ABSTRACT
Objective
To report data from an ITI chart review study (NCT03951103) for first‐time and rescue ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in persons with haemophilia A.
Methods
Retrospective and prospective real‐world data are reported from a non‐interventional, multicentre study of patients who had been or were currently being treated with rFVIIIFc ITI. ITI treatment outcome (defined by investigators) and regimens are reported.
Results
Forty‐one patients from 16 sites were included. First‐time ITI was used in 24 patients; 16 had an ITI outcome at study end. Thirteen patients (81.3%) had ITI success, and three had failure. Median (range) rFVIIIFc consumption was 300 (61–2800) IU/kg/week, and most (70.8%) used ≤ 300 IU/kg/week. The vast majority of patients (87.5%) received less than daily ITI.
Rescue ITI was used in 17 patients; 16 had an ITI outcome at study end. Eight patients (50.0%) had ITI success/partial success, seven had failure, and one withdrew early. Median (range) rFVIIIFc consumption was 536 (98–1435) IU/kg/week; 35.3% used ≤ 300 IU/kg/week and 52.9% used > 500 IU/kg/week. Most patients (64.7%) received daily ITI.
Conclusion
ITI with rFVIIIFc is likely to be successful in first‐time ITI patients and is an effective option for those who have previously experienced ITI failure.
Trial Registration: ClinicalTrials.gov identifier: NCT03951103
Keywords: factor VIII, haemophilia A, immune tolerance, quality of life, recombinant fusion protein, treatment outcome
1. Introduction
People with haemophilia A require lifelong therapy, typically with FVIII replacement. However, neutralising antibodies can arise in response to such treatment [1, 2]. In those with severe disease, up to ~30% may develop inhibitors [3, 4], rendering replacement treatment ineffective [5], while 3% with moderate and < 1% with mild disease may develop inhibitors, which can convert the phenotype to severe, making spontaneous bleeding episodes severe [4]. Being at a greater risk of more severe bleeding episodes can have a major impact on patients' clinical status, physical function and quality of life [1]. Subsequently, patients with inhibitors have significantly higher morbidity versus those without inhibitors [6]. Immune tolerance induction (ITI) is the gold standard to eradicate inhibitors in haemophilia A and involves repeated and frequent administration of FVIII to downregulate antibody response, tolerising the immune system to FVIII and restoring the clinical efficacy of FVIII replacement therapy [2, 7].
Preclinical data suggests an extended half‐life recombinant factor VIII Fc fusion protein, efmoroctocog alfa (Elocta; herein referred to as rFVIIIFc), has potential immunomodulatory properties, such as an enhanced ability to induce tolerance [8]. Retrospective clinical ITI data and case reports indicate earlier tolerance can be achieved using rFVIIIFc compared with standard half‐life (SHL) products [9, 10, 11, 12].
ITI therapy is not always successful, with complete ITI success rates between 38% and 83% for patients receiving first‐time ITI [13, 14, 15, 16, 17, 18, 19, 20, 21]. The wide variability in success rates in the literature may be influenced by differing FVIII product types, dosing regimens and patient‐related prognostic factors [13], such as a pre‐ITI inhibitor titre < 10 BU/mL, peak historical inhibitor titre < 200 BU/mL and ITI initiated ≤ 5 years after inhibitor diagnosis [9, 22]. Furthermore, patients who experience ITI failure can be exposed to subsequent ITI attempts, or ‘rescue ITI’ therapy. Although there are limited data on success rates and time to tolerance of rescue ITI treatments, a successful outcome is generally less likely than the first ITI attempt [9, 16, 17, 18]. Therefore, there is a need to optimise ITI treatment in patients who experienced previous ITI failure.
Responses to ITI with rFVIIIFc in first‐time and rescue ITI patients (defined as patients who had experienced prior ITI failure or had relapsed since prior attempts) have been reported in clinical interventional studies [23, 24]; however, information on how rFVIIIFc is used during ITI in clinical practice is limited. Here, we report real‐world data from an ITI chart review study (NCT03951103) for first‐time and rescue ITI with rFVIIIFc in persons with haemophilia A [25].
2. Materials and Methods
2.1. Study Design and Participants
Both retrospective and prospective real‐world data are reported from a non‐interventional, international, multicentre chart review study [25]. Persons with haemophilia A of all ages who had been or were currently being treated with rFVIIIFc ITI were enrolled in the study from Europe and the Middle East between November 2018 and September 2022. The study duration was approximately 4 years to capture long‐term outcome data of ITI treatment; all patients were followed for a minimum of 2 years. Patients were excluded from participation if they were already involved in another investigational medicinal product trial. Patients were prescribed factor treatment according to routine clinical practice and per labelled dosage guidance; the choice of treatment was not dictated by the study protocol.
All data were collected from the patients' medical records. At enrolment, patient characteristics and retrospective data were collected. Further data were collected once every year during the follow‐up period. The analysis population was stratified into two groups of patients: patients receiving ITI treatment for the first time (first‐time ITI) and patients who had experienced prior ITI treatment failure (rescue ITI).
2.2. Outcome Measures
Final retrospective and prospective medical record data are reported for short‐ and long‐term rFVIIIFc ITI outcomes and rFVIIIFc ITI treatment regimens, as judged by the investigator. Short‐term outcomes of rFVIIIFc ITI treatment were as follows: ITI outcome (success, partial success, failure, early withdrawal); inhibitor titre levels; FVIII half‐life and recovery level; proportion of patients reaching negative inhibitor titre (< 0.6 BU/mL) and normal recovery (in vivo recovery of ≥ 66% of the expected value) during ITI; time from ITI treatment start to first negative inhibitor titre, normal recovery and success/partial success; and annualised bleeding rate (ABR) during ITI.
ITI success and partial success were defined as below in the study protocol and were used as benchmarks to guide the investigators; however, as the study was observational in nature, ITI success was ultimately determined using the investigators' clinical judgment. ITI success was defined (based on the UK Haemophilia Centre Doctors Organisation guidelines) as the presence of an undetectable inhibitor titre (< 0.6 BU/mL), FVIII in vivo recovery of ≥ 66% of the expected value and FVIII half‐life ≥ 7 h after a 72‐h wash‐out period from the last infusion and the absence of anamnestic increase of inhibitor titre upon further FVIII exposure or as judged by the investigator [22, 26]. Partial ITI success was defined as an undetectable inhibitor titre but persistently abnormal FVIII recovery or half‐life after 33 months of ITI in association with a clinical response to FVIII replacement therapy without an anamnestic increase of the inhibitor titre or as judged by the investigator [15].
Blood samples for the determination of FVIII inhibitors were collected at all visits during the study. Samples were analysed at the local laboratory using the Nijmegen‐modified Bethesda assay, and local procedures for blood collection and processing were followed. The local laboratory that performed the determination of FVIII inhibitors was accredited. Inhibitor samples were also analysed centrally using the validated Nijmegen‐modified Bethesda assay. Fulfilment of the first criterion for ITI success after a negative titre for inhibitor (< 0.6 BU/mL by the Nijmegen‐modified Bethesda assay) was determined locally at two consecutive determinations.
Long‐term outcomes of rFVIIIFc ITI treatment included: occurrence of relapse since ITI success; time from ITI success to relapse; type of treatment and product used after ITI. Relapse was defined as inhibitor recurrence during the follow‐up period on prophylaxis after success, as evidenced by recurrent positive inhibitor titre or impaired FVIII pharmacokinetics or as judged by the investigator [15].
ITI treatment regimen outcomes were as follows: main weekly ITI dose; main ITI treatment regimen; overall duration of ITI (including off‐days); use of bypassing agents during ITI.
The study was not designed to answer safety questions. Therefore, only serious adverse events (SAEs), as well as non‐serious AEs leading to permanent discontinuation of rFVIIIFc treatment, were recorded. SAEs were classified as such if they: resulted in death; were life‐threatening; required inpatient hospitalisation or prolongation of existing hospitalisation; resulted in persistent or significant disability/incapacity; were a congenital anomaly/birth defect; or were a medically important AE (potentially requiring medical or surgical intervention).
2.3. Statistical Analysis
All endpoints were evaluated using descriptive statistics; no formal statistical tests were performed. The sample size was determined based on feasibility rather than formal calculation.
3. Results
3.1. Study Population
The study enrolled 42 patients, of which 41 were included in this analysis (one patient was excluded due to not having any documented treatment with rFVIIIFc ITI). These patients were treated across 16 sites in seven countries: Saudi Arabia (n = 17); France (n = 8); Germany (n = 6); Italy (n = 5); Norway (n = 3); Switzerland (n = 1) and Kuwait (n = 1). Of the 41 patients included, 40 had severe disease and one first‐time ITI patient had moderate disease (later became severe with inhibitory activity; Table 1). All patients were male and the majority were white (n = 29/41; 70.7%). The median (range) study observation period was 807.0 (282–1365) days. Forty out of these 41 patients were high responders (historical inhibitor titre ≥ 5 BU/mL); one rescue ITI patient was not a high responder. Initial rFVIIIFc ITI dose ranged from 100 to 1400 IU/kg/week and initial dosing frequency ranged from twice weekly to twice daily.
TABLE 1.
Baseline characteristics.
| Patient characteristics | First‐time ITI (n = 24) | Rescue ITI (n = 17) |
|---|---|---|
| Male, n (%) | 24 (100) | 17 (100) |
| Age at rFVIIIFc ITI start (years), median (range) | 3 (0–32) | 11 (2–53) |
| Haemophilia severity, n (%) | ||
| Severe | 23 (95.8) | 17 (100) |
| Moderate | 1 (4.2) | 0 |
| Haemophilia genotype, n (%) | ||
| Inversion (intron 1/22) | 4 (16.7) | 11 (64.7) |
| Large deletion | 0 | 0 |
| Nonsense | 0 | 1 (5.9) |
| Missense | 1 (4.2) | 0 |
| Splice site | 0 | 1 (5.9) |
| Other | 0 | 2 (11.8) |
| Unknown | 18 (75.0) | 2 (11.8) |
| Missing | 1 (4.2) | 0 |
| Family history of inhibitors, n (%) | ||
| Yes | 7 (29.2) | 6 (35.3) |
| No | 16 (66.7) | 8 (47.1) |
| Unknown | 1 (4.2) | 3 (17.7) |
| Bleeding episodes in the 12 months prior to rFVIIIFc ITI start, median (range) | 2 (0–7) | 5 (0–57) |
| Months from inhibitor detection to rFVIIIFc ITI start, median (range) | 3 (0–104) | 130 (12–500) |
| Inhibitor titre at rFVIIIFc ITI start (BU/mL), median (range) | 30 (1–734) | 5 (1–9601) |
| Historic peak inhibitor titre prior to rFVIIIFc ITI (BU/mL), median (range) | 33 (6–772) | 96 (1–9601) |
| Inhibitor titre ≥ 10 BU/mL at any ITI start, n (%) | 17 (70.8) | 14 (82.4) |
| Number of previous ITI attempts, median (range) | N/A | 2 (1–8) |
| Total duration of previous ITI (months), median (range) | N/A | 62 (9–289) |
Note: Continuous values are rounded to the nearest whole number. Percentages may not sum to 100 due to rounding.
Abbreviations: BU; Bethesda unit; ITI: immune tolerance induction; rFVIIIFc: recombinant factor VIII Fc fusion protein.
First‐time ITI with rFVIIIFc was used in 24 patients; median (range) age at initiation was 2.6 (0–32) years (Table 1). Inhibitor titres at their historical peak and at ITI start were 32.5 (6–772) and 29.9 (1–734) BU/mL, respectively. F8 gene mutations were reported in five patients (20.8%).
Rescue ITI with rFVIIIFc was used in 17 patients; median (range) age at initiation was 11.1 years (2–53) with a median of 2 (1–8) prior ITI attempts over a total duration of 61.9 (9–289) months (Table 1). Inhibitor titres at their historical peak and at ITI start were 96.0 (1–9601) and 5.4 (0.5–9601) BU/mL, respectively. F8 gene mutations were reported in 15 patients (88.2%).
3.2. First‐Time ITI Patients
3.2.1. Outcomes of rFVIIIFc ITI Treatment
In 16 patients with an ITI outcome, 13 (81.3%) had ITI success (Figure 1; with negative inhibitor titre), while three patients had failure; eight patients had ongoing ITI at study end. No patients relapsed. The median (range) time to ITI success was 346 (49–717) days. Of the 24 first‐time ITI patients, 14 (58.3%) achieved a negative inhibitor titre in a median (range) of 115 (22–569) days. Data on FVIII half‐life and patients achieving normal FVIII recovery are not reported as these measurements were rarely performed and not conducted in a standardised manner. The median peak inhibitor titre during rFVIIIFc ITI was 34.9 (0–1053) BU/mL. Of 15 first‐time ITI patients with recorded bleed data during rFVIIIFc ITI, the median (range) ABR was 0.0 (0.0–3.0) for any type of bleed. Ten of these patients did not experience any bleeds, two patients had 1 bleed, two patients had 2 bleeds and one patient had 3 bleeds. Out of 10 patients with available follow‐up data, all 10 recommenced haemophilia treatment with recombinant factor VIII products following rFVIIIFc ITI success; three of these patients also used other products. Nine of these 10 patients received prophylactic treatment and two received on‐demand treatment (one patient received both). The presence of risk factors did not seem to influence ITI success in this population, although the sample size was too small to draw definitive conclusions (Table S1).
FIGURE 1.
ITI outcomes for first‐time ITI patients receiving rFVIIIFc. ITI: immune tolerance induction; rFVIIIFc: recombinant factor VIII Fc fusion protein.
3.2.2. ITI Treatment Regimen
Median (range) weekly rFVIIIFc consumption was 300 (61–2800) IU/kg. The majority of first‐time ITI patients (70.8%) used ≤ 300 IU/kg/week, and 20.8% used > 500 IU/kg/week (Figure 2). The vast majority of patients (87.5%) received less than daily ITI; the most common treatment regimen was three times per week (29.2%). The overall median (range) rFVIIIFc treatment duration (including off‐days) was 614.5 (49–1697) days; 346.0 (49–717) days for patients with ITI success. Fifteen patients used prophylaxis with bypassing agents or non‐factor products during rFVIIIFc ITI. Ten (66.7%) of these patients used activated prothrombin complex concentrate (APCC) and eight (53.3%) used emicizumab; four patients used APCC and emicizumab simultaneously (APCC dose ranged between 50 and 100 IU/kg and dosing frequency ranged between 2 and 5 times/week). Nine patients used bypassing agents for on‐demand treatment; all used recombinant activated factor VII (rFVIIa). rFVIIIFc ITI outcomes and ABR for first‐time ITI patients stratified by dose and dosing frequency are shown in Tables S2 and S3, respectively.
FIGURE 2.
rFVIIIFc usage in first‐time ITI patients (n = 24). Percentages may not sum to 100 due to rounding. ITI: immune tolerance induction; IU: international unit; rFVIIIFc: recombinant factor VIII Fc fusion protein.
3.3. Rescue ITI Patients
3.3.1. Outcomes of rFVIIIFc ITI Treatment
In 16 patients with an ITI outcome, six (37.5%) had ITI success (Figure 3), while two patients had partial success, seven had failure, and one withdrew early; one patient had ongoing ITI at study end. All rescue ITI patients with ITI success/partial success had a negative inhibitor titre. One patient relapsed, 656 days after ITI success, while receiving prophylaxis during the follow‐up period. The median (range) time to ITI success was 542 (33–1888) days. Of the 17 rescue ITI patients, 12 (70.6%) achieved a negative inhibitor titre in a median (range) of 88 (0–769) days. As previously mentioned, data on FVIII half‐life and patients achieving normal FVIII recovery are not reported. The median peak inhibitor titre during rFVIIIFc ITI was 8.7 (0–8000) BU/mL. Of 15 rescue ITI patients with recorded bleed data during rFVIIIFc ITI, the median (range) ABR was 1.2 (0.0–57.0) for any type of bleed. Four of these patients did not experience any bleeds, three patients had 1 bleed, two patients had 2 bleeds and six patients had > 3 bleeds. Following rFVIIIFc ITI success, all five patients with available follow‐up data initiated haemophilia treatment with recombinant factor VIII products; one patient also used emicizumab. Following partial rFVIIIFc ITI success, the one patient with available data used emicizumab. All of these patients received prophylactic treatment following rFVIIIFc ITI. As above, the presence of risk factors in rescue ITI patients did not seem to impact rFVIIIFc ITI success (Table S1).
FIGURE 3.
ITI outcomes for rescue ITI patients receiving rFVIIIFc. ITI: immune tolerance induction; rFVIIIFc: recombinant factor VIII Fc fusion protein.
3.3.2. ITI Treatment Regimen
The median (range) weekly rFVIIIFc consumption was 536 (98–1435) IU/kg. Over a third of rescue ITI patients (35.3%) received ≤ 300 IU/kg/week and approximately half (52.9%) received > 500 IU/kg/week (Figure 4). Most patients (64.7%) received daily ITI. The overall median (range) rFVIIIFc treatment duration (including off‐days) was 500.0 (33–1888) days; 542.0 (33–1888) days for patients with ITI success. Four patients used prophylaxis with bypassing agents or non‐factor products during rFVIIIFc ITI. Three patients (75.0%) used APCC, one (25.0%) used emicizumab and one (25.0%) used rFVIIa; one patient used APCC and rFVIIa simultaneously. Eight patients used bypassing agents for on‐demand treatment. Seven of these eight patients (87.5%) used rFVIIa and three (37.5%) used APCC; one patient used rFVIIa and APCC simultaneously. rFVIIIFc ITI outcomes and ABR for rescue ITI patients stratified by dose and dosing frequency are shown in Tables S2 and S3, respectively.
FIGURE 4.
rFVIIIFc usage in rescue ITI patients (n = 17). ITI: immune tolerance induction; IU: international unit; rFVIIIFc: recombinant factor VIII Fc fusion protein.
3.4. Safety
3.4.1. First‐Time ITI
Overall, 14/24 (58.3%) first‐time ITI patients reported AEs. Twelve (50.0%) of these patients had SAEs, and five (20.8%) events were adjudicated as serious adverse drug reactions by the investigator (Table S4). None of these AEs led to permanent discontinuation of rFVIIIFc or a fatal event.
3.4.2. Rescue ITI
Overall, 7/17 (41.2%) rescue ITI patients reported AEs. Seven (41.2%) of these patients had SAEs, and one (5.9%) event was adjudicated as a serious adverse drug reaction by the investigator (Table S5).
4. Discussion
The results of this ITI chart review study indicate that ITI with rFVIIIFc is likely to be successful in persons with haemophilia A who have not previously had ITI treatment, and is an effective option for those who experienced ITI failure in the past. In first‐time ITI patients, the rFVIIIFc ITI success rate was high (81.3%) and success was reached within a median time of less than 12 months in patients reporting an outcome during the study. A large variation in ITI success rates has been reported in previous studies, ranging from 38% to 83% [13, 14, 15, 16, 17, 18, 19, 20, 21]. Similarly, a large variation in median time to success rates has been reported previously, ranging from 7 to 20 months [9, 13, 14, 18, 19, 21]; specifically, median time to success in patients receiving low‐dose and high‐dose ITI has been reported to be 9 and 5 months, respectively [15]. Yet, it is difficult to draw comparisons to these data due to differences in FVIII product type, treatment regimens and patient characteristics, as well as success criteria. Rescue ITI patients experienced a lower success rate of 37.5%, or 50.0% including those with partial success, and longer time to success; however, this is not unexpected as previous ITI failure is considered a high‐risk factor for poor ITI outcome [27]. Several of the known risk factors for poor ITI outcome were present in both treatment groups, but especially in the rescue ITI group, making these patients particularly difficult to treat. Such risk factors include high peak inhibitor values before ITI treatment and mutations in the F8 gene [27, 28]. F8 gene mutations were reported in 21% of first‐time ITI patients and 88% of rescue ITI patients, most of whom have high‐risk mutations. In addition, F8 gene mutations were unknown in 18 of the 24 first‐time ITI patients and two of 17 rescue ITI patients, so rates may have been higher in reality. The fact that gene mutations were unknown in so many first‐time ITI patients may reflect the greater need for establishing the presence of mutations in those who have previously experienced ITI treatment failure.
A large variation in initial weekly rFVIIIFc dose was observed within the study population, ranging from 100 to 1400 IU/kg/week. There was also a large range in weekly rFVIIIFc consumption within first‐time and rescue ITI patients; median rFVIIIFc consumption was lower in first‐time ITI patients than rescue ITI patients (300 vs. 536 IU/kg/week). Most first‐time ITI patients used doses of less than 300 IU/kg/week, whereas most rescue ITI patients used doses of greater than 500 IU/kg/week. The most common dosing frequency in first‐time ITI patients was three times per week (29.2%), whereas the most common was once daily in rescue ITI patients (64.7%). The distribution of dosing intervals was kept relatively stable throughout the main ITI treatment period within each group. These data indicate that in real‐world practice, a wide range of treatment regimens are used, although high‐dose ITI regimens are rare and first‐time ITI patients tend to receive lower doses and less frequent injections than rescue ITI patients. In addition, these findings suggest that first‐time ITI patients may find low, long‐interval dosing regimens beneficial initially, since the likelihood of success is high. Finding the optimal ITI regimen for each patient is essential to maximally benefit patients, especially those who are at risk of developing inhibitors later in life due to infrequent exposure to FVIII. However, it is difficult to draw firm conclusions on a potential relationship between ITI treatment regimen intensity and outcome from this study, due to differences in patient characteristics and small sample size after stratification by dose/dosing frequency. During the course of ITI treatment, investigators adjusted treatment regimens based on how difficult‐to‐treat their patients were, meaning individual patients' doses and dosing frequencies fluctuated (within the dose/dosing frequency distribution of their respective groups).
The relapse rate was low within the study period; one rescue ITI patient and no first‐time ITI patients relapsed. ITI with rFVIIIFc was well tolerated, with no unexpected adverse events and a safety profile in line with previous clinical studies [23, 24].
A key strength of this study was its non‐interventional design, which best reflects real‐world practice, as well as its retrospective and prospective data collection periods and long follow‐up, which allowed for a detailed understanding of each patient's ITI treatment. On the other hand, this study was limited by small sample sizes due to the rarity of haemophilia A and missing data due to expected omissions in patient medical record data and the infrequent undertaking of some measurements, such as FVIII half‐life and patients achieving normal FVIII recovery. The study protocol included highly stringent benchmark definitions for ITI success to guide the investigators, which, in theory, would allow for consistent categorisations of patients into those with ITI success and those with ITI failure. Indeed, all first‐time ITI patients with success and rescue ITI patients with success or partial success met at least one criterion (negative inhibitor titre). However, given the observational nature of the study, ITI success and failure were ultimately determined by the investigator, using their clinical judgement, not necessarily the criteria outlined in the protocol. Therefore, the subjectivity of the ITI success definition may limit comparison of these results with previously reported data.
5. Conclusion
To conclude, first‐time ITI patients had a high ITI success rate based on investigators' judgment, and most achieved a negative inhibitor titre using a relatively low rFVIIIFc dose. Several patients receiving rescue therapy with rFVIIIFc achieved ITI success, and the majority achieved a negative inhibitor titre. These findings suggest that ITI with rFVIIIFc can be beneficial not only to patients who have not previously received ITI but also to patients who have previously experienced ITI failure with other products.
Author Contributions
Substantial contributions to study conception and design: R.K., M.A.S., H.G., M.S., B.G., L.B., A.S., S.L. Substantial contributions to analysis and interpretation of the data: R.K., M.A.S., H.G., M.S., B.G., L.B., A.S., S.L. Drafting the article or revising it critically for important intellectual content: R.K., M.A.S., H.G., M.S., B.G., L.B., A.S., S.L. Final approval of the version of the article to be published: R.K., M.A.S., H.G., M.S., B.G., L.B., A.S., S.L.
Ethics Statement
This study's protocol received approval from institutional review boards and/or ethics committees at participating institutions. Patients provided signed and dated informed consent before participating in the study. For paediatric patients, assent was obtained in line with local regulations, and informed consent was provided by the patient's legally acceptable representative before any study‐related activities commenced. This study adhered to the International Conference on Harmonization Guidelines for Good Clinical Practice and ethical principles in compliance with the Declaration of Helsinki [29, 30]. The study is registered with ClinicalTrials.gov [25].
Consent
The authors have nothing to report.
Conflicts of Interest
R.K.: Grant/research support from Bayer and LEO; consultant for Bayer, BioMarin, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi and Takeda; speaker bureau of Bayer, BioMarin, Biotest, BMS, CSL Behring, Daiichi Sankyo, Grifols, LEO, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi and Takeda. M.A.S.: Research grant from Bayer; speaker/honoraria for Novo Nordisk, Roche and Sobi; consultation fees for CSL Behring, Novo Nordisk, Roche and Sobi. H.G.: Principal Investigator for studies by Baxalta (Takeda), Bayer, Novo Nordisk, Octapharma, Roche and Sobi (payment to institution, not to author). M.S.: Principal Investigator for studies by Baxalta, Novo Nordisk, Roche and Sanofi; speaker/honoraria for Novo Nordisk, Roche and Sobi; consultation fees for CSL Behring, Novo Nordisk, Roche and Sobi. B.G.: Principal investigator for studies by Baxalta/Shire/Takeda, CSL Behring, Novo Nordisk, Octapharma, Roche‐Chugaï and Sobi; speaker/honoraria for BioMarin, CSL Behring, LFB, Novo Nordisk, Roche‐Chugaï and Sobi; grant/research support from CSL Behring and Octapharma. L.B. and S.L.: Employees of Sobi and may hold shares and/or stock options in the company. A.S.: Former statistical consultant for Sobi, employed by Veramed GmbH (CRO). Current employee of Boehringer Ingelheim.
Supporting information
Table S1. rFVIIIFc ITI outcomes stratified by number of risk factors.
Table S2. rFVIIIFc ITI outcomes stratified by dose and dosing frequency.
Table S3. ABR stratified by dose and dosing frequency.
Table S4. SAEs and SADRs in first‐time ITI patients.
Table S5. SAEs and SADRs in rescue ITI patients.
Acknowledgements
The authors thank the patients, the investigators and their teams who took part in this study. The authors acknowledge Daniela Bruni, PharmD PhD, from Sobi, for publication coordination, and Yasha Najafi, MSc, from Costello Medical, UK, for medical writing and editorial assistance based on the authors' input and direction. The authors also acknowledge Viqaruddin Mohammed, from the King Faisal Specialist Hospital and Research Centre, for study management. Sobi and Sanofi reviewed and provided feedback on this manuscript. The authors had full editorial control of the manuscript and provided their final approval of all content. Further, the authors acknowledge that some data reported in this manuscript have been published previously at EAHAD 2024. This study was funded by Sobi.
Funding: This study was sponsored by Sobi (Swedish Orphan Biovitrum). This article was based on the original study NCT03951103 sponsored by Sobi. Support for third‐party writing assistance for this article, provided by Yasha Najafi, MSc, Costello Medical, UK, was funded by Sobi in accordance with Good Publication Practice (GPP) guidelines (https://www.ismpp.org/gpp‐2022).
Data Availability Statement
Sobi is committed to responsible and ethical sharing of data on participant level and summary data for medicines and indications approved by EMA and/or FDA, while protecting individual participant integrity and compliance with applicable legislation. Data access will be granted in response to qualified research requests. All requests are evaluated by a cross‐functional panel of experts within Sobi and a decision on sharing will be based on the scientific merit and feasibility of the research proposal, maintenance of personal integrity and commitment to publication of the results. To request access to study data, a data sharing request form (available at www.sobi.com) should be sent to medical.info@sobi.com. Further information on Sobi's data sharing policy and process for requesting access can be found at: https://www.sobi.com/en/policies.
References
- 1. Benson G., Auerswald G., Elezović I., et al., “Immune Tolerance Induction in Patients With Severe Hemophilia With Inhibitors: Expert Panel Views and Recommendations for Clinical Practice,” European Journal of Haematology 88 (2012): 371–379, 10.1111/j.1600-0609.2012.01754.x. [DOI] [PubMed] [Google Scholar]
- 2. Samuelson Bannow B., Recht M., Négrier C., et al., “Factor VIII: Long‐Established Role in Haemophilia A and Emerging Evidence Beyond Haemostasis,” Blood Reviews 35 (2019): 43–50, 10.1016/j.blre.2019.03.002. [DOI] [PubMed] [Google Scholar]
- 3. Fischer K., Lassila R., Peyvandi F., et al., “Inhibitor Development According to Concentrate in Severe Hemophilia: Reporting on 1392 Previously Untreated Patients From Europe and Canada,” Research and Practice in Thrombosis and Haemostasis 7 (2023): 102265, 10.1016/j.rpth.2023.102265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Srivastava A., Brewer A. K., Mauser‐Bunschoten E. P., et al., “Guidelines for the Management of Hemophilia,” Haemophilia 19, no. 1 (2013): e1–e47, 10.1111/j.1365-2516.2012.02909.x. [DOI] [PubMed] [Google Scholar]
- 5. Carcao M. and Goudemand J., Inhibitors in Hemophilia: A Primer, 5th ed. (WFH, 2018). [Google Scholar]
- 6. Walsh C. E., Soucie J. M., and Miller C. H., “Impact of Inhibitors on Hemophilia A Mortality in the United States,” American Journal of Hematology 90 (2015): 400–405, 10.1002/ajh.23957. [DOI] [PubMed] [Google Scholar]
- 7. Kempton C. L. and Meeks S. L., “Toward Optimal Therapy for Inhibitors in Hemophilia,” Blood 124 (2014): 3365–3372, 10.1182/blood-2014-05-577643. [DOI] [PubMed] [Google Scholar]
- 8. Krishnamoorthy S., Liu T., Drager D., et al., “Recombinant Factor VIII Fc (rFVIIIFc) Fusion Protein Reduces Immunogenicity and Induces Tolerance in Hemophilia A Mice,” Cellular Immunology 301 (2016): 30–39, 10.1016/j.cellimm.2015.12.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Carcao M., Shapiro A., Hwang N., et al., “Real‐World Data of Immune Tolerance Induction Using Recombinant Factor VIII Fc Fusion Protein in Patients With Severe Haemophilia A With Inhibitors at High Risk for Immune Tolerance Induction Failure: A Follow‐Up Retrospective Analysis,” Haemophilia 27 (2021): 19–25, 10.1111/hae.14192. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Malec L. M., Journeycake J., and Ragni M. V., “Extended Half‐Life Factor VIII for Immune Tolerance Induction in Haemophilia,” Haemophilia 22 (2016): e552–e554, 10.1111/hae.13064. [DOI] [PubMed] [Google Scholar]
- 11. Malec L. M., Ragni M. V., Journeycake J., and Alabek M., “Immune Tolerance Induction Using Rfviiifc (Eloctate),” Blood 126 (2015): 3531, 10.1182/blood.V126.23.3531.3531. [DOI] [Google Scholar]
- 12. Ragni M. V., Malec L. M., and Journeycake J., “Durability of ITI Utilizing Rfviiifc,” Blood 128 (2016): 3793, 10.1182/blood.V128.22.3793.3793. [DOI] [Google Scholar]
- 13. Coppola A., Margaglione M., Santagostino E., et al., “Factor VIII Gene (F8) Mutations as Predictors of Outcome in Immune Tolerance Induction of Hemophilia A Patients With High‐Responding Inhibitors,” Journal of Thrombosis and Haemostasis 7 (2009): 1809–1815, 10.1111/j.1538-7836.2009.03615.x. [DOI] [PubMed] [Google Scholar]
- 14. Dimichele D., “The North American Immune Tolerance Registry: Contributions to the Thirty‐Year Experience With Immune Tolerance Therapy,” Haemophilia 15 (2009): 320–328, 10.1111/j.1365-2516.2008.01880.x. [DOI] [PubMed] [Google Scholar]
- 15. Hay C. R. and DiMichele D. M., “The Principal Results of the International Immune Tolerance Study: A Randomized Dose Comparison,” Blood 119 (2012): 1335–1344, 10.1182/blood-2011-08-369132. [DOI] [PubMed] [Google Scholar]
- 16. Kreuz W., Escuriola Ettingshausen C., Vdovin V., et al., “First Prospective Report on Immune Tolerance in Poor Risk Haemophilia A Inhibitor Patients With a Single Factor VIII/von Willebrand Factor Concentrate in an Observational Immune Tolerance Induction Study,” Haemophilia 22 (2016): 87–95, 10.1111/hae.12774. [DOI] [PubMed] [Google Scholar]
- 17. Kurth M., Puetz J., Kouides P., et al., “The Use of a Single von Willebrand Factor‐Containing, Plasma‐Derived FVIII Product in Hemophilia A Immune Tolerance Induction: The US Experience,” Journal of Thrombosis and Haemostasis 9 (2011): 2229–2234, 10.1111/j.1538-7836.2011.04493.x. [DOI] [PubMed] [Google Scholar]
- 18. Oldenburg J., Jiménez‐Yuste V., Peiró‐Jordán R., Aledort L. M., and Santagostino E., “Primary and Rescue Immune Tolerance Induction in Children and Adults: A Multicentre International Study With a VWF‐Containing Plasma‐Derived FVIII Concentrate,” Haemophilia 20 (2014): 83–91, 10.1111/hae.12263. [DOI] [PubMed] [Google Scholar]
- 19. Nakar C., Manco‐Johnson M. J., Lail A., et al., “Prompt Immune Tolerance Induction at Inhibitor Diagnosis Regardless of Titre May Increase Overall Success in Haemophilia A Complicated by Inhibitors: Experience of Two U.S. Centres,” Haemophilia 21 (2015): 365–373, 10.1111/hae.12608. [DOI] [PubMed] [Google Scholar]
- 20. Gringeri A., “VWF/FVIII Concentrates in High‐Risk Immunotolerance: The RESIST Study,” Haemophilia 13, no. Suppl 5 (2007): 73–77, 10.1111/j.1365-2516.2007.01579.x. [DOI] [PubMed] [Google Scholar]
- 21. Haya S., López M. F., Aznar J. A., and Batlle J., “Immune Tolerance Treatment in Haemophilia Patients With Inhibitors: The Spanish Registry,” Haemophilia 7 (2001): 154–159, 10.1046/j.1365-2516.2001.00469.x. [DOI] [PubMed] [Google Scholar]
- 22. DiMichele D. M., Hoots W. K., Pipe S. W., Rivard G. E., and Santagostino E., “International Workshop on Immune Tolerance Induction: Consensus Recommendations,” Haemophilia 13, no. Suppl 1 (2007): 1–22, 10.1111/j.1365-2516.2007.01497.x. [DOI] [PubMed] [Google Scholar]
- 23. Malec L., Van Damme A., Chan A. K. C., et al., “Recombinant Factor VIII Fc Fusion Protein for First‐Time Immune Tolerance Induction: Final Results of the verITI‐8 Study,” Blood 141 (2023): 1982–1989, 10.1182/blood.2022017780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Königs C., Meeks S. L., Löfqvist M., et al., “Final Results of ReITIrate—A Prospective Study of Rescue Immune Tolerance Induction (ITI) With Recombinant Factor VIII Fc (rFVIIIFc) in Patients Who Have Failed Previous ITI Attempts,” Presented at ISTH 2021; PB0522.
- 25. ClinicalTrials.gov , “rFVIIIFc (Elocta) ITI Chart Review in Patients With Haemophilia A,” 05 February 2024, https://www.clinicaltrials.gov/study/NCT03951103.
- 26. Collins P. W., Chalmers E., Hart D. P., et al., “Diagnosis and Treatment of Factor VIII and IX Inhibitors in Congenital Haemophilia: (4th Edition). UK Haemophilia Centre Doctors Organization,” British Journal of Haematology 160 (2013): 153–170, 10.1111/bjh.12091. [DOI] [PubMed] [Google Scholar]
- 27. Ljung R., Auerswald G., Benson G., et al., “Inhibitors in Haemophilia A and B: Management of Bleeds, Inhibitor Eradication and Strategies for Difficult‐to‐Treat Patients,” European Journal of Haematology 102 (2019): 111–122, 10.1111/ejh.13193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Oomen I., Camelo R. M., Rezende S. M., et al., “Determinants of Successful Immune Tolerance Induction in Hemophilia A: Systematic Review and Meta‐Analysis,” Research and Practice in Thrombosis and Haemostasis 7 (2023): 100020, 10.1016/j.rpth.2022.100020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) , “ICH Harmonised Guideline—Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2),” 05 February 2024, https://www.ich.org/page/efficacy‐guidelines.
- 30. World Medical Association (WMA) , “WMA Declaration of Helsinki—Ethical Principles for Medical Research Involving Human Subjects,” 05 February 2024, https://www.wma.net/policies‐post/wma‐declaration‐of‐helsinki‐ethical‐principles‐for‐medical‐research‐involving‐human‐subjects/.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. rFVIIIFc ITI outcomes stratified by number of risk factors.
Table S2. rFVIIIFc ITI outcomes stratified by dose and dosing frequency.
Table S3. ABR stratified by dose and dosing frequency.
Table S4. SAEs and SADRs in first‐time ITI patients.
Table S5. SAEs and SADRs in rescue ITI patients.
Data Availability Statement
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