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Introduction: The phase 2/3 PROTECT VIII study demonstrated long-term efficacy and safety of damoctocog alfa pegol (BAY 94-9027; Jivi®), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to improve its pharmacokinetic profile. We report a post hoc assessment of bleeding and safety outcomes in the subgroup of patients, aged 12–<18 years at enrolment. Method: PROTECT VIII was a multicentre, open-label study of previously treated males aged 12–65 years with severe haemophilia A (FVIII <1%). Twelve patients were included in this analysis. All received damoctocog alfa pegol prophylaxis for the total time in study (median [range] time in study 4.0 [1.3–6.2] years). Results: Overall median (Q1; Q3) total and joint annualised bleeding rates were 1.8 (0.4; 5.1) and 0.7 (0.2; 1.8), respectively, for the entire study. During the last 6 months of treatment, eight (66.7%) and ten (83.3%) out of 12 patients experienced zero total and joint bleeds, respectively. No patient developed FVIII inhibitors. No deaths or thrombotic events were reported. Conclusion: Efficacy and safety of damoctocog alfa pegol were confirmed in adolescent patients with haemophilia A, with data for up to 6 years supporting its use as a long-term treatment option in this group as they transition into adulthood.

This research article gives further information about how well damoctocog alfa pegol works, and how safe it is, in those patients who were aged twelve to less-than-eighteen (“adolescents”) when they joined the PROTECT VIII clinical trial in patients 12–65 years with haemophilia A. People living with haemophilia A lack a part of their blood that normally allows clots to form. Damoctocog alfa pegol is a replacement for this missing “clotting factor”; it has also been altered to allow it to stay in the body for longer than other clotting factors, allowing for less frequent infusions. As children become adolescents and begin to manage their own factor replacement, rather than being helped by parents or others who take care of them, a treatment with less infusions is easier to follow. A clotting factor that stays in the body for longer, like damoctocog alfa pegol, might be useful for these adolescent patients. There were twelve people who were adolescents when they joined the PROTECT VIII trial. They spent an average of 4 years in the trial and had on average 1.8 bleeds every year. During the last 6 months of treatment, 8 patients had no bleeds. No study-drug-related serious adverse events were seen, no patient stopped treatment due to an adverse event, no deaths happened and no patients became immune to the treatment. This young, active patient group may benefit from the longer and more flexible dosing offered by damoctocog alfa pegol.

Replacement therapy with factor VIII (FVIII) concentrates is the long-established standard of care for patients with haemophilia A, successfully improving bleeding outcomes and thereby preventing joint damage when delivered as prophylaxis [1, 2]. Furthermore, individualised prophylaxis is now considered the optimal treatment approach, as it takes into account individual patient needs, lifestyles, pharmacokinetic parameters, and bleeding phenotypes, to provide greater cost-effectiveness and superior outcomes compared with fixed prophylactic regimens [3].

Paediatric patients with haemophilia A are typically dosed by parents or a nurse, and the transition to self-infusion in adolescence can lead to lower adherence rates [4]. Data on adherence in children and adolescents vary between studies [5], but a drop from high adherence during transition to self-infusion is common [6‒8]. A global survey of more than 16,000 patients with haemophilia A reports that very high adherence (defined as >90% adherent) drops from 59% in children aged under 13 years to 13% in patients aged 13–18 years, and further to 6% in patients aged 19–28 years [9]. Lower adherence at these age junctions is attributed to a range of factors that uniquely affect this age group, including reduced parental supervision compared with childhood, changes to or issues with insurance, and denial or lack of knowledge about the benefits of treatment and consequences of nonadherence [10]. A cross-sectional US study has shown that among adult patients who received prophylaxis during adolescence, nearly 20% switched to on-demand treatment upon reaching early adulthood, coinciding with moving away from home or other major changes in living situation [4], or difficulties with navigating the healthcare system to maintain their health insurance [7, 10]. Early engagement of adolescents in the initial transition from the paediatric to adult model of care is thus considered beneficial, allowing time for increased awareness, acceptance of responsibility, and support of both patients and families [11]. As such, this subpopulation in particular may benefit from a tailored prophylaxis regimen that can maintain sufficient levels of clotting factor with an acceptable infusion frequency and additional considerations for physical activity level and perceived risk of injury. In addition, commitment to long-term prophylaxis is essential for achieving optimal clinical outcomes [3].

Damoctocog alfa pegol is a recombinant FVIII (rFVIII) product, site-specifically conjugated to a single, dual-branched 60 kDa polyethylene glycol (PEG) molecule (two 30 kDa PEG) to reduce clearance and prolong its time in circulation. This extended half-life (∼19 h vs. 13 h standard sucrose-formulated rFVIII) [12], combined with an individually tailored regimen, has successfully allowed for reduced dosing frequency while maintaining effective prophylaxis treatment [13].

Results from the PROTECT VIII (NCT01580293) trial and its extension (up to 7.0 years of damoctocog alfa pegol prophylaxis) demonstrated the efficacy and safety of damoctocog alfa pegol for the prevention and treatment of bleeding episodes in adults and adolescents with severe haemophilia A, at dose intervals of up to every 7 days [13, 14]. In addition, damoctocog alfa pegol has demonstrated improved pharmacokinetic profiles compared with other extended half-life FVIII products, rFVIIIFc (Elocta®/Eloctate®) and rurioctocog alfa pegol (BAX 855, Adynovi®/Adynovate®), in head-to-head, crossover studies [15, 16]. Here, we describe the efficacy and safety of damoctocog alfa pegol in a group of adolescent patients with haemophilia A, who were aged 12–<18 years at the time of their enrolment into PROTECT VIII.

Patients

Inclusion criteria for PROTECT VIII have been described elsewhere [13, 14]. Briefly, patients were male, aged 12–65 years with severe haemophilia A (FVIII <1%) and ≥150 FVIII exposure days. Patients aged 12–<18 years at the time of enrolment into the PROTECT VIII main study were included in this post hoc subgroup analysis.

Study Design

The design, patient eligibility, treatment schedule, and statistical analyses for PROTECT VIII and its extension study have been previously described [13, 14, 17]. PROTECT VIII was a phase 2/3, partially randomised, open-label trial evaluating the efficacy and safety of damoctocog alfa pegol. Patients with a history of inhibitors (titre ≥0.6 Bethesda units) were excluded from the trial.

At enrolment, patients selected on-demand or prophylaxis treatment. Patients receiving prophylactic therapy at the time of enrolment were only eligible for the prophylaxis arm of the study. Patients previously receiving on‐demand therapy could choose to either receive BAY 94‐9027 on demand for 36 weeks or enter the prophylaxis arm of the study. After a 10-week run-in period with 25 IU/kg twice-weekly (2×W) prophylaxis, patients with ≤1 spontaneous joint or muscle bleed were randomised to a regimen of 45–60 IU/kg damoctocog alfa pegol every 5 days (E5D) or 60 IU/kg every 7 days (E7D). Patients with >1 bleed during the run-in period and patients enrolled after the randomisation arms were full, continued a 2×W regimen of 30–40 IU/kg. The main study continued for a total of 36 weeks, including the run-in period, during which patients were treated with damoctocog alfa pegol either on-demand, or as prophylaxis with one of the regimens assigned after the run-in period and treated on-demand while having a bleed. Switching to more frequent dosing regimens was permitted in case of inadequate protection from bleeds, as determined by each patient’s treating physician.

Patients completing the main study could enter an extension, continuing damoctocog alfa pegol on the same regimen or any regimen used in the main study. At the start and at any time during the extension study, the infusion frequency and dosage could be adapted to individual needs within these prespecified groupings, as determined by the treating physician. Patients who switched after the first 7 days of the extension period were analysed as the variable frequency group.

Efficacy and Safety Assessments

Bleeding events and administered infusions were recorded by patients using an electronic patient diary. Total annualised bleeding rates (ABRs) and joint ABRs were recorded from medical records for the 12 months prior to study entry and reported through the electronic patient diary during the main and extension studies. Patients were analysed by damoctocog alfa pegol prophylaxis regimen as described above. Resolution of target joints, based on joint status as reported by the investigator at baseline, was assessed after the first 12 months of damoctocog alfa pegol treatment and again during the last 12 months of treatment. Target joint resolution was defined according to ISTH definitions as ≤2 spontaneous bleeds over a 12-month period [18]. A new target joint was defined as ≥3 spontaneous bleeds into the same joint during a 6-month period [18].

Throughout the extension study, patients were monitored at visits every 6 months for the occurrence of adverse events (AEs), which were documented in terms of type, severity, and relationship to study drug. Quantitative, free PEG levels in plasma were monitored, with a lower limit of quantification of 0.1 mg/L. Serum and urine samples were collected at baseline, at the end of the main study and throughout the extension study to measure levels of hepatic (alanine aminotransferase [ALT], aspartate transaminase) and renal (serum creatinine, and creatinine clearance calculated using the Cockcroft-Gault formula) biomarkers.

FVIII Utilisation and Adherence to Schedule

Total and prophylaxis doses of FVIII were calculated annually and per infusion during the main study and the extension study. Adherence to study treatment was calculated based on the ratio of total number of prophylaxis infusions administered to expected number of infusions per regimen.

Statistical Analyses

Statistical analysis was performed using SAS software 9.2. Summary statistics were calculated for continuous data, and frequencies were calculated for categorical data. No formal statistics were performed, and the analysis was descriptive.

Patients

In total, 134 patients were enrolled in PROTECT VIII. Of these, 13 patients were aged between 12 and <18 years at enrolment and 12 were included in this analysis (Table 1. One adolescent patient withdrew from the main study after one exposure day and was not included in the post hoc analysis [14]). The median age (range) of patients was 13.5 (12–17) years at enrolment and 18.0 (15–23) years at final visit. Prior to PROTECT VIII enrolment, 11 patients received FVIII prophylaxis and one received on-demand treatment. Ten patients (83.3%) presented with a target joint at screening, as reported by the investigator, with a median (range) number of target joints per patient of 1.0 (0–4). The median (range) total time treated with damoctocog alfa pegol (during both main and extension) was 4.0 (1.3–6.2) years, and 3.3 (0.6–5.5) years during the extension study.

Table 1.

Patient demographics

CharacteristicN = 12
Age at enrolment, median (range), years 13.5 (12–17) 
Age at end of study, median (range), years 18.0 (15–23) 
Target joints at enrolment* n (%) 10 (83.3) 
 Median per patient (range) 1.0 (0–4) 
Number of bleeds in 12 months pre-study, median (Q1; Q3) 8.0 (3; 11) 
Prior FVIII treatment, n 
 Prophylaxis 11 
 On-demand 
Dosing group in main study, n 
 2×W 
 E5D 
 E7D 
Dosing group in extension study, n 
 2×W 
 E5D 
 E7D 
 VAR 
Prophylaxis regimen during last 6 months in extension study, n 
 2×W 
 E5D 
 E7D 
CharacteristicN = 12
Age at enrolment, median (range), years 13.5 (12–17) 
Age at end of study, median (range), years 18.0 (15–23) 
Target joints at enrolment* n (%) 10 (83.3) 
 Median per patient (range) 1.0 (0–4) 
Number of bleeds in 12 months pre-study, median (Q1; Q3) 8.0 (3; 11) 
Prior FVIII treatment, n 
 Prophylaxis 11 
 On-demand 
Dosing group in main study, n 
 2×W 
 E5D 
 E7D 
Dosing group in extension study, n 
 2×W 
 E5D 
 E7D 
 VAR 
Prophylaxis regimen during last 6 months in extension study, n 
 2×W 
 E5D 
 E7D 

2×W, twice weekly; FVIII, factor VIII; Q, quartile; VAR, variable frequency.

*Reported by investigator at screening.

PROTECT VIII Prophylaxis Regimen Allocation

All 12 patients received damoctocog alfa pegol prophylaxis during the main and extension studies, and their prophylaxis regimens during the main study after randomisation and during the extension study are shown in Table 1. During the main study, 3 patients received 2×W prophylaxis, 6 patients received E5D prophylaxis, and 3 patients received E7D prophylaxis. Prophylaxis regimen switching throughout the study is shown at a patient level in Figure 1. Six (50%) patients continued with the same regimen throughout the entire study (2×W, n = 2; E5D, n = 3; E7D, n = 1). The remaining six (50%) patients switched treatment regimens in the extension. Overall, of the patients who switched regimen, 4 patients ended their time in the extension with a more frequent dosing regimen than their main study regimen (1 patient shortened interval between doses because of undetectable FVIII levels at day 7 while receiving E7D prophylaxis, the other three due to an increase in bleeding frequency) and 2 patients with a less frequent dosing regimen.

Fig. 1.

PROTECT VIII prophylaxis regimen allocation and switching throughout the study in patients aged 12–<18 years. Each row represents 1 patient. The final patient switched twice during the extension (from E5D to 2×W and back to E5D) so is therefore analysed in the variable frequency group. 2×W, twice weekly; E5D, every 5 days; E7D, every 7 days; VAR, variable frequency.

Fig. 1.

PROTECT VIII prophylaxis regimen allocation and switching throughout the study in patients aged 12–<18 years. Each row represents 1 patient. The final patient switched twice during the extension (from E5D to 2×W and back to E5D) so is therefore analysed in the variable frequency group. 2×W, twice weekly; E5D, every 5 days; E7D, every 7 days; VAR, variable frequency.

Close modal

Bleeding Outcomes

Total and Joint ABRs

Pre-study, main study and extension study total and joint ABRs are presented in Figure 2. Pre-study median (Q1; Q3) total and joint ABRs were 8.0 (3.0; 11.0) and 5.0 (0.5; 8.5), respectively. During the main study, median (Q1; Q3) total and joint ABRs were 1.0 (0.0; 7.1) and 1.0 (0.0; 5.0), respectively. During the extension study, median (Q1; Q3) total and joint ABRs were 1.3 (0.5; 4.2) and 0.6 (0.0; 0.9), respectively, and 0.0 (0.0; 2.0) and 0.0 (0.0; 1.0), respectively, during patients’ last 12 months in the extension (n = 10). Overall, median (Q1; Q3) total and joint ABRs were 1.8 (0.4; 5.1) and 0.7 (0.2; 1.8), respectively.

Fig. 2.

Total and joint ABRs during PROTECT VIII in patients <18 years of age at enrolment (N = 12). *Prior to study entry, all patients included in this analysis were on regular FVIII prophylaxis treatment, except one (on-demand FVIII treatment). ABR, annualised bleeding rate; FVIII, factor VIII; Q, quartile.

Fig. 2.

Total and joint ABRs during PROTECT VIII in patients <18 years of age at enrolment (N = 12). *Prior to study entry, all patients included in this analysis were on regular FVIII prophylaxis treatment, except one (on-demand FVIII treatment). ABR, annualised bleeding rate; FVIII, factor VIII; Q, quartile.

Close modal

Zero Bleeds

The proportions of patients with zero total and joint bleeds during their last 12 and 6 months in the extension are presented in Figure 3. Of the 10 patients who were in the extension for 12 months or more, seven (70%) reported zero total and joint bleeds during the last 12 months they were in the extension. During the last 6 months of the study, eight (66.7%) and ten (83.3%) out of 12 patients experienced zero total and joint bleeds, respectively.

Fig. 3.

Patients with zero total and joint bleeds during the last 12* and 6 months of the PROTECT VIII extension (N = 12*). *2 patients were in the extension for less than 12 months.

Fig. 3.

Patients with zero total and joint bleeds during the last 12* and 6 months of the PROTECT VIII extension (N = 12*). *2 patients were in the extension for less than 12 months.

Close modal

Target Joints

Within the first 12 months of treatment with damoctocog alfa pegol, all except one of the target joints reported by the investigator at baseline (n = 15) or that developed during the first 12 months (n = 1) resolved. The one target joint that developed during the study was in the left elbow of a patient in the variable frequency group during the extension, who completed the extension on a twice-weekly prophylaxis regimen. This patient was on prophylaxis prior to entering the main study, with one target joint (left knee) reported pre-study by the investigator. He reported a total of 23 bleeds during the full study (18 total bleeds during the extension; 16 joint bleeds during the extension and two joint bleeds during the last 12 months of the extension), with a total ABR of 5.5 during his entire time in study. During the final 12 months of treatment, all target joints reported by the investigator at baseline, and the one target joint that developed during the study, were resolved (≤2 spontaneous bleeds in 12 months) [18].

FVIII Utilisation Data

The median (range) annual total FVIII consumption was 3,721.4 (2,842.7–4,294.7) IU/kg/year in the main study and 4,083.1 (2,789.6–4,429.0) IU/kg/year during the extension. Specifically, 3,338.4 (2,643.0–4,143.9) IU/kg/year and 3,563.6 (2,702.2–4,390.0) IU/kg/year FVIII were administered for prophylaxis in the main study and during the extension with a total median (range) dose per infusion of 44.9 (36.7–57.0) IU/kg and 48.8 (37.5–61.0) IU/kg, respectively. The median (range) number of prophylaxis infusions per year was 84.0 (66.4–104.3) and 74.0 (49.7–104.1) during the main and the extension phase, respectively.

Adherence with Prophylaxis Schedule

Overall, adherence with prophylaxis schedule was >95% throughout the study. In the main and extension studies, mean adherence (standard deviation) for the 12 patients was 98.9% (4.17). Adherence for patients analysed in the 2×W (n = 3), E5D (n = 3), E7D (n = 2) and variable frequency (n = 4) groups was 97.4% (2.88), 103.0% (3.44), 96.4% (1.11), and 98.4% (5.16), respectively. An adherence value greater than 100% means that patients had a higher number of actual infusions compared with their number of expected infusions.

Safety

Treatment-emergent AEs (TEAE) during total time in study (main and extension periods) are presented in Table 2. Eleven patients experienced an AE, the majority of which were mild or moderate in intensity. One drug-related TEAE was reported by the investigator: arthrosis in the right ankle of moderate intensity, the patient increased his dose from E5D to twice-weekly following a bleed in his elbow during the study. Four serious AEs (SAE) were reported, although none were related to the study drug. No patients developed FVIII inhibitors (titre ≥0.6 Bethesda units) or PEG antibodies during the entire study, and no AE-related discontinuations or deaths occurred. During the study, transient free PEG (0.106 mg/L) in plasma, just above the lower limit of quantification, was detected in 1 patient during the extension that was no longer detectable at his final visit of the extension.

Table 2.

Treatment-emergent AEs during PROTECT VIII main study and its extension (N = 12)

Any AE, n (%) 11 (91.7) 
 Mild 4 (33.3) 
 Moderate 3 (25.0) 
 Severe 4 (33.3) 
Any study drug-related AE, n (%) 1 (8.3)* 
Any AE related to procedures as per protocol, n (%) 0 (0.0) 
AE-related deaths, n (%) 0 (0.0) 
Any SAE, n (%) 4 (33.3) 
Any study drug-related SAE, n (%) 0 (0.0) 
Any SAE related to procedures as per protocol, n (%) 0 (0.0) 
Discontinuation due to AE, n (%) 0 (0.0) 
Discontinuation due to SAE, n (%) 0 (0.0) 
Development of FVIII inhibitors (titre ≥0.6 Bethesda units), n (%) 0 (0.0) 
Any AE, n (%) 11 (91.7) 
 Mild 4 (33.3) 
 Moderate 3 (25.0) 
 Severe 4 (33.3) 
Any study drug-related AE, n (%) 1 (8.3)* 
Any AE related to procedures as per protocol, n (%) 0 (0.0) 
AE-related deaths, n (%) 0 (0.0) 
Any SAE, n (%) 4 (33.3) 
Any study drug-related SAE, n (%) 0 (0.0) 
Any SAE related to procedures as per protocol, n (%) 0 (0.0) 
Discontinuation due to AE, n (%) 0 (0.0) 
Discontinuation due to SAE, n (%) 0 (0.0) 
Development of FVIII inhibitors (titre ≥0.6 Bethesda units), n (%) 0 (0.0) 

AE, adverse event; FVIII, factor VIII; SAE, serious adverse event.

*Arthrosis in the right ankle of moderate intensity.

Overall, levels of serum creatinine, creatinine clearance, aspartate transaminase, and ALT remained within the normal ranges provided by the central laboratory, except for 2 patients with a slightly increased ALT (<2 × upper limit of normal) at the final visit of the extension study (Table 3). These patients were 17 and 23 years old at their final visits of the extension. No other abnormalities were found, and the investigator did not comment on these findings.

Table 3.

Renal and liver biomarker levels at each patient’s final visits of the main study and extension

PatientCreatinine clearance, mL/minSerum creatinine, mg/dLSerum AST, U/LSerum ALT, U/L
main study final visitextension final visitmain study final visitextension final visitmain study final visitextension final visitmain study final visitextension final visit
217.2 152.0 0.7 1.0 18.0 32.0 37.0 74.0* 
142.2 NA 0.8 NA 25.0 NA 19.0 NA 
141.1 94.1 0.6 0.9 26.0 22.0 14.0 18.0 
130.2 101.3 0.7 0.9 25.0 14.0 17.0 13.0 
111.3 111.3 1.1 1.1 18.0 18.0 11.0 19.0 
133.1 108.9 0.9 1.1 22.0 17.0 16.0 21.0 
148.2 123.2 0.8 1.0 21.0 20.0 12.0 18.0 
141.2 131.3 0.6 0.6 23.0 19.0 15.0 15.0 
208.9 205.5 0.7 0.7 16.0 11.0 17.0 10.0 
10 106.3 117.3 1.1 1.0 27.0 22.0 25.0 18.0 
11 78.0 74.0 0.8 0.9 18.0 16.0 12.0 16.0 
12 113.4 87.0 0.7 1.0 23.0 35.0 42.0 85.0* 
Overall, median 137.12 111.29 0.77 0.97 22.50 19.0 16.50 18.00 
PatientCreatinine clearance, mL/minSerum creatinine, mg/dLSerum AST, U/LSerum ALT, U/L
main study final visitextension final visitmain study final visitextension final visitmain study final visitextension final visitmain study final visitextension final visit
217.2 152.0 0.7 1.0 18.0 32.0 37.0 74.0* 
142.2 NA 0.8 NA 25.0 NA 19.0 NA 
141.1 94.1 0.6 0.9 26.0 22.0 14.0 18.0 
130.2 101.3 0.7 0.9 25.0 14.0 17.0 13.0 
111.3 111.3 1.1 1.1 18.0 18.0 11.0 19.0 
133.1 108.9 0.9 1.1 22.0 17.0 16.0 21.0 
148.2 123.2 0.8 1.0 21.0 20.0 12.0 18.0 
141.2 131.3 0.6 0.6 23.0 19.0 15.0 15.0 
208.9 205.5 0.7 0.7 16.0 11.0 17.0 10.0 
10 106.3 117.3 1.1 1.0 27.0 22.0 25.0 18.0 
11 78.0 74.0 0.8 0.9 18.0 16.0 12.0 16.0 
12 113.4 87.0 0.7 1.0 23.0 35.0 42.0 85.0* 
Overall, median 137.12 111.29 0.77 0.97 22.50 19.0 16.50 18.00 

Normal ranges: creatinine clearance = 77–160 mL/min; serum creatinine = 0.5–1.3 mg/mL; AST = 11–36 U/L; ALT = 6–43 U/L.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; NA, not available.

*Increased ALT values (<2 × upper limit of normal). Patient 1 was 23 years old, and patient 12 was 17 years old. No other abnormalities were found and the investigator did not comment on these findings.

This post hoc subgroup analysis of PROTECT VIII shows that efficacy of damoctocog alfa pegol prophylaxis is maintained over 6 years of observation in a group of adolescent individuals with haemophilia A, aged 12–<18 years at study enrolment. Improvements in bleeding rates over pre-study prophylaxis treatment with standard half-life FVIII products were observed, with median total and joint ABRs reduced from pre-study values to <2.0 during the extension with damoctocog alfa pegol prophylaxis. Most patients achieved zero bleeds during the last 12 and 6 months of their time in the extension. All target joints were resolved.

While obtained from a small sample size (n = 12), these data suggest that damoctocog alfa pegol effectively reduces bleeds in younger patients and corroborate those of the total PROTECT VIII population [14]. Good adherence with all prophylaxis regimens was observed for the entire study and with all regimens. Data on the efficacy of damoctocog alfa pegol during major and minor surgeries have been published previously [19, 20]. Six adolescent patients underwent six minor surgeries (five tooth extractions, one frenulum excision). Adequacy of hemostasis was rated as “excellent” or “good” in all cases, other than one tooth extraction where no rating was provided (although in this case blood loss during and after surgery was recorded as 0 mL) [20].

The key strength of the PROTECT VIII extension study design was that patients had the freedom to change their regimen to suit their needs, reflecting real-world clinical practice. After initial randomisation to the extended prophylaxis regimens during the main study, half of the cohort adapted their regimen for the extension mainly to a higher but some also to a lower frequency regimen. This flexibility enables patients to individualise their prophylaxis, which may be particularly beneficial to the adolescent age group who may need to accommodate an active lifestyle [3]. Additionally, two-thirds of patients either stayed with the same damoctocog alfa pegol regimen throughout or switched to a lower dosing frequency, suggesting that continued use of damoctocog alfa pegol could also allow less frequent dosing over time.

Damoctocog alfa pegol was well-tolerated in this population throughout the main and extension periods in which no study drug-related SAEs were observed, no discontinuations due to an AE or deaths occurred and no patients developed FVIII inhibitors. No PEG antibodies were observed throughout the entire study, and no free PEG was detectable in plasma at the end of the study. These results confirmed the pre-clinical results and model-based predictions of PEG levels for humans. This combination of nonclinical and clinical safety data, the demonstrated excretion mechanism of PEG, and the concept that no further increases of PEG in blood or tissue concentrations are observed after a steady state is reached, supports that there are no long-term safety consequences expected [21, 22]. Median levels of renal and hepatic biomarkers remained within the normal ranges.

One limitation of this subgroup analysis is the small sample size and the limited follow-up for some patients. In fact, other previously reported clinical subgroup analyses in adolescents with haemophilia A are also limited in cohort size to between 6 and 24 patients, or 6.4% and 16% of their respective total study populations [23‒25]. However, of the 12 patients included in this analysis, nine (75.0%) were treated for over 3 years with damoctocog alfa pegol. In addition, the data for this subgroup are similar to the data for the whole group of 121 patients treated in the extension study [14]. Another limitation to this subgroup analysis is that physical activity data were not collected, which may have provided insight into whether individualised prophylaxis with damoctocog alfa pegol indeed allowed a more active lifestyle in these young patients. However, data such as these will be collected in a real-world observational study (HEM-POWR) that will include patients aged 12 years and older [26].

Overall, the PROTECT VIII study has the longest individual patient follow-up among other extension studies in adolescents and adults with severe haemophilia A [14, 27‒29]. The data from this subgroup analysis of PROTECT VIII support the favourable benefit-risk profile of damoctocog alfa pegol prophylaxis and its use as a long-term treatment option for adolescent patients with haemophilia A as they transition into adulthood. To support and accommodate the possibility of an active lifestyle, and fulfil other needs associated with this population, it is important that individualised treatment regimens are offered [3]. Thus, this young, active patient group may benefit from the extended and flexible dosing regimens offered by damoctocog alfa pegol, which allow for individualised treatment accommodating these patients’ needs.

This analysis was based on data from a previously published phase 2/3 trial (PROTECT VIII). Written informed consent was provided by all patients or their legal guardians before entry into the study, and the study protocol was approved by each site’s Independent Ethics Committee/Institutional Review Board. This full list of participating sites and Ethics Committees can be found in the online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000538702). Informed consent for this analysis was not required given the use of anonymised data from the previously published PROTECT VIII study.

Mark T. Reding has received grants and research support from Bayer and BioMarin; honoraria and consultation fees from Bayer, CSL Behring, HEMA Biologics, Novo Nordisk, Sanofi Genzyme, and Takeda; and participates in a company sponsored speakers bureau for Bayer, CSL Behring, Sanofi Genzyme, and Takeda. Mindy Simpson has received institutional research grants from Bayer, Bioverativ/Sanofi, Daichii-Sankyo, Octapharma, Novo Nordisk, Baxalta (Shire, Takeda), and Roche (Genentech) and received honoraria and consultation fees from Bayer, CSL Behring, Octapharma, Novo Nordisk, Roche, and Takeda/Shire. Jonathan Ducore has received consultancy fees from Bayer and HEMA Biologics and has participated in speaker bureau for Bayer. Pål Andrè Holme has received grants and research support to institution from Bayer, Octapharma, Pfizer, and Shire and consultation fees from Bayer, Novo Nordisk, Octapharma, Pfizer, Shire, and Sobi. Monika Maas Enriquez is an employee at Bayer. Maria Elisa Mancuso has acted as paid consultant/advisor/speaker for Bayer, Biomarin, CSL Behring, Grifols, Kedrion, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Sobi, Takeda, and UniQure.

PROTECT VIII was funded by Bayer. Medical writing assistance was provided by Rachel Price, PhD, of Darwin Health Communications and was fully funded by Bayer.

M.T.R., M.S., J.D., P.A.H., and M.E.M. contributed to the acquisition and the interpretation of the data. M.M.E. contributed to the design of the study and the interpretation of the data. All authors critically reviewed and approved the submitted manuscript.

Availability of the data underlying this publication will be determined later according to Bayer’s commitment to the EFPIA/PhRMA “Principles for responsible clinical trial data sharing.” This pertains to scope, time point, and process of data access.

As such, Bayer commits to sharing upon request from qualified scientific and medical researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the USA and European Union as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the European Union and USA regulatory agencies on or after January 1, 2014.

Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymised patient-level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the study sponsors section of the portal.

Data access will be granted to anonymised patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded.

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