Final data from the German AHEAD study: effectiveness and safety of octocog alfa and rurioctocog alfa pegol for hemophilia A in a real-world setting

Abstract

Background:

Octocog alfa and rurioctocog alfa pegol have demonstrated efficacy in the prevention and management of bleeding associated with hemophilia A (HA) in clinical trials. The German AHEAD study (DRKS00000556) was designed to provide real-world data over a long period to complement these studies.

Objectives:

To assess real-world long-term outcomes in patients with moderate/severe HA receiving octocog alfa or rurioctocog alfa pegol in routine clinical practice

Design:

Noninterventional, prospective, study conducted between 2010 and 2022.

Methods:

The primary endpoint was the incidence of hemophilia-affected joint arthropathy. Secondary endpoints included annualized bleeding rate and joint bleeding rate (ABR/AJBR), and octocog alfa and rurioctocog alfa pegol consumption. Final data are presented.

Results:

The analysis included 377 patients aged 1–80 years who received octocog alfa (severe HA, n = 309; moderate HA, n = 68) and 99 patients aged ⩾12 years who received rurioctocog alfa pegol (severe, n = 82; moderate, n = 17). Over 8 years of follow-up, average Gilbert scores were maintained with prophylaxis. In patients with severe HA, median ABRs/AJBRs were generally lower with prophylaxis versus on-demand treatment, whereas in moderate HA, bleeding rates were similar. Treatment-related adverse events (AEs) and serious treatment-related AEs were reported in 5.3% and 4.2% (35 events including hemorrhage, arthropathy, and factor FVIII (FVIII) inhibitor development) of patients receiving octocog alfa, respectively, and 5.1% and 4.0% of patients receiving rurioctocog alfa pegol, respectively. One previously treated patient receiving octocog alfa developed de novo FVIII inhibitors.

Conclusion:

These real-world data corroborate previous clinical trial and real-world data demonstrating the long-term effectiveness and safety of octocog alfa and rurioctocog alfa pegol in patients with HA. In patients with severe HA, octocog alfa prophylaxis was associated with reduced bleeding rates compared with on-demand therapy.

Trial registration:

Deutsches Register Klinischer Studien (German Clinical Trials Register): DRKS00000556.

Plain language summary

Effectiveness and safety of octocog alfa and rurioctocog alfa pegol to treat hemophilia A in the real world

Hemophilia A is a rare inherited condition in which the blood of a patient does not clot properly. Over time, bleeding into joints such as the knees and elbows can cause severe damage, leading to pain and reduced mobility. Octocog alfa and rurioctocog alfa pegol are treatments for hemophilia that can be used when needed to stop bleeding (“on-demand treatment”) and can also be taken regularly to prevent future bleeds (“prophylaxis”). Clinical trials have shown that these treatments are effective, but it is important to know if the treatments work just as well when they are used in the real world. In the German AHEAD study, we looked at the effectiveness and safety of octocog alfa and rurioctocog alfa pegol in patients with hemophilia A who were prescribed treatment by their doctor. The joint health of patients was measured using the Gilbert scale, which takes into account pain, bleeding, and examination of the joint by the doctor. Over time, Gilbert scores improved, particularly for patients who received prophylaxis rather than on-demand treatment. Similarly, the number of bleeds patients experienced per year tended to be lower in those receiving prophylaxis rather than on-demand treatment, although this German ADVATE / ADYNOVI Hemophilia A Outcome Database (AHEAD) study only applied for patients with severe hemophilia. In those with moderate hemophilia, the number of bleeds per year was similar with prophylaxis and on-demand treatment. The safety of octocog alfa and rurioctocog alfa pegol was similar to what has previously been seen in clinical trials. Overall, the results from this study show that octocog alfa and rurioctocog alfa pegol are as effective for managing hemophilia A in the real world as they are in clinical trials, particularly when given as regular prophylaxis to prevent bleeding.

Graphical Abstract

Keywords

hemophilia A octocog alfa prophylaxis real-world clinical trial rurioctocog alfa pegol

Introduction

The severity of hemophilia A (HA) is based on the percentage of residual clotting factor VIII (FVIII) activity, with activity <1% of normal classified as severe and 1%−5% classified as moderate.¹ More recently, it has become clear that many patients with moderate FVIII activity experience a severe phenotype with overt arthropathy.^2–4 Advances in management of HA have led to a shift from management of life-threatening bleeding to the preservation of joint health and improvement in quality of life over the longer term.⁵

Standard prophylaxis for HA is weight-based and may not account for individual variability.^6,7 Individualized pharmacokinetic (PK)-guided prophylaxis takes into account bleeding phenotype, joint status, individual PK, and patient self-assessment and preference, helping to maintain targeted trough levels and reduce bleeding risk.^1,6,7 Although a 1% trough level was considered to be an adequate goal, a level >3%−5% is now preferred to reduce bleeding in patients with HA.^1,8

Octocog alfa (ADVATE; Takeda Manufacturing Austria AG, Vienna, Austria) and rurioctocog alfa pegol (ADYNOVI; Baxalta Innovations GmbH, Vienna, Austria) are effective for the prevention and treatment of bleeding episodes associated with HA.^9–14 Both treatments are reimbursed by statutory health insurance in Germany. The German ADVATE / ADYNOVI Hemophilia A Outcome Database (AHEAD) study was a noninterventional, prospective, real-world study assessing long-term outcomes in patients receiving octocog alfa or rurioctocog alfa pegol in clinical practice in terms of effectiveness, safety, drug utilization, immunogenicity, and quality of life (QoL). Here, we report final data for patients with moderate or severe HA who received octocog alfa or rurioctocog alfa pegol. Statistical analyses were performed using SAS software (SAS Institute, Inc., Cary, North Carolina, United States), version 9.4.

Methods

Study design

The German AHEAD study is a noninterventional, prospective, open-label, multicenter, real-world study in Germany that began in June 2010 and was terminated by the sponsor in March 2022. Participants comprised those receiving octocog alfa or rurioctocog alfa pegol, including patients switching from octocog alfa to rurioctocog alfa pegol. Treatment, including purpose and treatment regimen, was at the discretion of the treating physician. Adults and children aged ⩾12 years could receive rurioctocog alfa pegol in the study after the product became available for this population in Germany in January 2018. The study was reviewed/approved by the relevant institutional review boards/ethics committees of all participating centers.

Objectives

The primary objective was to determine joint health outcomes in patients receiving octocog alfa or rurioctocog alfa pegol. Secondary objectives included determining hemostatic effectiveness in a variety of clinical settings, consumption of octocog alfa and rurioctocog alfa pegol, the impact of treatment on QoL, and the safety and immunogenicity of treatment.

Patients

Eligible patients had moderate or severe HA (baseline FVIII ⩽5%). The study was open to patients of any age, sex, or ethnicity, although patients receiving rurioctocog alfa pegol were required to be ⩾12 years of age, in accordance with the European product label.¹³ Patients with known hypersensitivity to the active substances or any of the excipients, or allergy to mouse or hamster proteins, were excluded. Written informed consent was provided before study enrollment.

Endpoints

The primary endpoint was the incidence of hemophilia-affected joint arthropathy evaluated by the treating physician in routine clinical practice using imaging techniques (e.g., magnetic resonance imaging, X-ray, and ultrasound) and by assessing the pain, bleeding, and physical exam parameters of the Gilbert scale.¹⁵ The Gilbert scale measures hemophilia joint health status in the absence of acute bleed, acute pain, and acute inflammation in the evaluated joint. Although the scale often incorporates four parameters—pain (score 0−3), bleeding (score 0−3), physical examination (score 0−12), and X-ray (score 0−13)—this analysis used the three-dimensional score, excluding the X-ray component.

Secondary endpoints included annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR); consumption of octocog alfa and rurioctocog alfa pegol (annualized total dose); and health-related QoL (Short-Form 12-item version 2 questionnaire, mental component score (MCS-12), and physical component score (PCS-12)). Incidences of adverse events (AEs) and de novo FVIII inhibitors were assessed.

Treatment and study procedures

Treatment regimens included on-demand treatment, prophylaxis (standard or individualized PK-guided) or immune tolerance induction (ITI). Prophylaxis was defined as regular (at least once weekly) continuous replacement therapy, with frequency, dosing, and duration at the investigator’s discretion. A prophylaxis regimen using individual PK characteristics to guide the dose could be employed to maintain FVIII trough levels >1% above baseline at 72 h intervals, as previously described.¹⁶ PK-guided prophylaxis was performed using myPKFit,¹⁷ or other software, including Web-Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS-Hemo),¹⁸ NONMEM (Nonlinear Mixed Effects Modelling; ICON plc, Dublin, Ireland), SAS (SAS Institute, Inc., Cary, NC, USA), TCIWorks,¹⁹ or Phoenix WinNonlin (Certara, Princeton, NJ, USA). Frequency of monitoring (laboratory, radiologic, and clinical) was determined by the treating physician.

Patients used their own treatment diary or the optional study-specific patient diary to record an infusion log; bleed treatment record (bleed location, bleed type, and etiology); hemostatic effectiveness rating; days off work or school owing to bleeding episodes; pain associated with bleeding event; concomitant medications; and AEs. Information from patient diaries, laboratory forms/notes, X-ray scan results, and QoL questionnaires was documented on an electronic case report form. Bleeding episodes resulting from injury caused by a definable external agent or other physical injury (e.g., related to blunt or sharp impact, or a sprained ankle, elbow, or wrist) were defined as “trauma-related.”

The planned participation period was 8 years from the baseline to the eighth follow-up visit for patients receiving octocog alfa at baseline; ⩾4 years after the switch for patients switching from octocog alfa to rurioctocog alfa pegol; or ⩾4 years from baseline for patients prescribed rurioctocog alfa pegol when enrolled into the study.

Statistical methods

Given the low prevalence of HA, which is considered to be an orphan disease, the number of patients eligible for documentation is limited. Therefore, no formal sample size calculation was performed to determine the number of patients for inclusion. Instead, the sample size was based on feasibility, with a planned enrolment of 450 (400 receiving octocog alfa and 50 receiving rurioctocog alfa pegol). The safety analysis set was used for all endpoints and comprised data for all enrolled patients who received at least one infusion of octocog alfa or rurioctocog alfa pegol. Statistical analyses were performed using SAS software (SAS Institute, Inc., Cary, North Carolina, United States), version 9.4.

All analyses were descriptive; continuous variables are expressed as means ± standard deviations and medians (interquartile ranges, IQRs); categorical variables are expressed as frequencies and percentages.

For missing enrollment start dates, administration of study medication or AEs, missing day was assumed to be the first day of the month, and missing day and month as 1 January, unless the timing of the AE versus the first administration was unclear, in which case the day of study medication administration was used. For missing end dates, the missing day was assumed to be the last day of the month, and missing day and month as 31 December. No imputation was made for missing dates for the switch between octocog alfa and rurioctocog alfa pegol.

Results

Study participants

In total, 405 male patients were enrolled in the study from 36 sites between June 7, 2010, and March 31, 2022, 380 of whom received at least one infusion of octocog alfa and/or rurioctocog alfa pegol (Figure 1) and comprised the safety analysis set. Of the 380 patients, 377 were initiated on octocog alfa, and three were initiated on rurioctocog alfa. During the study, 96 patients switched from octocog alfa to rurioctocog alfa pegol (Figure 1). A total of 102 patients completed the study before its termination. The median (range) study duration was 2598 (101−3903) days for octocog alfa and 1056 (156−1373) days for rurioctocog alfa pegol.

Figure 1.

Patient disposition.

Baseline characteristics

Octocog alfa

The median (range) age of the 377 patients receiving octocog alfa during the study was 25 (1−80) years (Table 1). The majority of these patients (n = 300; 79.6%) received prophylaxis at screening, 71 patients (18.8%) received on-demand treatment, and 6 patients (1.6%) received ITI (data not reported for this regimen). PK-guided prophylaxis was received by 81 patients (My PKFit, n = 80; other PK-guided prophylaxis, n = 1; targeted trough levels over time are shown in Supplemental Figure 1). Overall, 309 patients had severe HA (82.0%; prophylaxis, n = 270; on demand, n = 33; ITI, n = 6) and 68 patients had moderate HA (18.0%; prophylaxis, n = 30; on demand, n = 38). Overall, 101 patients (26.8%; prophylaxis, n = 86; on demand, n = 13) had already received FVIII treatment with one or more products (mostly octocog alfa) in the 24 months before study entry. While female patients were eligible for the study, no female patients were enrolled. Baseline characteristics of patients who completed the study versus those who terminated early are summarized in Supplemental Table 1. Three patients receiving octocog alfa prophylaxis and two receiving ITI had a positive FVIII inhibitor titer detected at the most recent assessment before study treatment.

Table 1.

Baseline characteristics of patients receiving octocog alfa and/or rurioctocog alfa pegol by treatment regimen at screening (safety analysis set).

Characteristic	Octocog alfa			Rurioctocog alfa pegol
Characteristic	Prophylaxis (n = 300)	On demand (n = 71)	Total (N = 377)^a	Prophylaxis (n = 92)	On demand (n = 7)	Total (N = 99)
Median (range) age, years	22.5 (1.0–72.0)	39.0 (2.0–80.0)	25.0 (1.0–80.0)	39.0 (12.0–76.0)	43.0 (17.0–65.0)	40.0 (12.0–76.0)
Age category, n (%)	n = 300	n = 71	n = 377	n = 92	n = 7	n = 99
0 to < 2 years	14 (4.7)	0	15 (4.0)	0	0	0
2 to <12 years	63 (21.0)	6 (8.5)	74 (19.6)	0	0	0
12 to <18 years	35 (11.7)	1 (1.4)	36 (9.5)	10 (10.9)	1 (14.3)	11 (11.1)
18 to <40 years	113 (37.7)	30 (42.3)	143 (37.9)	36 (39.1)	1 (14.3)	37 (37.4)
40 to <65 years	72 (24.0)	30 (42.3)	102 (27.1)	41 (44.6)	4 (57.1)	45 (45.5)
65 to >80 years	3 (1.0)	4 (5.6)	7 (1.9)	5 (5.4)	1 (14.3)	6 (6.1)
Severity of HA, n (%)	n = 300	n = 71	n = 377	n = 92	n = 7	n = 99
Severe HA (FVIII <1%)	270 (90.0)	33 (46.5)	309 (82.0)	80 (87.0)	2 (28.6)	82 (82.8)
Moderate HA (FVIII 1%—5%)	30 (10.0)	38 (53.5)	68 (18.0)	12 (13.0)	5 (71.4)	17 (17.2)
Age at HA diagnosis, n (%)	n = 300	n = 70	n = 376	n = 92	n = 6	n = 98
0 to <2 years	243 (81.0)	35 (50.0)	283 (75.3)	68 (73.9)	2 (33.3)	70 (71.4)
2 to <12 years	46 (15.3)	22 (31.4)	69 (18.4)	20 (21.7)	3 (50.0)	23 (23.5)
12 to <18 years	5 (1.7)	5 (7.1)	10 (2.7)	2 (2.2)	1 (16.7)	3 (3.1)
⩾18 years	6 (2.0)	8 (11.4)	14 (3.7)	2 (2.2)	0 (0)	2 (2.0)
FVIII mutation genotype, n (%)	n = 253^b	n = 62	n = 319	n = 83^c	n = 7	n = 90^c
Intron-22-inversion	99 (39.1)	7 (11.3)	109 (34.2)	27 (32.5)	1 (14.3)	28 (31.1)
Intron-1-inversion	13 (5.1)	2 (3.2)	15 (4.7)	5 (6.0)	0	5 (5.6)
Stop mutation	34 (13.4)	2 (3.2)	36 (11.3)	12 (14.5)	0	12 (13.3)
Missense mutation	53 (20.9)	34 (54.8)	87 (27.3)	18 (21.7)	4 (57.1)	22 (24.4)
Large deletion	7 (2.8)	0	7 (2.2)	2 (2.4)	0	2 (2.2)
Small deletion/small insertion	27 (10.7)	7 (11.3)	35 (11.0)	13 (15.7)	1 (14.3)	14 (15.6)
Splice site mutation	7 (2.8)	5 (8.1)	12 (3.8)	1 (1.2)	1 (14.3)	2 (2.2)
Gene duplication	1 (0.4)	1 (1.6)	2 (0.6)	0	0	0
Unknown mutation	9 (3.6)	2 (3.2)	11 (3.4)	3 (3.6)	0	3 (3.3)

Includes six patients who received immune tolerance induction at screening; data during immune tolerance induction not reported.

Information on specific mutations was not reported for three patients.

Information on specific mutations was not reported for two patients.

FVIII, factor VIII; HA, hemophilia A.

Rurioctocog alfa pegol

The median (range) age of the 99 patients treated with rurioctocog alfa pegol was 40 (12−76) years. Most patients (n = 92; 92.9%) received prophylaxis at screening and seven (7.1%) received on-demand therapy. PK-guided prophylaxis was received by 68 patients, all of whom used MyPKFit; targeted trough levels are shown in Supplemental Figure 1. Overall, 82 had severe HA (82.8%; prophylaxis, n = 80; on demand, n = 2) and 17 (17.2%; prophylaxis, n = 12; on demand, n = 5) had moderate HA. Again, all enrolled patients were male.

Joint health: Gilbert scores and development of new arthropathies

In patients receiving octocog alfa prophylaxis, median average Gilbert scores decreased from 1.0 at year 1 to 0.3 at year 6; the number of patients with data decreased over this period from 83 to 25 (Figure 2). Information on the percentage of patients with missing data at each timepoint is shown in Supplemental Table 2. Gilbert scores were available for only six patients receiving rurioctocog alfa pegol during follow-up (data not shown).

Figure 2.

Joint health: annual development of average Gilbert score (three-dimensional; all joints). Includes all patients treated with octocog alfa.

A higher proportion of patients receiving octocog alfa on-demand therapy developed new arthropathies during the study than those receiving octocog alfa prophylaxis (13/80 (16.3%) vs 37/324 (11.4%), Supplemental Table 3). This also applied to octocog alfa-treated patients with pre-existing target joints (i.e., joints with recurrent bleeding episodes; on-demand: 7/37 (18.9%) vs prophylaxis: 17/124 (13.7%)). Only three patients receiving rurioctocog alfa pegol experienced new arthropathies during the study.

Bleeding rates: ABR/AJBR

Bleeding rates for patients receiving octocog alfa, stratified by treatment regimen and HA severity, are shown in Figures 3 and 4. In patients with severe HA, ABRs, and AJBRs tended to be lower in patients receiving octocog alfa prophylaxis than in those receiving on-demand treatment: median ABRs during follow-up (⩽8 years) were 1.0−2.0 versus 2.4−13.0 and median AJBRs were 0.0 versus 1.7−7.0, respectively. However, it should be noted that most patients with severe HA received prophylaxis (272–64 patients from year 1 to 8 vs 31–8 patients for on-demand therapy). Percentages of patients with severe HA and an ABR or AJBR of zero were correspondingly higher with prophylaxis than on-demand therapy (Figures 3 and 4). In patients with moderate HA receiving octocog alfa, median ABRs were 1.0−3.0 with prophylaxis versus 0.0−3.0 for on-demand therapy, and median AJBRs were 0.0−1.0 for both treatment regimens (Figures 3 and 4). In year 8, severe bleeds were reported in 1/21 patients with data (4.8%) receiving on-demand octocog alfa and in 0/60 patients (0%) receiving prophylaxis.

Figure 3.

Median (IQR) ABRs, and percentages of patients with an ABR of zero, in patients with (a) severe and (b) moderate hemophilia A treated with octocog alfa.

Figure 4.

Median (IQR) AJBRs, and percentages of patients with an AJBR of 0, in patients with (a) severe and (b) moderate hemophilia A treated with octocog alfa.

ABRs in patients with severe HA receiving octocog alfa prophylaxis are presented by prophylaxis type in Figure 5. Bleeding rates were generally similar between standard and PK-guided prophylaxis, although few patients received PK-guided prophylaxis.

Figure 5.

Median (IQR) (a) ABRs and (b) AJBRs, and percentage of patients with an ABR/AJBR of zero, in patients with severe hemophilia A treated with octocog alfa prophylaxis.

Most patients receiving rurioctocog alfa pegol had severe HA and received prophylaxis. In this subgroup of patients, median ABRs and AJBRs were 0.0 from years 1 to 3 (Supplemental Figures 2 and 3).

In patients who switched from octocog alfa to rurioctocog alfa pegol prophylaxis, ABRs and AJBRs tended to be lower after switching for standard and PK-guided prophylaxis (Supplemental Figure 4).

Adverse events

In total, 84.4% of patients receiving octocog alfa and 66.7% of patients receiving rurioctocog alfa pegol reported one or more AEs (Table 2). Treatment-related AEs and serious treatment-related AEs were reported in 5.3% and 4.2% (including hemorrhage, arthropathy, and FVIII inhibitor development) of patients receiving octocog alfa and 5.1% and 4.0% (including hemorrhage or arthropathy) of patients receiving rurioctocog alfa pegol, respectively. The two thrombotic events that occurred with octocog alfa (acute myocardial infarction and jugular vein thrombosis) resolved without requiring a change in the octocog alfa dose.

Table 2.

Summary of AEs in patients with severe or moderate hemophilia A.

AE	Octocog alfa^a (N = 377)			Rurioctocog alfa pegol (N = 99)
AE	Patients, n (%)	Events, n	AE incidence per 100 PYs	Patients, n (%)	Events, n	AE incidence per 100 PYs
⩾1 AE	318 (84.4)	2153	94.4	66 (66.7)	217	100.9
⩾1 treatment-related AE	20 (5.3)	39	1.7	5 (5.1)	7	3.3
⩾1 serious AE	156 (41.4)	374	16.4	26 (26.3)	35	16.3
⩾1 serious treatment-related AE	16 (4.2)	35^b	1.5	4 (4.0)	4^c	1.9
⩾1 AE leading to discontinuation	7 (1.9)	22	1.0	0	0	0
⩾1 AE leading to death	1 (0.3)^d	3	0.1	0	0	0

Total number of patients enrolled on octocog alfa, including those switched to rurioctocog alfa pegol.

Hemorrhage (hemarthrosis (n = 2); postprocedural hemorrhage, renal hemorrhage, tooth socket hemorrhage, and unspecified hemorrhage (all n = 1)); factor VIII inhibitor development (n = 3); contusion and fall (n = 2); abdominal pain, acute myocardial infarction, ataxia, blood urine present, device leakage, device-related infection, dizziness, drug ineffective, epilepsy, face edema, hepatitis C, jugular vein thrombosis, loss of consciousness, papule, polyneuropathy, product preparation error, pruritus, rash, swelling face, tooth disorder, vertigo, and vomiting (all n = 1).

Drug ineffective, epilepsy, intra-abdominal hemorrhage, and synovitis (all n = 1).

Of unknown cause.

AE, adverse event; PY, patient-year.

Eight patients receiving octocog alfa developed a positive titer for neutralizing antibodies against FVIII during the study (according to local cut-off or ⩾0.6 Bethesda units (BU)). These patients were negative for FVIII inhibitors at study entry (<local cut-off or 0.6 BU/ml) and consisted of two previously untreated patients (i.e., without previous exposure to FVIII), one minimally treated patient (1–4 FVIII exposure days) and five previously treated patients (⩾5 FVIII exposure days). One of the previously untreated patients had severe baseline hemophilia and developed inhibitors at a low titer on prophylactic octocog alfa treatment. The second previously untreated patient, who had moderate baseline hemophilia, no family history of inhibitors and was treated with ITI octocog alfa, developed a high-titer inhibitor (>5 BU/ml) during the study. The minimally treated patient, who had severe baseline hemophilia and was receiving prophylactic octocog alfa, developed a high inhibitor titer during the study. The five previously treated patients (1.7% (5/302)) developed low inhibitor titers (local cut-off or ⩾0.6 and ⩽5 BU/ml) during the study. Four of these patients had severe baseline hemophilia. The fifth previously treated patient had moderate baseline hemophilia and developed a de novo inhibitor (i.e., at least two positive inhibitor measurements during the study (titer ⩾0.6 BU/ml or confirmed positive) and no historical titer ⩾0.6 BU/ml or positive inhibitor titer at screening). This patient had a FVIII missense mutation, concurrent autoimmune disorders (lupus anticoagulants antibodies, anti-phospholipid syndrome), and was receiving octocog alfa on-demand therapy (32 infusions over a 6-year period). The patient had previously received >150 exposure days of octocog alfa on-demand therapy. Low positive inhibitor titers (1.11−2.97 BU/ml) were observed at various timepoints starting 1 year after the baseline visit and continuing until study closure. FVIII plasma trough levels at these timepoints were between 1.1% and 5.7%. No action was taken in relation to the de novo inhibitor development. There were no other de novo inhibitors.

No patients receiving rurioctocog alfa pegol had positive FVIII inhibitor titers at baseline or developed positive inhibitor titers during the study.

Study drug consumption

The mean annualized total dose for octocog alfa was 4907 IU/kg for standard prophylaxis and 5223 IU/kg for PK-guided prophylaxis (Figure 6; Supplemental Table 4). For rurioctocog alfa pegol, mean annualized total doses were 4309 and 4596 IU/kg, respectively (Figure 6; Supplemental Table 4).

Figure 6.

Consumption of octocog alfa and rurioctocog alfa pegol prophylaxis in patients with severe or moderate hemophilia A.

In prophylaxis-treated patients who switched from octocog alfa to rurioctocog alfa pegol, mean annualized total dose before switching was 4477 IU/kg for standard prophylaxis and 5070 IU/kg for PK-guided prophylaxis (Supplemental Figure 5). After switching, mean annualized total doses were 4348 and 4596 IU/kg, respectively (Supplemental Figure 5).

Quality of life

In patients aged ⩾18 years with HA treated with octocog alfa, mean scores for PCS-12 and MCS-12 remained constant throughout follow-up (Figure 7(a) and (b)). There were greater variations in PCS-12 and MCS-12 scores with rurioctocog alfa pegol (Figure 7(c) and (d)), although numbers of patients with these data varied during follow-up (up to 4 years).

Figure 7.

Mean ± SD Short-Form 12-item version 2 physical and mental component scores in patients aged ⩾18 years with severe or moderate hemophilia A treated with octocog alfa (a and b) or rurioctocog alfa pegol (c and d).

Discussion

Final results of the AHEAD German study in patients with HA receiving octocog alfa corroborate interim data demonstrating long-term effectiveness of octocog alfa, regardless of severity.^20,21 The results are also consistent with 7-year data from the separate AHEAD international study (n = 711), in which patients with moderate or severe HA who received octocog alfa prophylaxis had low ABRs and AJBRs at all timepoints.²² Furthermore, in the present analysis a greater proportion of patients with severe HA receiving prophylaxis had an ABR of zero than those receiving on-demand therapy, reflecting previous clinical trial data.^16,23 Gilbert scores also remained low in patients with HA receiving octocog alfa prophylaxis, and a lower proportion of these patients developed new arthropathies during the study than those receiving on-demand therapy.

Over time, ABRs in patients with severe HA receiving octocog alfa prophylaxis generally remained stable and ABRs did not reduce as much as expected. The higher-than-expected mean ABRs and AJBRs reported in this study in patients with severe HA may be related to the wide range of bleeding rates, which might be due to variations in self-reporting by patients, and increased physical activity. Indeed, a systematic review of 36 articles on physical activity in people with hemophilia suggested that improvements in prophylactic regimens have been associated with increased activity levels, particularly among people with severe hemophilia.²⁴ Similarly, a study of adherence to prophylactic octocog alfa therapy found that high adherence was associated with increased participation in all forms of sport, as well as improved performance in endurance sports.²⁵ Notably, the 2020 treatment guidelines from the World Federation of Haemophilia recommend personalizing prophylaxis regimens based on activities, lifestyle, and PK handling of FVIII.¹ In this study, similar bleeding rates were observed with PK-guided and standard prophylaxis with octocog alfa in patients with severe HA at Year 1, with the number of patients receiving PK-guided prophylaxis being too small to make comparisons thereafter. Notably, annualized doses were higher in patients receiving PK-guided prophylaxis compared with standard prophylaxis. This may be a form of selection bias, in that the patients most likely to receive PK-guided prophylaxis are those who require improvement of their treatment. Conversely, patients receiving standard prophylaxis may have started treatment years earlier based on clinical presentation and achieved sufficient bleeding control, making treatment adjustments unnecessary. In addition, PK-driven therapy depends on the target FVIII level of the laboratory, which is almost always higher than the patient’s actual FVIII level, leading to dose increases in patients who undergo PK evaluation.

A similar number of patients with moderate HA received octocog alfa prophylaxis and on-demand therapy, and bleeding rates were broadly similar in the two groups, although higher than expected for a population with moderate HA. This suggests that deciding between prophylaxis and on-demand therapy for these patients is more challenging than in severe HA, and also that moderate HA may be undertreated. Findings from the present analysis are consistent with previous studies showing that patients with moderate HA, especially those with a baseline FVIII level of 1−3 IU/dl, are at risk of joint bleeds and progressive arthropathy.^26
–28 The pattern of bleeding and joint scores in patients with baseline FVIII 1−3 IU/dl differed from that in patients with levels of 3−5 IU/dl.²⁷ This suggests that the definition of moderate HA (1−5 IU/dl) might be too broad, potentially underestimating the severity of HA in patients with FVIII levels at the lower end of the moderate range.²⁹

In this study, most patients receiving rurioctocog alfa pegol had severe HA and were receiving prophylaxis. In these patients, low bleeding rates were observed over a 3-year period (median ABRs of 0.0), consistent with previous clinical trial data.¹² Real-world data have also demonstrated the effectiveness of FVIII products with extended half-lives.^30–32 In a retrospective observational study in the United States, for example, switching from a standard half-life product to rurioctocog alfa pegol was associated with significantly fewer bleeding episodes (p < .001), as a result of more effective prophylaxis and improved adherence.³⁰ Similarly, studies in Portugal and the United Kingdom have shown that switching to efmoroctocog alfa from prophylaxis with a standard half-life product can improve bleeding rates and FVIII consumption.^31,32

The incidence of AEs in patients receiving rurioctocog alfa in real-world practice was consistent with previous reports.¹³ The overall incidence of AEs was higher in patients receiving octocog alfa than in those receiving rurioctocog alfa pegol, although the incidence per 100 patient-years was broadly similar between treatments. With both octocog alfa and rurioctocog alfa pegol, treatment-related AEs occurred in 5%, and treatment-related SAEs in 4% of patients including disease-related events (e.g., hemorrhage, increased bleeding frequency, and arthropathy) or FVIII inhibition. The higher absolute incidence of AEs may reflect the longer duration of follow-up in patients receiving octocog alfa and the demographic and disease characteristics in patients who continued octocog alfa compared with those who switched to rurioctocog alfa pegol. Potential reporting issues such as coding of bleeding events as AEs may have also contributed to the frequency of AEs reported with octocog alfa. De novo inhibitor development was reported in one previously treated patient during the study. This patient received octocog alfa and had moderate HA with concomitant autoimmune disorders.

When interpreting the results of the AHEAD German study, it is important to consider the limitations of noninterventional observational studies, such as the lack of a standardized treatment regimen and control group, and the small number of patients receiving on-demand therapy versus prophylaxis. Enrollment in the study was dynamic and numbers of patients varied year on year, which could account for variability in outcomes over the follow-up period. In addition, there was no formal definition of PK-guided prophylaxis in the study protocol. Effectiveness and safety data were largely collected using diaries and are potentially susceptible to inaccurate recall of bleeding events and AEs by patients. Moreover, no data on adherence were collected. Efficacy was assessed using Gilbert scores, as this was standard practice at the time the study was designed. However, practice patterns have since changed and Gilbert scores have been superseded by the Hemophilia Joint Health Score in some countries. Analysis of efficacy may also have been limited by the young age of the population, the existence of less advanced or minimal joint disease, and the lack of an X-ray component. There is also likely to have been a clinical bias between the prophylactic and on-demand cohorts, as patients with fewer bleeds are more likely to have continued on-demand therapy rather than receiving prophylaxis. Finally, it should be noted that the study was terminated early by the sponsor because of low retention of enrolled patients. As a result, there is a difference in follow-up duration between octocog alfa and rurioctocog alfa pegol. For patients receiving octocog alfa, the most common reason for discontinuation was a switch to another FVIII product (34% of patients who discontinued), which may have led to withdrawal bias if patients with higher bleeding rates withdrew from the study to change therapies, leading to an apparent improvement in outcomes over time. In the octocog alfa group, 8% of patients who did not complete the study withdrew because of early termination of the study, while for rurioctocog alfa pegol, 90% of patients who discontinued did so because of early study termination. Patients with severe HA appeared to be more likely to complete the study than those with moderate HA in the prophylaxis group, although there was no clear trend in the on-demand group. Earlier diagnosis (<2 years) also appeared to be associated with higher follow-up, especially in the prophylaxis group. There were no clear trends with respect to FVIII mutation genotype (Supplemental Table 1).

Conclusion

In conclusion, these real-world data show that long-term prophylaxis with octocog alfa or rurioctocog alfa pegol is associated with reduced bleeding rates compared with on-demand therapy in patients with severe HA, while maintaining low Gilbert scores and lower AJBRs. The higher-than-expected bleeding rates in patients with moderate HA suggest that these patients, especially those with FVIII levels at the lower end of the 1%−5% range, may benefit from more individualized FVIII replacement therapy.

Supplemental Material

sj-docx-1-tah-10.1177_20406207261419337 – Supplemental material for Final data from the German AHEAD study: effectiveness and safety of octocog alfa and rurioctocog alfa pegol for hemophilia A in a real-world setting

Supplemental material, sj-docx-1-tah-10.1177_20406207261419337 for Final data from the German AHEAD study: effectiveness and safety of octocog alfa and rurioctocog alfa pegol for hemophilia A in a real-world setting by Robert Klamroth, Karin Kurnik, Swee Wenning, Carmen Escuriola-Ettingshausen, Stephan Regensburger, Leilei Tang, Joan Gu, Randy Guerra and Johannes Oldenburg in Therapeutic Advances in Hematology

Supplemental Material

sj-docx-2-tah-10.1177_20406207261419337 – Supplemental material for Final data from the German AHEAD study: effectiveness and safety of octocog alfa and rurioctocog alfa pegol for hemophilia A in a real-world setting

Supplemental material, sj-docx-2-tah-10.1177_20406207261419337 for Final data from the German AHEAD study: effectiveness and safety of octocog alfa and rurioctocog alfa pegol for hemophilia A in a real-world setting by Robert Klamroth, Karin Kurnik, Swee Wenning, Carmen Escuriola-Ettingshausen, Stephan Regensburger, Leilei Tang, Joan Gu, Randy Guerra and Johannes Oldenburg in Therapeutic Advances in Hematology

Supplemental Material

sj-docx-3-tah-10.1177_20406207261419337 – Supplemental material for Final data from the German AHEAD study: effectiveness and safety of octocog alfa and rurioctocog alfa pegol for hemophilia A in a real-world setting

Supplemental material, sj-docx-3-tah-10.1177_20406207261419337 for Final data from the German AHEAD study: effectiveness and safety of octocog alfa and rurioctocog alfa pegol for hemophilia A in a real-world setting by Robert Klamroth, Karin Kurnik, Swee Wenning, Carmen Escuriola-Ettingshausen, Stephan Regensburger, Leilei Tang, Joan Gu, Randy Guerra and Johannes Oldenburg in Therapeutic Advances in Hematology

Footnotes

Acknowledgements

Under the direction of the authors, medical writing support was provided by Joanne Vaughan, employee of Envision Catalyst, an Envision Medical Communications agency, a part of Envision Pharma Group (Fairfield, CT) and was funded by Takeda Pharmaceuticals International AG, Zurich, Switzerland.

Declarations

ORCID iDs

Karin Kurnik

Carmen Escuriola-Ettingshausen

Stephan Regensburger

Supplemental material

Supplemental material for this article is available online.

References

Srivastava

Santagostino

Dougall

, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020; 26(Suppl. 6): 1–158.

Di Minno

Ambrosino

Franchini

, et al. Arthropathy in patients with moderate hemophilia A: a systematic review of the literature. Semin Thromb Hemost 2013; 39: 723–731.

Gooding

Thachil

Alamelu

, et al. Asymptomatic joint bleeding and joint health in hemophilia: a review of variables, methods, and biomarkers. J Blood Med 2021; 12: 209–220.

Hermans

Dolan

Pharmacokinetics in routine haemophilia clinical practice: rationale and modalities—a practical review. Ther Adv Hematol 2020; 11: 2040620720966888.

Gualtierotti

Giachi

Suffritti

, et al. Optimizing long-term joint health in the treatment of hemophilia. Expert Rev Hematol 2024; 17: 713–721.

Valentino

LA.

Considerations in individualizing prophylaxis in patients with haemophilia A. Haemophilia 2014; 20: 607–615.

Tegenge

Yang

Forshee

RA.

Predicting dose sparing benefit and bleeding risk of pharmacokinetic-based personalized prophylactic dosing of factor VIII products. Haemophilia 2017; 23: 705–711.

German Medical Association (Bundersärtztekammer). Cross-sectional guidelines for therapy with blood components and plasma derivatives (5th ed.) [publication in German], https://www.bundesaerztekammer.de/fileadmin/user_upload/downloads/pdf-Ordner/MuE/Querschnitts-Leitlinien_BAEK_zur_Therapie_mit_Blutkomponenten_und_Plasmaderivaten-Gesamtnovelle_2020.pdf (2020, accessed 13 January 2022).

Klamroth

Windyga

Radulescu

, et al. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study. Blood 2021; 137: 1818–1827.

10.

Konkle

Stasyshyn

Chowdary

, et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 2015; 126: 1078–1085.

11.

Shapiro

AD.

Anti-hemophilic factor (recombinant), plasma/albumin-free method (octocog-alpha; ADVATE) in the management of hemophilia A. Vasc Health Risk Manag 2007; 3: 555–565.

12.

Chowdary

Mullins

Konkle

, et al. Long-term safety and efficacy results from the phase 3b, open-label, multicentre Continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe haemophilia A. Haemophilia 2020; 26: e168–e178.

13.

Baxalta Innovations GmBH. ADYNOVI, Summary of product characteristics, https://www.ema.europa.eu/en/documents/product-information/adynovi-epar-product-information_en.pdf (2023, accessed 8 February 2023).

14.

Takeda Manufacturing Austria AG. ADVATE, Summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/advate-epar-product-information_en.pdf. (2023, accessed 8 February 2023).

15.

Gilbert

MS.

Prophylaxis: musculoskeletal evaluation. Semin Hematol 1993; 30(3 Suppl 2): 3–6.

16.

Valentino

Mamonov

Hellmann

, et al. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012; 10: 359–367.

17.

Reininger

Spotts

Löw-Baselli

, et al. OR07: Optimizing prophylaxis: development of an advate PK calculator and dosing medical device based on a bayesian population PK model [abstract]. Haemophilia 2014; 20(Suppl 2): 15.

18.

McEneny-King

Foster

Iorio

, et al. Data analysis protocol for the development and evaluation of population pharmacokinetic models for incorporation into the Web-accessible Population Pharmacokinetic Service–Hemophilia (WAPPS-Hemo). JMIR Res Protoc 2016; 5: e232.

19.

Fuchs

Csajka

Thoma

, et al. Benchmarking therapeutic drug monitoring software: a review of available computer tools. Clin Pharmacokinet 2013; 52: 9–22.

20.

Oldenburg

Ozelo

Klamroth

, et al. P115: AHEAD international and German studies: 6-year interim effectiveness and safety outcomes in patients with hemophilia A receiving antihemophilic factor (recombinant) in a real-world setting [abstract]. Haemophilia 2020; 26(Suppl 2): 87.

21.

Tsakiris

Oldenburg

Klamroth

, et al. Effectiveness and safety outcomes in patients with hemophilia a receiving antihemophilic factor (recombinant) for at least 5 years in a real-world setting: 6-year interim analysis of the Ahead International and German studies. Blood 2020; 136(Suppl 1): 1.

22.

Ozelo

Hermans

Carcao

, et al. The effectiveness and safety of octocog alfa in patients with hemophilia A: up to 7-year follow-up of the real-world AHEAD international study. Ther Adv Hematol 2024; 15: 20406207231218624.

23.

Shapiro

Gruppo

Pabinger

, et al. Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A. Expert Opin Biol Ther 2009; 9: 273–283.

24.

Kennedy

O’Gorman

Monaghan

, et al. A systematic review of physical activity in people with haemophilia and its relationship with bleeding phenotype and treatment regimen. Haemophilia 2021; 27: 544–562.

25.

Zanon

Tagliaferri

Pasca

, et al. Physical activity improved by adherence to prophylaxis in an Italian population of children, adolescents and adults with severe haemophilia A: the SHAPE Study. Blood Transfus 2020; 18: 152–158.

26.

den Uijl

Fischer

Van Der Bom

, et al. Clinical outcome of moderate haemophilia compared with severe and mild haemophilia. Haemophilia 2009; 15: 83–90.

27.

den Uijl

Mauser Bunschoten

Roosendaal

, et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia 2011; 17: 849–853.

28.

Scott

Xiang

Hart

, et al. Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: the THUNDER study. Haemophilia 2019; 25: 205–212.

29.

Collins

Obaji

Roberts

, et al. Clinical phenotype of severe and moderate haemophilia: who should receive prophylaxis and what is the target trough level? Haemophilia 2021; 27: 192–198.

30.

Aledort

Milligan

Watt

, et al. A retrospective observational study of rurioctocog alfa pegol in clinical practice in the United States. J Manag Care Spec Pharm 2020; 26: 492–503.

31.

Campaniço

Rodrigues

Pereira

, et al. PB0594: Years of prophylaxis with rFVIII-Fc in haemophilia in a Portuguese haemophilia center: did doctors and patients see a change? [abstract]. Res Pract Thromb Haemost 2021; 5(Suppl 2): 449.

32.

Scott

Wall

Xiang

, et al. P0073: A within-patient and matched-pair comparison of real-world outcomes in patients using rFVIII and rFVIIIFc prophylaxis, in the UK [abstract]. Haemophilia 2020; 26(Suppl 2): 63.

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