Results

Patient disposition and demographics

In the phase 3 study, 25 eligible patients (female, n = 15 [60%]; male, n = 10 [40%]) were enrolled in the on-demand treatment arm, received ≥1 dose of rVWF, and were included in the SAS (Figure 1) (≥12 to <18 years, n = 9 [36%]; ≥6 to <12 years, n = 11 [44%]; <6 years, n = 5 [20%]). The numbers of patients with VWD types 1, 2, and 3 were 5 (20%), 9 (36%), and 11 (44%), respectively. Eighteen of the 25 patients who experienced ≥1 bleeding event that was treated with rVWF were included in the FAS. Baseline characteristics are shown in Table 1 for the SAS and in Supplementary Table 3 for the FAS. Distribution of VWD types by age cohort in the SAS is shown in Table 2. Twenty-four patients completed the study after a treatment period of ∼12 to 17 months. One patient discontinued the study at 10.5 months because of the physician’s decision to start prophylaxis.

Figure 1: Patient disposition. aAll enrolled patients who received any infusion of recombinant von Willebrand factor. bAll enrolled patients met all eligibility criteria, had received any amount of study drug, and provided ≥1 hemostatic assessment within 24 hours of a study drug infusion. cAll patients who completed the required washout, received an on-demand infusion followed by PK analysis, were not actively bleeding at the time of the recombinant von Willebrand factor infusion, were not bleeding during the PK assessment, and had ≥1 quantifiable postdose measurement. PK, pharmacokinetic.

Characteristic | Phase 3 study (N = 25) | Phase 3b rollover pediatric OD treatment cohort (N = 16)
Age (y)
Mean (SD) | 10.2 (5.2) | 10.4 (5.4)
Median (range) | 11.0 (1-17) | 10.5 (2-18)
Age category
18 y | 0 | 2 (13)
≥12 to <18 y | 9 (36) | 6 (38)
≥6 to <12 y | 11 (44) | 5 (31)
<6 y | 5 (20) | 3 (19)
Sex
Female | 15 (60) | 9 (56)
Male | 10 (40) | 7 (44)
Female patient of childbearing potentiala
Yes | 6 (40) | 3 (33)
VWD type
1 | 5 (20) | 4 (25)
2A | 6 (24) | 1 (6)
2B | 3 (12) | 3 (19)
3 | 11 (44) | 8 (50)
Body mass index (kg/m2)
Mean (SD) | 20.2 (6.3) | 21.7 (7.8)
Median (range) | 18.6 (12.8-40.7) | 19.9 (13.4-40.6)
Raceb
White | 21 (91) | 14 (93)
Asian | 1 (4) | 0
Multiple | 1 (4) | 1 (7)
Not reported | 2 | 1
Ethnicityb
Hispanic or Latino | 3 (13) | 1 (7)
Not Hispanic or Latino | 21 (88) | 14 (93)
Not reported | 1 | 1

VWD type, n (%) | Phase 3 study (N = 25) | Phase 3b rollover pediatric OD treatment cohort (N = 16)a
Age ≥12 to <18 y (n = 9) | Age ≥6 to <12 y (n = 11) | Age <6 y (n = 5) | Age ≥12 to ≤18 y (n = 8) | Age ≥6 to <12 y (n = 5) | Age <6 y (n = 3)
1 | 0 | 2 (18) | 3 (60) | 1 (13) | 0 | 3 (100)
2A | 4 (44) | 2 (18) | 0 | 1 (13) | 0 | 0
2B | 1 (11) | 2 (18) | 0 | 2 (25) | 1 (20) | 0
3 | 4 (44) | 5 (45) | 2 (40) | 4 (50) | 4 (80) | 0

Of the 24 patients who completed the on-demand treatment arm of the phase 3 study, 19 transitioned into the phase 3b study and continued for up to 3 additional years in the rollover on-demand treatment cohort (see further for phase 3b study results).

Hemostatic efficacy

Overall, in the phase 3 study, 104 nonsurgical BEs (minor/mild, n = 48; moderate, n = 31; major/severe, n = 2; unknown severity, n = 23) were treated with rVWF (without or with rFVIII) in 18 patients in the on-demand treatment arm. BEs were categorized as traumatic (52 BEs [50%]), spontaneous (33 BEs [32%]), menstrual (11 BEs [11%]), and unknown (8 BEs [8%]). Of 104 treated bleeds, 57 (55%) were reported in patients aged ≥12 to <18 years, 37 (36%) in patients aged ≥6 to <12 years, and 10 (10%) in patients aged <6 years. Fifty (48%) of the total 104 bleeds were reported in patients with type 3 VWD (Table 3). Most BEs were mucosal (nasopharyngeal, mouth/oral cavity, and menstrual/menorrhagia; 51 BEs; 49%) or joint bleeds (17 BEs; 16%) (Supplementary Table 4).

Parameter | Full analysis set (N = 18) | Age group (y) | VWD type
≥12 to <18 (n = 6) | ≥6 to <12 (n = 9) | <6 (n = 3) | Type 1 (n = 2) | Type 2A (n = 3) | Type 2B (n = 2) | Type 3 (n = 11)
Treated nonsurgical bleeding events (n) | 104 | 57 | 37 | 10 | 12 | 37 | 5 | 50
Bleeding events per patient
Mean (SD) | 5.8 (5.0) | 9.5 (6.9) | 4.1 (2.7) | 3.3 (0.6) | 6.0 (4.2) | 12.3 (9.5) | 2.5 (0.7) | 4.5 (2.3)
Median (Q1, Q3) | 4.0 (3.0, 7.0) | 7.5 (5.0, 12.0) | 3.0 (2.0, 6.0) | 3.0 (3.0, 4.0) | 6.0 (3.0, 9.0) | 12.0 (3.0, 22.0) | 2.5 (2.0, 3.0) | 4.0 (3.0, 6.0)
Treatment successa
n (%) | 18 (100) | 6 (100) | 9 (100) | 3 (100) | 2 (100) | 3 (100) | 2 (100) | 11 (100)
95% CI | 81.5-100 | 54.1-100 | 66.4-100 | 29.2-100 | 15.8-100 | 29.2-100 | 15.8-100 | 71.5-100
Efficacy rating score per patient
Mean (SD) | 1.01 (0.04) | 1.00 (0.00) | 1.02 (0.06) | 1.00 (0.00) | 1.00 (0.00) | 1.00 (0.00) | 1.00 (0.00) | 1.02 (0.05)
Median (Q1, Q3) | 1.0 (1.0, 1.0) | 1.0 (1.0, 1.0) | 1.0 (1.0, 1.0) | 1.0 (1.0, 1.0) | 1.0 (1.0, 1.0) | 1.0 (1.0, 1.0) | 1.0 (1.0, 1.0) | 1.0 (1.0, 1.0)
Bleeding events with efficacy rating of good/excellent
Bleeding events with a known efficacy rating (n) | 98 | 52 | 36 | 10 | 12 | 32 | 5 | 49
n (%)b | 98 (100) | 52 (100) | 36 (100) | 10 (100) | 12 (100) | 32 (100) | 5 (100) | 49 (100)
95% CI | 96.3-100 | 93.2-100 | 90.3-100 | 69.2-100 | 73.5-100 | 89.1-100 | 47.8-100 | 92.7-100

The primary end point of treatment success was achieved in all 18 (100%) patients (95% CI, 81.5-100.0). The mean (SD) efficacy rating score according to a predefined 4-point scale was 1.01 (0.04), and the mean (SD) number of treated BEs per patient was 5.8 (5.0) (Table 3). The secondary end point, based on individual BE assessments, showed treatment hemostatic efficacy for all 98 (100%) BEs with nonmissing ratings; all reported efficacy ratings were assessed as either excellent or good, with excellent being reported for the majority (99%) of BEs. Efficacy results were consistent across age groups, VWD types, bleeding severity categories, and BE locations (Figure 2 and Supplementary Table 4).

Figure 2: Hemostatic efficacy ratings by BE in the phase 3 study (FAS). Efficacy ratings were available for 98 of 104 treated BEs. Percentages are based on BEs with known hemostatic efficacy ratings. BE, bleeding event; FAS, full analysis set; VWD, von Willebrand disease.

Drug consumption

In the phase 3 study, most BEs (82%) resolved with 1 infusion of rVWF, with a similar percentage in each age group (Table 4). The median (range) total dose of rVWF per event was 51.0 (17.6-365.9) IU/kg. This total dose was notably higher in patients aged <6 years driven by 1 outlier. This individual experienced 2 moderate joint BEs in the left ankle (1 traumatic and 1 spontaneous) that were treated with 9 and 8 infusions of rVWF, respectively, including doses to maintain hemostasis after the bleeding stopped. The overall mean (SD) rVWF dose per infusion per event was 48.4 (8.1) IU/kg (median [range]: 48.5 [17.6-63.0] IU/kg) and was similar across age groups. rFVIII was administered for 28 of the 104 BEs (27%) in 7 patients (39%; VWD type 1, n = 1; VWD type 3, n = 6), all of whom received a single infusion of rFVIII per bleed. The mean (SD) total dose of rFVIII per event was 30.8 (8.6) IU/kg and was similar across age groups (Table 4). Of the 28 BEs for which rFVIII was administered, the most common locations were recorded as joints (9 bleeds) and mucosal nose (8 bleeds) (Supplementary Table 5). Fifteen of the bleeds for which treatment included rFVIII were mild, 12 were moderate, and 1 was of unknown severity (Table 4).

Parameter | Full analysis set (N = 18) | Age group (y)
≥12 to <18 (n = 6) | ≥6 to <12 (n = 9) | <6 (n = 3)
Treated nonsurgical bleeding events (n) | 104 | 57 | 37 | 10
No. of rVWF infusions per bleed, n (%)a
1 | 80 (82) | 44 (85) | 28 (78) | 8 (80)
2 | 12 (12) | 7 (14) | 5 (14) | 0
3 | 4 (4) | 1 (2) | 3 (8) | 0
>5 | 2 (2) | 0 | 0 | 2 (20)
Missing | 6 | 5 | 1 | 0
Total rVWF dose per bleed (IU/kg) | 98 bleeds | 52 bleeds | 36 bleeds | 10 bleeds
Mean (SD) | 64.4 (48.3) | 56.8 (22.6) | 62.6 (32.2) | 110.5 (124.7)
Median (range) | 51.0 (17.6-365.9) | 49.8 (17.6-145.5) | 51.9 (18.3-169.8) | 53.0 (41.2-365.9)
Average rVWF dose per infusion per bleed (IU/kg) | 98 bleeds | 52 bleeds | 36 bleeds | 10 bleeds
Mean (SD) | 48.4 (8.1) | 48.4 (7.5) | 48.0 (9.0) | 49.4 (8.0)
Median (range) | 48.5 (17.6-63.0) | 48.5 (17.6-59.7) | 51.3 (18.3-63.0) | 49.7 (40.7-62.4)
Bleeds treated with rFVIII in addition to rVWF, n (%) | 28 (27) | 15 (26) | 9 (24) | 4 (40)
Bleeds treated with 1 rFVIII infusion, n (%) | 28 (100) | 15 (100) | 9 (100) | 4 (100)
Total rFVIII dose per bleed (IU/kg) | 28 bleeds | 15 bleeds | 9 bleeds | 4 bleeds
Mean (SD) | 30.8 (8.6) | 32.2 (8.8) | 27.5 (9.7) | 32.8 (1.5)
Median (range) | 32.9 (9.1-45.0) | 35.4 (18.0-42.7) | 26.1 (9.1-45.0) | 32.9 (30.8-34.5)
 | Bleed severity
 | Minor/mild (n = 13) | Moderate (n = 13) | Major/severe (n = 2) | Unknown (n = 3)
Treated nonsurgical bleeding events (n) | 48 | 31 | 2 | 23
No. of rVWF infusions per bleed, n (%)a
1 | 37 (84) | 23 (77) | 1 (50) | 19 (86)
2 | 6 (14) | 4 (13) | 0 | 2 (9)
3 | 1 (2) | 1 (3) | 1 (50) | 1 (5)
>5 | 0 | 2 (7) | 0 | 0
Missing | 4 | 1 | 0 | 1
Total rVWF dose per bleed (IU/kg) | 44 bleeds | 30 bleeds | 2 bleeds | 22 bleeds
Mean (SD) | 55.1 (24.8) | 79.4 (75.4) | 108.4 (86.8) | 58.6 (24.5)
Median (range) | 50.6 (17.6-156.7) | 53.0 (42.7-365.9) | 108.4 (47.0-169.8) | 48.5 (46.9-145.5)
Average rVWF dose per infusion per bleed (IU/kg) | 44 bleeds | 30 bleeds | 2 bleeds | 22 bleeds
Mean (SD) | 46.4 (10.4) | 50.0 (6.2) | 51.8 (6.8) | 49.7 (3.3)
Median (range) | 47.1 (17.6-59.7) | 51.3 (37.9-62.4) | 51.8 (47.0-56.6) | 48.5 (46.9-63.0)
Bleeds treated with rFVIII in addition to rVWF, n (%) | 15 (31) | 12 (39) | 0 | 1 (4)
Bleeds treated with 1 rFVIII infusion, n (%) | 15 (100) | 12 (100) | 0 | 1 (100)
Total rFVIII dose per bleed (IU/kg) | 15 bleeds | 12 bleeds | 0 bleeds | 1 bleed
Mean (SD) | 27.6 (9.4) | 34.2 (6.2) | – | 36.3 (–)
Median (range) | 26.1 (9.1-42.7) | 34.6 (18.0-45.0) | – | 36.3 (36.3-36.3)
 | VWD type
 | 1 | 2A | 2B | 3
Treated nonsurgical bleeding events (n) | 12 | 37 | 5 | 50
No. of rVWF infusions per bleed, n (%)a
1 | 9 (75) | 31 (89) | 4 (80) | 36 (78)
2 | 2 (17) | 3 (9) | 0 | 7 (15)
3 | 1 (8) | 1 (3) | 1 (20) | 1 (2)
>5 | 0 | 0 | 0 | 2 (4)
Missing | 0 | 2 | 0 | 4
Total rVWF dose per bleed (IU/kg) | 12 bleeds | 35 bleeds | 5 bleeds | 46 bleeds
Mean (SD) | 66.9 (36.7) | 55.1 (22.1) | 76.7 (52.2) | 69.5 (63.1)
Median (range) | 53.1 (18.3-156.7) | 48.5 (17.6-145.5) | 51.9 (50.8-169.8) | 51.6 (25.5-365.9)
Average rVWF dose per infusion per bleed (IU/kg) | 12 bleeds | 35 bleeds | 5 bleeds | 46 bleeds
Mean (SD) | 49.6 (10.6) | 48.2 (6.5) | 54.0 (3.5) | 47.6 (8.7)
Median (range) | 52.2 (18.3-63.0) | 48.5 (17.6-57.9) | 51.9 (50.8-58.9) | 47.7 (25.5-62.4)
Bleeds treated with rFVIII in addition to rVWF, n (%) | 7 (58) | 0 | 0 | 21 (42)
Bleeds treated with 1 rFVIII infusion, n (%) | 7 (100) | 0 | 0 | 21 (100)
Total rFVIII dose per bleed (IU/kg) | 7 bleeds | 0 bleeds | 0 bleeds | 21 bleeds
Mean (SD) | 24.7 (8.0) | — | — | 32.8 (7.9)
Median (range) | 26.1 (9.1-36.3) | — | — | 34.5 (18.0-45.0)

PK and PD analyses

VWF plasma concentrations increased rapidly after a single infusion of 50 IU/kg rVWF. Median levels of VWF:RCo, VWF:Ag, and VWF:CB were highest at 15 minutes after infusion, decreased steadily through 12 hours, then decreased gradually to 48 hours, and remained stable through the last assessment at 96 hours (Supplementary Figure 2). Regarding PD, median levels of FVIII:C showed a trend of increase through the 30-hour assessment, reflecting stabilization of FVIII by rVWF, and then a decrease through the 96-hour assessment.

The PK/PD exposure parameters derived from combined concentration data across time points by age cohort with and without individual baseline correction were evaluated following rVWF infusions to construct an individual PK profile or to collect data on individual PK (Supplementary Table 6). Slightly lower VWF:Ag, VWF:CB, and FVIII:C levels were observed in patients aged <6 years, without causing any discernible difference in the number of infusions or average doses per kilogram administered to these patients. However, no conclusion can be drawn because of the sparse samples used in the calculation.

Safety

Overall, 122 TEAEs were reported in 23 (92%) patients, with 5 (20%) patients reporting 6 serious TEAEs (Yersinia sp. infection; obsessive-compulsive disorder; vascular device infection; pyrexia; urinary tract infection; and traumatic hematoma) (Table 5). The majority of the TEAEs were mild, with 2 (8.0%) patients experiencing 3 severe TEAEs. Only 1 TEAE (nausea; moderate severity) was considered by the investigator to be related to rVWF. No serious AEs were considered to be related to study treatment. No thromboembolic events, allergic reaction TEAEs, or severe hypersensitivity reaction TEAEs were reported. There were no deaths or TEAEs leading to treatment discontinuation. No neutralizing antibodies to VWF or FVIII; binding antibodies to VWF; or antibodies to Chinese hamster ovary proteins, murine IgG, or recombinant furin were detected.

Adverse events | Phase 3 study (N = 25) | Phase 3b rollover pediatric OD treatment cohort (N = 16)
Patients, n (%) | Events (n) | Patients, n (%) | Events (n)
Any TEAEs | 23 (92) | 122 | 15 (94) | 117
Treatment-related TEAEs |  |  |  | 
TEAEs related to rVWFa | 1 (4) | 1a | 0 | 0
TEAEs related to rFVIII | 0 | 0 | 0 | 0
TEAEs related to study procedures | 0 | 0 | 0 | 0
TEAEs temporally associated with rVWF | 9 (36) | 13 | 4 (25) | 7
TEAEs temporally associated with rFVIII | 3 (12) | 3 | 2 (25) | 3
Severity of TEAEs |  |  |  | 
Mild | 20 (80) | 81 | 14 (88) | 87
Moderate | 16 (64) | 38 | 11 (69) | 29
Severe | 2 (8) | 3 | 1 (6) | 1
Serious TEAEs | 5 (20) | 6b | 3 (19) | 5c
Treatment-related serious TEAEs | 0 | 0 | 0 | 0
TEAEs leading to treatment discontinuation | 0 | 0 | 0 | 0
Deaths | 0 | 0 | 0 | 0
TEAEs of interest |  |  |  | 
Thromboembolic events | 0 | 0 | 0 | 0
Allergic reactions to rVWF or rFVIII | 0 | 0 | 0 | 0
Severe hypersensitivity reactions | 0d | 0 | 0 | 0
TEAEs in ≥10% of patients in either the phase 3 or the phase 3b study |  |  |  | 
Pyrexia | 4 (16) | 9 | 2 (13) | 2
Upper respiratory tract infection | 4 (16) | 6 | 6 (38) | 9
Vomiting | 4 (16) | 5 | 4 (25) | 6
Cough | 3 (12) | 4 | 4 (25) | 7
Diarrhea | 3 (12) | 6 | 1 (6) | 1
Iron deficiency anemia | 3 (12) | 3 | 2 (13) | 2
Rash | 3 (12) | 3 | 0 | 0
Oropharyngeal pain | 2 (8) | 2 | 3 (19) | 3
Headache | 1 (4) | 1 | 2 (13) | 4
Iron deficiency | 1 (4) | 1 | 2 (13) | 2
Nasal congestion | 1 (4) | 1 | 2 (13) | 2
Pain in extremity | 1 (4) | 1 | 2 (13) | 2
COVID-19 | 0 | 0 | 8 (50) | 8
Coronavirus infection | 0 | 0 | 3 (19) | 3
Alanine aminotransferase increased | 0 | 0 | 2 (13) | 2
Limb injury | 0 | 0 | 2 (13) | 2
Sunburn | 0 | 0 | 2 (13) | 2
Viral infection | 0 | 0 | 2 (13) | 2

Phase 3b study rollover on-demand treatment cohort

In the phase 3b rollover pediatric on-demand treatment cohort of the continuation study, 16 of 19 rollover patients received study drug for on-demand treatment during the study and were included in the SAS and FAS (Figure 1). Baseline characteristics for patients in the rollover cohort are shown in Table 1 and Supplementary Table 3. In the 16 treated patients, a hemostatic efficacy rating of excellent or good was achieved for 100% of 166 treated BEs with nonmissing ratings, and efficacy was consistent across all 3 age groups. BEs were treated with a mean (SD) of 1.1 (0.7) infusions of rVWF per bleed (without or with rFVIII) (Supplementary Table 7). rFVIII was administered in addition to rVWF for 46 of 167 treated BEs (28%) in 7 patients. All cases in the continuation study used 1 or 2 rFVIII infusions per bleed (mean [SD]: 1.1 [0.25]).

Among the 16 treated rollover patients, 15 (94%) patients reported 117 TEAEs, with 3 (19%) patients reporting 5 serious TEAEs (fall, medical device site extravasation, coronavirus infection, hypotension, and spinal compression fracture) (Table 5). None of the reported TEAEs were considered to be related to study treatment. No thromboembolic events, allergic reaction TEAEs, or severe hypersensitivity reaction TEAEs were reported. No neutralizing antibodies to VWF or FVIII; binding antibodies to VWF; or antibodies to Chinese hamster ovary proteins, murine IgG, or recombinant furin were detected. One patient in the continuation study tested positive for binding IgG antibody to FVIII at month 18 before the first rVWF treatment in this study and then after treatment at the month 24, month 33, and end of study visits. The patient did not receive rFVIII during the study and the FVIII-binding IgG antibody did not have a notable impact on the efficacy and safety responses in this patient. rVWF remained efficacious for this patient: a hemostatic efficacy rating of excellent was achieved for the treatment of BEs that the patient experienced (2 BEs; both moderate severity).