A New Risk-Based Scoring Approach to Individualize Prophylaxis in Patients with Hemophilia A: Results from the PREDICT Study

Abstract

Introduction

There is currently no consensus on optimal prophylaxis with clotting factor concentrates in hemophilia A. With or without pharmacokinetic data, prophylaxis regimens are often based on local practice and patient-specific factors, including bleeding history and activity level. The PREDICT study evaluated a baseline clinical risk score, based on phenotypic and biologic variables, to guide prophylactic regimen selection when switching from standard half-life (SHL) factor VIII concentrates to damoctocog alfa pegol.

Methods

This multicenter, prospective study enrolled 21 participants aged ≥ 12 years with congenital hemophilia A of any severity who had received SHL prophylaxis for ≥ 6 months. Each participant was assigned a risk score (low, medium, high) based on five predefined variables: bleeding phenotype, treatment frequency, active target joints, von Willebrand factor levels, and physical activity. All participants initiated damoctocog alfa pegol at twice-weekly dosing for 4 weeks, after which regimens were individualized: 2×/week for high risk, every 5 days (Q5D) for medium risk, and Q5D for 4 weeks followed by less frequent dosing for low risk participants. A favorable outcome was defined as a reduction in annualized bleeding rate (ABR) and/or infusion frequency compared with previous SHL prophylaxis.

Results

Among 17 evaluable participants, 12 (70.6%) achieved a favorable outcome for treated and untreated bleeds. All 12 had improved ABR, and 11 required fewer infusions. When considering only treated bleeds, 77% achieved a favorable outcome. Mean ABR decreased by 8.01 and infusion frequency reduced by a mean of 6.9 infusions/month. The 25 active target joints identified at baseline were reduced by 96% at study completion.

Conclusions

The PREDICT risk-based scoring system-guided individualized prophylaxis with damoctocog alfa pegol, yielding improved bleeding outcomes and reduced treatment burden in most participants. These findings support the use of structured, risk-adapted approaches to personalize prophylaxis when transitioning from SHL to damoctocog alfa pegol.

Trial Registration

NCT05036278.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-026-03560-0.

Plain Language Summary

The PREDICT study looked at a new way to help treat patients with hemophilia A, a disease that makes it difficult for blood to clot. Usually, patients receive many infusions of standard half-life (SHL) clotting factor products to stop or prevent bleeding; newer extended-half-life (EHL) treatments like damoctocog alfa pegol, allow for fewer infusions. Finding the best treatment plan for each patient is still challenging without thorough pharmacokinetic testing, which shows the body’s effect on the medicine as it gets absorbed, broken down, and removed from the body. To help with this, a scoring system was created that includes things like how many times a patient bleeds, how often they infuse, if they bleed into their joints, their von Willebrand factor level, and how active they are. A total of 21 participants with hemophilia A, who were at least 12 years old and had been getting SHL treatment for at least 6 months, took part in this study. Each participant got a score of low, medium, or high, and followed a special treatment plan with damoctocog alfa pegol for 6 months. The study showed that 70.6% of participants (12 out of 17) had better results, meaning they had fewer bleeds and/or needed fewer infusions compared to their previous treatment. This suggests that using a scoring system to create individual treatment plans can help patients with hemophilia A do better when switching from an SHL to damoctocog alfa pegol.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-026-03560-0.

Key Summary Points

Why carry out this study?

There is currently no established standard of care or validated clinical criteria for selecting the most optimal prophylactic regimen for patients with hemophilia A, when transitioning from standard half-life (SHL) to damoctocog alfa, resulting in reliance on trial-and-error approaches.

Frequent infusions required by current prophylactic treatments (SHL FVIII products) negatively impact patient compliance and quality of life, highlighting the need for individualized regimens.

This study aimed to evaluate whether a novel risk score, based on specific phenotypic and biological factors, could guide clinicians in tailoring the most appropriate prophylaxis regimen for patients transitioning from an SHL FVIII product to damoctocog alfa pegol, addressing gaps in evidence-based dosing strategies.

What was learned from the study?

Utilizing the PREDICT risk score to guide damoctocog alfa pegol prophylaxis resulted in favorable outcomes of improved annualized bleeding rates and/or infusion frequency for most participants compared with their prior treatment regimen with standard half-life clotting products.

This risk-based approach provides early evidence as a potential clinical guide for providers and patients to tailor prophylaxis regimens.

Introduction

Hemophilia A is an X-linked inherited bleeding disorder caused by a deficiency or dysfunction of coagulation factor VIII (FVIII) [1]. Patients with hemophilia A experience spontaneous or trauma-related bleeding episodes that can be life-threatening or lead to chronic arthropathy and reduced quality of life (QoL). The treatment for hemophilia A typically involves FVIII replacement therapy, administered either on demand to control acute bleeds or as prophylaxis to prevent bleeds. Although individualized prophylactic regimens are essential for preventing spontaneous bleeds, the need for frequent infusions can negatively impact treatment adherence. Over the past decade, the treatment landscape for hemophilia A with clotting factor concentrates has evolved from the use of standard half-life (SHL) recombinant coagulation FVIII (rFVIII) products for routine prophylaxis to extended half-life (EHL) products, which enable less frequent dosing and improved patient outcomes [2, 3].

Damoctocog alfa pegol was developed as an EHL rFVIII product for prophylaxis, perioperative management, and treatment of acute bleeding events. Site-specific polyethylene glycol (PEGylation) was used to extend FVIII plasma half-life, allowing for more flexible and individualized dosing schedules. The efficacy and safety of damoctocog alfa pegol have been demonstrated in pivotal trials (NCT01184820, NCT01580293, NCT01580293).

Despite these advancements, there are no universal guidelines on optimizing prophylactic intravenous treatment regimens with clotting factor concentrates for patients with hemophilia. In the absence and potential burdensome sample collections for traditional or population-based pharmacokinetic (PK) analyses of rFVIII decay curves, clinicians often rely on patient characteristics and clinical history to guide dosing when transitioning patients from SHL to EHL products. This empirical trial-and-error approach may result in periods of suboptimal prophylaxis, either increasing bleeding risk or leading to higher rFVIII usage, which can have economic implications and may not alleviate the burden of frequent infusions [4].

Given the substantial interindividual variability in disease expression, driven by specific phenotypic and biologic factors, tailoring prophylaxis requires a more structured, patient-specific approach. The aim of this study was to assess the effect of using a new risk score approach that incorporates defined variables to guide regimen selection to achieve a favorable outcome when previously treated patients (PTPs) with congenital hemophilia A switch from an SHL rFVIII product to damoctocog alfa pegol, an EHL product. The variables included in this risk score have not been prospectively examined for their ability to guide the selection of optimal dosing regimens, nor have their combined use been previously evaluated.

Methods

Study Design

The PREDICT study was a phase 4, multicenter, open-label, interventional, single-arm, prospective study conducted at 14 centers in the USA. The total study duration was approximately 7.5 months, consisting of up to 30 days for screening, 6 months of treatment, and a safety follow-up period of 7–14 days after the last treatment dose. This study was conducted in accordance with the ethical standards of the local institutional review boards for each study site and with the Declaration of Helsinki and its later amendments or comparable ethical standards. Written informed consent was obtained from all participants before study participation.

Participants

The study enrolled male and female PTPs who were ≥ 12 years old with any severity of congenital hemophilia A and a history of at least 150 exposure days with any FVIII product. All participants had received prophylaxis with any SHL FVIII product (this was defined as any rFVIII product that is not Eloctate, Adynovate, Esperoct, or Jivi, which were the only EHL products available at the time of study start) with a minimum of 18 weeks of treatment for at least 6 consecutive months within 12 months prior to the screening visit. Participants were excluded from the study if they had any other inherited or acquired bleeding disorder in addition to hemophilia A, a platelet count of < 100,000/mm³, evidence of inhibitors to FVIII (≥ 0.6 BU/mL) within the last year, or any major surgery planned. Participants were also excluded if documentation for any of the following risk parameters was missing or unknown: annualized bleeding rate (ABR), pre-study treatment frequency, number of active target joints, and von Willebrand factor (vWF) antigen levels.

Scoring

At baseline, participants’ total risk scores were determined based on five individually weighted variables: pre-study bleeding phenotype determined by ABR and previous treatment frequency during the stable SHL treatment period, number of active target joints, vWF antigen levels, and physical activity (Table 1). These variables have been established in the literature and by physicians in clinical practice in an informal way as providing predictive potential in guiding prophylaxis regimens.

Table 1.

Parameters for determining participant risk scores

Participant variables	Score assignment
Bleed phenotype (total bleeds occurring during the stable SHL period)
ABR ≤ 1	− 2
1 < ABR ≤ 4	+ 2
ABR > 4	+ 3
Treatment frequency derived from the stable SHL period
< 3×/week	− 1
3×/week	0
> 3×/week	+ 1
Number of active target jointsa
0	− 1
1	0
2	+ 1
> 2	+ 2
vWF antigen levels (within previous 12 months)
vWF ≥ 150%	− 1
100% ≤ vWF < 150%	0
vWF < 100%	+ 2
Physical activityb
Low (noncontact sports)c	− 1
Sedentaryd	0
Medium/high (contact sports)e	+ 1

The addition of all score assignments led to an individual participant score within a range of − 6 (low risk) to + 9 (high risk)

ABR annualized bleeding rate, SHL standard half-life, vWF von Willebrand factor

^aDerived at baseline from the patients' current status

^bRefers to a participant’s usual physical activity level, based on the last 12 months. If a significant change in activity level was expected in the next 6 months, the criterion for the physical activity variable was to be based on that anticipated level (National Bleeding Disorders Foundation 2025. Activity Ratings Chart)

^cLow intensity activities were those that involved gentle and fluid motions, and included noncontact sports, such as swimming, elliptical training, or archery

^dSedentary behavior referred to time spent sitting or lying down (except when sleeping), with very little energy expenditure

^eMedium/high activities were those that required some effort or led to harder breathing or puffing and panting (depending on fitness), including contact sports

Bleed Phenotype

The ABR is a key clinical marker of bleeding risk and phenotype in patients with hemophilia A. Tailoring prophylactic dosing regimens based on baseline ABRs leads to equal or improved bleed control compared with previous treatments, underscoring the importance of individualized, phenotype-driven therapy [5]. The PROTECT VIII study, conducted in patients receiving prophylactic damoctocog alfa pegol dosing regimens, showed that those randomized based on baseline bleeding phenotype, as determined through a run-in period with low-dose damoctocog alfa pegol, achieved bleeding control that was better than or comparable to their pre-study levels [5]. Most patients in a study conducted by Lalezari et al. who were categorized as low risk (≤ 1 bleed) benefited from higher prophylaxis dosing intervals (every 5 or 7 days) and maintained good bleed control [6]. Consequently, the ABR should be incorporated into risk scoring systems nonlinearly, assigning significantly greater risk to those with a pre-study ABR > 4.

Treatment Frequency

Patients with hemophilia A also demonstrate variations in infusion frequency that often correspond to differences in their bleeding risk, which should be accounted for in phenotype-guided dosing schemes. The relevance of prior treatment frequency in tailoring an appropriate prophylaxis regimen is supported by the results of the PROTECT VIII study [5]. Baseline treatment frequency, as characterized during the PROTECT VIII low-frequency run-in period, reflects the underlying bleeding phenotype and informs the prophylactic intensity required for effective bleed control beyond the distinction of prophylaxis versus on-demand therapy. The frequency variable was based on treatment frequency around a 3×/week dosing, as this is the most common indication for marketed SHL FVIII products [7, 8].

Number of Active Target Joints

Regarding joint status, the presence of two or more target joints in patients with hemophilia A has been shown to be strongly associated with reduced health-related QoL [9]. Prophylactic treatment in Ay et al. [10] demonstrated a fivefold reduction in ABR at target joints compared with on-demand therapy. Therefore, individual differences in the number and location of frequently bleeding joints are important considerations when determining how often prophylaxis should be administered.

von Willebrand Factor Antigen Levels

Endogenous vWF levels are vital for personalized dosing, as they correlate with the half-life of FVIII. Higher vWF levels are linked to slower clearance of FVIII and lower ABRs [11]. Integrated analyses across multiple clinical studies confirm that vWF antigen levels are consistently related to FVIII PK, supporting their value in selecting dosing regimens [12].

Physical Activity

Lastly, physical activity, particularly contact sports, increases bleeding risk; however, low physical activity, such as noncontact sports, may actually reduce bleeding episodes compared with sedentary behavior or no physical activity by supporting bone, joint, and muscle health [13, 14]. Broderick et al. [15] reported that in children and adolescents, vigorous exercise posed a moderate bleeding risk that could be mitigated with standard prophylactic regimens. Thus, assessing the type and intensity of physical activity, alongside patient age, is essential for tailoring prophylaxis.

The score assignment breakdown based on participant variables is summarized in Table 1. Participants were scored on a range of − 6 (low risk) to + 9 (high risk). If the physical activity variable was unavailable, a value of 0 was assigned. For the other parameters, missing values were not permitted.

Intervention

All eligible participants started treatment with damoctocog alfa pegol, in line with the approved United States Prescribing Information (USPI), at a dose of 40 IU/kg two times per week for the first 4 weeks. At the time the study was conducted, Jivi was only approved for ages ≥ 12; in May 2025, the label was subsequently expanded to include ages ≥ 7. On the basis of their risk score, participants were then assigned to one of three prophylaxis treatment regimens (Fig. 1). Participants with a high risk score (> 4) received damoctocog alfa pegol 40 IU/kg twice weekly and those with a medium risk score and according to the USPI (2–4) received 50 IU/kg every 5 days (Q5D) until the end of the study period. Those with a low risk score (< 2) received damoctocog alfa pegol 50 IU/kg Q5D for 4 weeks (until week 8), followed by a switch to 60 IU/kg administered less frequently (e.g., every 7 days), for the remainder of the study. All participants received treatment with damoctocog alfa pegol for a total of 6 months, for both prophylaxis and treatment of any breakthrough bleeds.

Fig. 1.

Schema for dosing regimen assignment. Prophylactic regimens were not altered during the study period unless a participant experienced ≥ 2 muscle or joint bleeds (without evident trauma) during any given 8-week period during the 6-month study. Those participants would be assigned to the next-highest dosing frequency. Q5D every 5 days, Q7D every 7 days, SHL standard half-life

Endpoints

The primary endpoint was the occurrence of a favorable outcome on the score-selected dosing regimen. A favorable outcome was defined as no change or deviation from the score-assigned dosing regimen during the study, along with one of the following: improved ABR and decreased frequency of administration, improved ABR with similar frequency, or decreased frequency with similar ABR. An improved ABR was defined as a reduction of at least 1 from the pre-study ABR, a similar ABR was an absolute change of less than 1, and a worse ABR was an increase of at least 1. For infusion frequency, a decreased frequency was defined as at least 2 fewer infusions per month compared with pre-study, similar frequency was an absolute change of fewer than 2 infusions, and worse frequency was an increase of at least 2 infusions per month. Investigators could modify treatment regimens at any time during the study if the score-assigned regimen was deemed inappropriate for the patient. Also, if 2 or more spontaneous bleeds occurred during any given 8-week period during the study, the patient was escalated to the next highest dosing frequency.

The key secondary endpoints were ABR (total, joint, spontaneous) and change in total ABR from pre-study; change in the frequency of damoctocog alfa pegol administration (infusions/month) from pre-study SHL treatment; occurrence of participants with 0 and ≤ 1 spontaneous bleed; and the change from baseline in active target joint status (according to the ISTH definition of 3 or more spontaneous bleeds into a single joint within a consecutive 6-month period, compared with a pro-rated criteria for resolution of ≤ 1 spontaneous bleed during the final 6 months of the study) [16]. The Supplementary Index discusses an additional secondary endpoint of change in the Haemophilia Quality of Life Questionnaire (Haem-A-QoL or Haemo-QoL) score from baseline and another prespecified endpoint to evaluate whether ABO blood type and/or body mass index (BMI) would have led to a different risk score group assignment.

Safety Analysis

All safety analyses were performed on the safety analysis set (SAF) and presented overall. Adverse events (AEs) were reported using the latest version of the Medical Dictionary for Regulatory Affairs during and at end of study.

Statistical Analysis

This study was not designed to test any predefined hypotheses. All analyses were descriptive or exploratory. Categorical variables were summarized using frequency tables that included both absolute and relative frequencies. Metric (or continuous) variables were described using standard sample statistics, such as mean, standard deviation (SD), minimum, median, quartiles, and maximum. When applicable, continuous variables were also reported as absolute values and as changes from baseline at each analysis time point.

While it was not necessarily possible to draw any conclusions based on the reduced sample size, the study was designed to provide preliminary insights into whether the risk scoring approach could be useful in clinical practice. The primary objective was analyzed using the modified intention-to-treat (mITT) population with a censored analysis approach, in the following referred to as “mITT, censored analysis set”. As per study protocol, ABR required 4 months of documented bleed data; participants who discontinued or switched regimens prior to this time point were censored for ABR analysis. All other endpoints were analyzed in the mITT population without censoring.

Results

A total of 21 participants were enrolled, assigned to treatment, and included in the SAF. Of these, 19 completed the study and were included in the mITT analysis, while 2 participants discontinued in the first 4 months of treatment (Fig. 2). Both participants who discontinued cited personal decision as the reason, with one also reporting an AE of abdominal pain. Stratified by risk score, the mITT analysis set included 6 participants in the high risk score group, 8 in the medium risk score group, and 5 in the low risk score group. The mITT censored analysis set excluded 2 additional participants from the medium risk score group who switched regimens prior to 4 months (total of 17 participants); one participant was excluded based on physician decision to keep him on a twice-weekly regimen owing to the participant’s strenuous occupation and the other was never transitioned to the assigned treatment regimen.

Fig. 2.

Patient enrollment and disposition. mITT modified intention-to-treat, SAF safety analysis set

In the mITT analysis, the median age of participants was 36 years, with ages ranging from 13 to 68 (Table 2). Most participants were male (89.5%) and white (68.4%). Two participants were female: one was 68 years old and white, and the other was 13 years old and race was not reported. All participants in this study had received previous FVIII treatment at the time of informed consent. Disease characteristics for all participants in the mITT set are summarized in Table 2.

Table 2.

Patient demographics and characteristics, mITT analysis

Risk score	High (N = 6)	Medium (N = 8)	Low (N = 5)	Total (N = 19)
Sex, n (%)
Male	6 (100.0)	7 (87.5)	4 (80.0)	17 (89.5)
Femalea	0	1 (12.5)	1 (20.0)	2 (10.5)
Age, median (range), years	37.5 (15–44)	39.0 (19–68)	18.0 (13–28)	36.0 (13–68)
Age group, n (%)
12–17 years	1 (16.7)	0	2 (40.0)	3 (15.8)
≥ 18 years	5 (83.3)	8 (100)	3 (60.0)	16 (84.0)
BMI, mean (SD), kg/m2	24.27 (4.87)	28.00 (6.39)	24.42 (3.62)	25.88 (5.37)
Race, n (%)
White	6 (100)	6 (75.0)	1 (20.0)	13 (68.4)
Black/African American	0	1 (12.5)	0	1 (5.3)
Asian	0	0	2 (40.0)	2 (10.5)
Not reported	0	1 (12.5)	2 (40.0)	3 (15.8)
Ethnicity, n (%)
Not Hispanic or Latino	3 (50.0)	4 (50.0)	2 (40.0)	9 (47.4)
Hispanic or Latino	3 (50.0)	4 (50.0)	3 (60.0)	10 (52.6)
Age at first treatment, years
Mean (SD)	0.82 (1.58)	13.07 (23.31)	4.67 (2.93)	7.12 (16.07)
Median (range)	0.13 (0–4)	1.50 (0–66)	5.13 (1–7)	1 (0–66)
Modality of first treatment, n (%)
On demand	2 (33.3)	6 (75.0)	3 (60.0)	11 (57.9)
Prophylaxis	1 (16.7)	1 (12.5)	2 (40.0)	4 (21.1)
Unknown	3 (50.0)	1 (12.5)	0	4 (21.1)
Type of first treatment, n (%)
Recombinant FVIII	1 (16.7)	4 (50.0)	2 (40.0)	7 (36.8)
Plasma-derived FVIII	2 (33.3)	0	1 (20.0)	3 (15.8)
FVIII	0	2 (25.0)	0	2 (10.5)
Other	3 (50.0)	2 (25.0)	2 (40.0)	7 (36.8)
History of inhibitor, n (%)
No	6 (100)	7 (87.5)	5 (100)	18 (94.7)
Yes	0	1 (12.5)	0	1 (5.3)
Hemophilia A disease severity, n (%)b
Severe, < 1%	6 (100)	6 (75.0)	1 (20.0)	13 (68.4)
Moderate, 1–5%	0	1 (12.5)	2 (40.0)	3 (15.8)
Mild, > 5%	0	1 (12.5)	2 (40.0)	3 (15.8)
Number of target joints per participant at baseline, n (%)
Mean (SD)	2.7 (1.37)	1.1 (1.13)	0	1.3 (1.45)
Median (range)	3 (1–4)	1 (0–2)	0 (0–0)	1 (0–3)
0	0	3 (37.5)	5 (100)	8 (42.1)
1	2 (33.3)	2 (25.0)	0	4 (21.1)
2	0	2 (25.0)	0	2 (10.5)
3	2 (33.3)	1 (12.5)	0	3 (15.8)
4	2 (33.3)	0	0	2 (10.5)
ABR during stable SHL period
Mean (SD)	22.8 (16.69)	12.6 (16.33)	5.0 (8.40)	13.8 (15.69)
Median (range)	16.5 (8–52)	6.5 (2–48)	1 (1–20)	8 (1–52)
Previous SHL product, n (%)
Octocog alfa (Advate)	0	5 (62.5)	2 (40.0)	7 (36.8)
Lonoctocog (Afstyla)	1 (16.7)	0	0	1 (5.3)
Octocog alfa (Kogenate)	0	1 (12.5)	0	1 (5.3)
Octocog alfa (Kovaltry)	1 (16.7)	0	2 (40.0)	3 (15.8)
Turoctocog alfa (Novoeight)	0	1 (12.5)	0	1 (5.3)
Simoctocog alfa (Nuwiq)	2 (33.3)	0	0	2 (10.5)
Moroctocog alfa (Xyntha)	2 (33.3)	1 (12.5)	1 (20.0)	4 (21.1)
Dosing frequency during stable SHL period (total doses/month)
Mean (SD)	16.3 (7.5)	12.2 (2.3)	9.54 (3.6)	12.8 (5.3)
Median (range)	14.1 (8.7–30.4)	13.0 (8.7–15.2)	8.7 (4.3–13.0)	13.0 (4.3–30.4)

^aFemales were not included in the pivotal trials used to support damoctocog alfa pegol indication

^bPersons with mild and moderate hemophilia A were not included in the pivotal trials used to support damoctocog alfa pegol indication

This mITT analysis excluded 2 participants who discontinued treatment within the first 4 months, n = 19

ABR annualized bleeding rate, BMI body mass index, FVIII factor VIII, mITT modified intention-to-treat, SAF safety analysis set, SD standard deviation, SHL standard half-life

During the stable SHL period, the most used SHL products were Advate (7/19 [36.8%] participants) and Xyntha (4/19 [21.1%]). Most participants (68.4%) had severe hemophilia A (FVIII levels < 1%) while 15.8% had moderate (1–5%) and 15.8% had mild (> 5%) disease. One patient also had a history of inhibitors. The mean (SD) ABR during the stable SHL period in the mITT set was 13.8 (15.69), and the mean (SD) ABR for joint bleeds was 7.7 (9.02). All participants in the high risk score group and the majority (5/8 [62.5%]) of participants in the medium risk score group had a history of 1 to 4 active target joints at baseline. The reason for this variability in active target joints despite prophylaxis during the stable SHL period is unknown, but could be attributed to several factors, such as lack of adherence, strenuous occupation or high-risk physical exercise, existing target joints that bleed frequently, or potential other trauma bleeds. In the low risk score group, participants had no history of target joints and no active target joints at baseline, as anticipated per the study design.

Primary Outcomes

Most participants reported favorable outcomes following the use of the baseline risk score to guide their prophylaxis treatment regimen, without changing regimens due to bleeding. Considering both treated and untreated bleeds, 12 of 17 (70.6%) participants in the mITT censored analysis set experienced a favorable outcome with damoctocog alfa pegol compared with their prior SHL treatment (95% CI 44.04–89.69) (Table 3). When only treated bleeds were considered, 13 of 17 (76.5%) participants demonstrated a favorable outcome. Notably, more than 70% of participants treated according to the score-assigned regimen achieved favorable outcomes in this study. Overall, 12 out of 17 participants had an improved ABR, and none had a similar ABR to pre-study values. Regarding infusion frequency, all 17 participants reported either improved or similar frequency of administration (15/17, improved; 2/17, similar). When examining disease severity, among participants with severe disease (n = 11), 7 (63.6%) had improved or stable ABR and 10 (90.9%) had improved treatment frequency on their risk score-assigned regimen. Among participants with mild or moderate disease (n = 6), 5 (83.3%) showed improvements in both ABR and administration frequency.

Table 3.

Primary outcome: favorable outcome responder rate, mITT censored analysis

Risk group score–assigned dosing	High (N = 6) 2×/week	Medium (N = 6) Q5D	Low (N = 5) < Q5D (e.g., Q7D)	Total (N = 17)
Favorable outcome: yes
N (%)	5 (83.3)	4 (66.7)	3 (60.0)	12 (70.6)
95% CI	(35.88–99.58)	(22.28–95.67)	(14.66–94.73)	(44.04–89.69)
Improved ABR with improved frequency
N (%)	5 (83.3)	4 (66.7)	2 (40.0)	11 (64.7)
95% CI	(35.88–99.58)	(22.28–95.67)	(5.27–85.34)	(38.33–85.79)
Improved ABR with similar frequency
N (%)	0	0	1 (20.0)	1 (5.9)
95% CI	(0–45.93)	(0–45.93)	(0.51–71.64)	(0.15–28.69)

This mITT censored analysis excluded 4 participants who discontinued or switched treatment regimens within the first 4 months, n = 17

ABR annualized bleeding rate, Q5D every 5 days, Q7D every 7 days, SHL standard half-life

Key Secondary Outcomes

In the mITT censored analysis set, the overall mean ABR for all bleeds significantly decreased compared with pre-study ABR, with a mean (SD) reduction of 8.01 (15.24). For treated bleeds, the mean on-study ABR also improved substantially compared with the pre-study ABR, with a mean (SD) reduction of 8.48 (14.96). The mean (SD) pre-study ABRs for the high, medium, and low risk score groups were 22.83 (16.69), 7.50 (9.33), and 5.00 (8.40), respectively. The mean (SD) on-study ABR for the high, medium, and low risk score groups were 6.63 (7.95), 3.50 (3.91), and 2.04 (2.86), respectively. The high risk score group experienced the greatest change from the pre-study ABR (Fig. 3). The changes in ABR stratified by disease severity are presented in the Supplementary Index.

Fig. 3.

Change from pre-study ABR, all bleeds, mITT censored analysis. Excluded 4 participants who discontinued or switched treatment regimens within the first 4 months, n = 17. ABR annualized bleeding rate, mITT modified intention-to-treat, Q1 first quartile, Q3 third quartile

Most participants (13/17; 76.5%) showed an improvement in treated ABRs during the study compared with their pre-study ABRs. Additionally, most participants in the mITT analysis set (16/19; 84.2%) reported a reduction in infusion frequency, defined as at least 2 fewer infusions per month. Participants in the high risk score group reported the greatest change from pre-study frequency (Fig. 4). The remaining 3 participants (15.8%) maintained an infusion frequency similar to their baseline, with changes of fewer than 2 infusions per month. Notably, no participant reported an increase in the frequency of monthly infusions.

Fig. 4.

Change from pre-study frequency, mITT analysis. Dosing frequency for prophylaxis (frequency/month) was transcribed from previous hemophilia treatment for a minimum of 6 months during stable SHL prophylaxis. Excluded 2 participants who discontinued or switched treatment regimens within the first 4 months, n = 19. mITT modified intention-to-treat, Q1 first quartile, Q3 third quartile

In terms of spontaneous bleeding events, most participants across all risk score categories in the mITT set reported 0 spontaneous bleeds (high risk, 4/6 [66.7%]; medium risk, 5/8 [62.5%]; low risk, 4/5 [80.0%]; total, 13/19 [68.4%]). No new target joints were identified in any participant across all groups during the study. All participants in the high risk score group, and 5 of 8 participants in the medium risk score group had at least one target joint at baseline (total = 25 active target joints). By the end of the study, all but 1 participant had target joint resolution (Fig. 5).

Fig. 5.

Summary of target joints, mITT analysis. The data from 2 participants who discontinued within the first 4 months were excluded. mITT modified intention-to-treat

Results of the secondary endpoint of QoL and the prespecified endpoint of the participant score based on ABO/BMI are presented in the Supplementary Index.

Safety

Nine out of the 21 (42.9%) participants in the SAF set experienced treatment-emergent AEs (TEAEs) during the study (Table 4), which were primarily classified under musculoskeletal and connective tissue disorders, as well as nervous system disorders. Most of the reported events were classified as mild to moderate. Three (14.3%) participants experienced four TEAEs considered related to study drug. These included injection site bruising in one participant (leading to study discontinuation because of a TEAE of abdominal pain not considered to be related to study drug), taste disorder and dizziness in another (no dose change), and headache in a third participant (no change in dosage). The one participant (4.8%) who experienced injection site bruising and discontinued the study due to abdominal pain also experienced multiple non-serious TEAEs including extremity pain, peripheral swelling, and acne. Two of the 21 (9.5%) participants experienced serious AEs (SAEs), both involving muscle hemorrhage and requiring hospitalization. This hemorrhage occurred in one of the participants due to several planned prophylactic doses not given in a timely manner. The second participant experienced an acute left psoas bleed without any identified trauma. None of the SAEs were attributed to study drug, procedures, or medical devices, and neither resulted in discontinuation of the study intervention. No AEs led to death or inhibitor development. Overall, no new safety concerns were identified, and findings were consistent with the established safety profile of damoctocog alfa pegol observed during clinical development and post-marketing surveillance.

Table 4.

Safety summary, SAF

Participants with TEAEs, n (%)	Total N = 21
Any AE	9 (42.9)
Any study drug–related AEa	3 (14.3)
Mild	2 (9.5)
Moderate	1 (4.8)
Any AE leading to discontinuation of study interventionb	1 (4.8)
Any study procedure-related AEa	2 (9.5)
Any SAEc	2 (9.5)
Any SAE leading to discontinuation of study intervention	0
AE of special interestd	0
AE with outcome of death	0

The safety analysis set included all participants enrolled in the trial, N = 21

AE adverse event, SAE, serious adverse event, SAF safety analysis set, TEAE treatment-emergent adverse event

^aInjection site bruising; taste disorder; dizziness; headache

^bAbdominal pain (in combination with other concurrent TEAEs)

^cTwo muscle hemorrhages requiring hospitalization

^dAEs of special interest were defined as events of hypersensitivity and loss of efficacy

Discussion

The PREDICT study evaluated a novel risk score derived from five predictive phenotypic and biological factors designed to guide the selection of an individualized prophylaxis dosing regimen with damoctocog alfa pegol. In real-world practice, damoctocog alfa pegol is often not used to its full extended-interval potential. Many patients remain on twice-weekly dosing, which might reflect convenience, patient preference, or concern among healthcare professionals (HCPs) and patients regarding bleeding risk when intervals are extended [17]. These findings underscore a clinical need for a structured, evidence-based system that can help clinicians and patients confidently extend dosing intervals when using EHL therapies. Although PK profiling provides valuable individualized data, it can be burdensome for patients and is not feasible in clinical settings. When determining the most optimal prophylaxis regimen, bleeding phenotype is important to consider as it varies across patients due to metabolic and/or lifestyle differences. HCPs often apply similar reasoning when making these clinical decisions, but a standardized and reproducible scoring framework may facilitate consistent decision-making across centers and improve the management of patients transitioning from a SHL product to damoctocog alfa pegol.

Limitations

It is important to determine if the variables used to calculate the participants’ risk scores were appropriately selected and weighed. For instance, target joint data can be challenging to interpret according to the ISTH definition, as some patients might not meet the criteria yet still experience functional limitations; therefore, expanding the target joint variable to include “affected joints” could better capture the clinical burden and patient-reported impact. ABO blood type and BMI were collected as exploratory parameters as part of the scoring system but were ultimately excluded from the final scoring model because they would not have altered risk categorization or regimen assignment. Inclusion of ABO blood type, for example, could have shifted some patients to a lower risk group, leading to a less stringent score. For participants who did not achieve favorable outcomes, PK-guided data might have provided additional insight; integrating PK information into future iterations of the scoring model could enhance its predicted accuracy. Lastly, the vWF variable could have been weighed more heavily, particularly at low levels approaching the diagnostic range of von Willebrand disease. Although the results of this study offer preliminary support for the feasibility and clinical utility of a risk-based approach, the relative small sample size (n = 21) limits statistical power and generalizability. While there are currently no models to demonstrate the impact of this scoring system, future larger-scale evaluations could validate this tool and explore its applicability to other EHL products or prophylactic regimens.

Conclusions

The findings from this study demonstrate that employing the PREDICT scoring system to guide individualized prophylactic regimens with damoctocog alfa pegol resulted in favorable outcomes for most participants transitioning from an SHL to damoctocog alfa pegol. These results offer early evidence that a risk-based scoring system incorporating both clinical and biological characteristics could serve as a practical clinical tool to support decision-making for both HCPs and patients.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Fernando F. Corrales-Medina, Doris Quon, Miguel Escobar, Lisa Boggio, Akshat Jain, Mark T. Reding, Robert F. Sidonio, and Janice Staber were principal investigators and contributed patients. Doris Quon, Robert F. Sidonio, Janice Staber, and Mark T. Reding were part of the steering committee and contributed to the study design. Jessica Charlet, an employee of Bayer, contributed to the concept and design of the study, protocol development, data analysis, and interpretation. All authors provided feedback on the manuscript during development, and they read and approved the final manuscript.

Funding

This study was sponsored by Bayer. Bayer is also funding the Rapid Service and Open Access fees for this paper.

Data Availability

Availability of the data underlying this publication will be determined 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 United States (USA) and European Union (EU) as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized 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 member section of the portal. Data access will be granted to anonymized 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.

Declarations

Conflict of Interest

Doris V. Quon: Bayer, Biomarin Pharmaceutical Inc., CSL Behring, Hema Biologics/LFB, Genentech/Roche, Novo Nordisk, Pfizer, Sanofi, Takeda. Miguel Escobar: Genentech, HEMA Biologics, LFB, Novo Nordisk, Sanofi, Takeda, uniQure, BioMarin, CSL Behring, Kedrion, NHF, Pfizer. Lisa Boggio: Regeneron, Kedrion, Novo Nordisk, Octapharma, Sanofi, Alnylam, Genentech. Fernando F. Corrales-Medina: Genentech, Novo Nordisk, Octapharma, Bayer (consultancy), Takeda, Sanofi. Akshat Jain: NovoNordisk, Sanofi, Pfizer, Bayer (Speaker); Pfizer, Beam Therapeutics (grant funding); End point adjudication committee (Beam, Genetix). Mark T. Reding: Institutional research support: Bayer, Be Biopharma, Biomarin. Advisory board: Bayer, CSL Behring, Genentech, HEMA Biologics, Novo Nordisk, Sanofi, Spark, Takeda; Speaker bureau: Bayer, CSL Behring, Sanofi, Takeda. Robert F. Sidonio, Jr: Advisory board: Bayer, Genentech, Roche, HEMA Biologics, LFB, Novo Nordisk, Sanofi, Sobi, Takeda, Octapharma, Alnylam and HEMAb. IIS: Takeda, LFB, HEMA Biologics, Octapharma. Other: ATHN Chair, HFA medical advisor. Janice Staber: Bayer, BioMarin, Genentech, NovoNordisk, Sanofi. Jessica Charlet: Current Bayer employee.

Ethical Approval

The results presented in this article are based on the PREDICT study. All procedures performed in the study were in accordance with the ethical standards of the local institutional review board (IRB) for each site and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The central IRB was WCG and their reference number is 20215317. Written informed consent was obtained from all participants before study participation.