII inhibition and VWF inhibition were reported.

Out of a total clinical exposure of 246 patients, one serious case of ischemic stroke deemed unrelated to pdVWF/FVIII administration was reported within pharmacovigilance reporting of clinical trials but was not part of the studies included in this review. No case reports pertaining to hypersensitivity and/or anaphylaxis were identified from clinical trials. One serious case of transmission of infectious agents reported an Epstein–Barr virus infection, comprising two AEs in one patient; however, the virus transmission was not confirmed to be associated with pdVWF/FVIII administration.[20]

Pharmacovigilance Data Reported in Postmarketing Surveillance

From first marketing authorization in 2000 until May 31, 2023, 1,375,313,750 IU of FVIII (representing 3,300,753,000 IUs VWF) were sold globally corresponding to 916,875 single-dose exposures, or 5,877 patient-years (using 1,500 IU FVIII/3,600 IU VWF as standard dose per single administration; [Table 5]). A total of 241 case reports for pdVWF/FVIII with 494 ADRs were received. Of these, 150 cases with 378 ADRs pertain specifically to Voncento/Biostate; cases pertaining to Human Factor VIII VWF (generic) were excluded.

The number of case reports associated with the development of FVIII/VWF inhibitors was nine and described a total of 11 ADRs (10 serious, one nonserious); there was only one event of VWF inhibition.[21]

Cumulatively, five serious cases of TEEs for pdVWF/FVIII were reported; two within the OPALE noninterventional study (one case unpublished),[13] the other three reported spontaneously. A total of 34 cases reported 62 ADRs (34 serious, 28 nonserious) pertaining to hypersensitivity reactions. The most common hypersensitivity ADRs were mild (rash, urticaria, hypersensitivity, angioedema). Seven cases described anaphylactic reactions. One case report was received for transmission of infectious agents pertaining to pdVWF/FVIII and reported a viral infection, presumed to be mumps. This infection was attributed to a mumps outbreak in the region where the patient lived and hence did not present a transmission of an infectious agent associated with pdVWF/FVIII.

Discussion

This systematic review summarizes eight individual study cohorts from 11 publications where pdVWF/FVIII was used in treatment of adults and children with inherited VWD, and reports over 20 years of pharmacovigilance surveillance data for the first time.

Most of the included clinical trial publications reported single-arm interventional studies, with four reporting main phase II/III clinical trials.[6] [8] [9] [10] All study cohorts met the European Medicines Agency guidelines for appropriate study population size for trials in VWD (≥12 patients with severe VWD, including six with type 3 VWD [most severe]).[22] Pediatric and adult patients were included in most studies, with approximately half of patients being female.

For patients treated OD, the bleeding pattern tended toward mucosal and mild bleeding events, with the majority of events being spontaneous, as expected in VWD.[1] [23] Prophylactic treatment was reserved for patients with severe phenotypes and recurrent bleeding history, in line with current treatment guidelines.[2] Although annualized bleeding rate may be considered a valuable outcome to assess prophylaxis efficacy, this was only included in three studies.[6] [11] [13]

Overall, hemostatic efficacy for pdVWF/FVIII treatment was rated good/excellent in 96.8, 96.0, and 97.4% of patients for the OD, LTP, and SP regimens, respectively. This agrees with a previously published survey, where overall hemostatic efficacy for pdVWF/FVIII was excellent/good in 90 to 100% of cases receiving SP.[24] Hemostatic efficacy according to the VWD type was inconsistently reported, although no obvious differences in responses by type were reported.

This review included studies of intermittent prophylaxis; however, only one case was reported within an LTP cohort as “monthly prophylactic dosing”.[6] Consumption data reporting varied between studies, with doses being reported per event, per infusion or per patient, making comparisons difficult. Preoperative loading doses were also inconsistently reported, although doses were in line with guidelines at the time of the study.[25]

Safety data were heterogeneously reported across studies but the rate of SAEs was low with no cases of severe hypersensitivity reactions, in agreement with previous studies with similar products.[24] [26] The only TEE reported from 307 clinical trial patients within this review was a DVT, and was classified as unrelated to treatment.[13]

Pharmacovigilance data summarized key risks associated with pdVWF/FVIII treatment including development of FVIII/VWF inhibitors, TEEs, hypersensitivity reactions including anaphylaxis, and transmission of infectious agents. Of 11 ADRs that identified the development of inhibitors, the majority were to FVIII and one case reported alloantibodies to VWF in a type 3 VWD patient.[21] It was not always possible to discern whether FVIII inhibitors were in patients with hemophilia A or VWD. The pharmacovigilance findings agree with published literature, where inhibitors against FVIII are more common than those against VWF,[27] developing in approximately 30% of previously untreated patients with hemophilia A.[27] The majority of VWD patients that develop inhibitors to VWF are those with partial or complete VWF gene deletions.[1] [28] [29] VWF alloantibodies have been reported in approximately 10 to 15% of type 3 VWD patients who have received multiple transfusions[30] [31]; where type 3 VWD prevalence is <10% of all VWD cases.[28] Risk factors for inhibitor development include patient- and treatment-related factors,[32] [33] including genetics, positive family history for inhibitors, FVIII genotype, polymorphisms in immune modulatory genes, intensity of FVIII treatment, severity of disease, and number of exposure days.[34]

Three instances of TEEs were reported in pharmacovigilance surveillance, two were reported in the OPALE study, and were considered not caused by treatment,[13] continuing to support a low TEE incidence with pdVWF/FVIII administration (an incidence of 0.82% in pharmacovigilance data from clinical studies). The annual incidence of venous thromboembolism in the general population is estimated to be 0.44 per 1,000 person-years in males and 0.55 per 1,000 person-years in females[35]; risk increases with age where TEE incidence varies between 1 per 10,000 person-years in childhood to 1% in the elderly.[36] [37] [38] Risk factors for TEEs include increased FVIII levels and it is recommended to monitor FVIII:C in patients undergoing surgery or receiving multiple pdVWF/FVIII doses.[2]

Potential transmission of infectious agents is a known class effect of blood/plasma-derived products.[39] One report for transmission was received in postmarketing surveillance in addition to one reported in clinical trials. However, transmission of infectious agents was not confirmed in any case and there was no indication that viruses were transmitted via the product. One case of viral infection, presumed to be mumps, was considered attributable to an outbreak in the patient's local region. The manufacturing process for pdVWF/FVIII includes two dedicated virus inactivation steps: solvent detergent treatment and dry heat treatment.[8] These steps are considered effective for enveloped viruses such as human immunodeficiency virus, hepatitis B and hepatitis C, and the nonenveloped virus hepatitis A, yet may have limited value against nonenveloped viruses such as parvovirus B19.[40]

The authors have several reflections for further work to bridge literature gaps. Monitoring of factor levels following pdVWF/FVIII administration for surgery was not included in most studies. Adjunctive therapy was not reported according to VWD type; therefore, it was unclear whether these therapies were administered according to guidelines.[2] Intermittent prophylaxis was not studied as an outright treatment regimen and only one case was reported within an LTP cohort.[6] Cases of HMB treated with an OD regimen reported moderate hemostatic efficacy in a separate study.[8] The authors identify particular knowledge gaps in treatment of HMB with pdVWF/FVIII. The included studies did not report dosing per menstruation and no data were found on the use of adjunctive therapies such as TXA or hormonal therapies. This may be due to the search strategy employed, as pdVWF/FVIII is not a first-line therapy for women with HMB.[2]

The authors note several limitations of this review. First, only observational studies and nonrandomized, noncontrolled trials, mostly of single-arm design, were included. Second, although pdVWF/FVIII is predominantly used for patients with inherited VWD, the product label also includes hemophilia A[5] and limitations in pharmacovigilance reporting methods meant that the indication was not specified for the reported ADRs.

In conclusion, this systematic literature review constitutes a comprehensive summary of the interventional and noninterventional studies conducted to evaluate the use of pdVWF/FVIII. Hemostatic efficacy was rated as excellent/good in the majority of patients across all studies, in all treatment regimens, for all bleeding types and severity and across all VWD types and no treatment-related SAEs were reported. These results confirm the long-term efficacy and safety of pdVWF/FVIII when used for OD, LTP, and SP treatment regimens in adult and pediatric patients with VWD of all types.

LTP, long-term prophylaxis; OD, on demand; pdVWF/FVIII, plasma-derived human coagulation FVIII/human VWF; SP, surgical prophylaxis; VWD, von Willebrand disease; VWF, von Willebrand factor.

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