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Zero incidence of factor VIII inhibitors and successful haemostatic response in previously factor VIII‐treated patients with haemophilia A switching to turoctocog alfa in a noninterventional study

Abstract Introduction Turoctocog alfa (NovoEight®) is a B‐domain‐truncated recombinant factor VIII (FVIII) approved for patients with haemophilia A. Aim To investigate the long‐term safety and efficacy of turoctocog alfa in routine clinical practice. Methods Guardian 5 was a prospective, multinational, non‐interventional, post‐authorisation safety study. Male previously treated patients (> 150 exposure days [EDs]) of any age with severe/moderately severe haemophilia A (FVIII ≤ 2%) and a negative inhibitor test prior to first dosing (independent of FVIII‐inhibitor history) were included to receive prophylaxis or on‐demand treatment. The primary endpoint was the proportion of patients developing FVIII inhibitors (≥.6 Bethesda Units [BU]) after baseline visit, measured as per routine practice of each study site during clinic visits. Secondary endpoints included haemostatic effect, annualised bleeding rate (ABR), and adverse reactions assessment. The study concluded when 50 patients reached 100 EDs/patient minimum. Results Seventy patients were screened and 68 exposed to turoctocog alfa; 63 (92.6%) were on prophylaxis and five received on‐demand treatment. Six (8.8%) patients reported a history of positive inhibitors. During the study, patients were exposed to turoctocog alfa for a mean (standard deviation) of 131.9 (99.0) days/patient. Fifty‐five of 58 patients who completed the study were tested for FVIII inhibitors; no positive tests were reported. Overall success rate of turoctocog alfa for treatment of bleeds was 87.3%. Among patients receiving prophylaxis, median (range) ABR was 1.97 (.0–25.5) bleeds/year; estimated ABR (negative binomial model) was 3.65 (95% confidence interval: 2.53–5.25). Conclusion Turoctocog alfa was safe and efficacious for haemophilia A treatment in routine clinical practice.


K E Y W O R D S
factor VIII inhibitors, haemophilia A, prophylaxis, real-world evidence, recombinant factor VIII, turoctocog alfa INTRODUCTION Haemophilia A is a congenital bleeding disorder characterised by a deficiency in coagulation factor VIII (FVIII) that results in an increased tendency for spontaneous or traumatic bleeding events. 1 Prophylaxis with clotting factor concentrates or other haemostatic agents is the standard of care for patients with severe haemophilia A to prevent bleeding. 1 The major complication in the treatment of haemophilia A with clotting factor concentrates is the development of alloantibodies (inhibitors) against exogenous FVIII. 2 Inhibitors neutralise the clotting activity of FVIII therapy, which may result in an increased risk of severe bleeding and, subsequently, higher risk of morbidity, mortality and disability, and decreased quality of life. 3,4 Switching FVIII concentrates in previously treated patients (PTPs; > 75-150 exposure days [EDs]) is not associated with a higher risk of developing inhibitors 5 ; however, data for PTPs with a history of inhibitors are sparse because they are usually excluded from Phase 1-3 clinical studies. 6,7 Turoctocog alfa (NovoEight ® ) is a third-generation, recombinant, B-domain-truncated human coagulation FVIII molecule developed by Novo Nordisk A/S and approved for prophylaxis and treatment of bleeding episodes in haemophilia A in all age groups. [8][9][10] The safety and efficacy of turoctocog alfa have been demonstrated across several Phase 3 clinical studies in PTPs (guardian 1, 2, 3 and 7) and previously untreated patients (guardian 4) with haemophilia A. 6,7,[11][12][13] Real-world studies help to understand treatments in broader, more representative patient populations than those used in interventional clinical studies, 14 which may exclude patient groups such as those with a history of inhibitors. Additionally, treatment practices may vary in the real-world setting due to differences in regional procedures and prescribing patterns. Issues with adherence can arise outside a controlled clinical study setting. 14 The aim of the guardian 5 study was to evaluate the real-world immunogenicity, safety and clinical efficacy of turoctocog alfa for prophylaxis, treatment of bleeding episodes and for surgery in PTPs with severe and moderately severe haemophilia A.

Study design
Guardian 5 was a prospective, multinational, non-interventional, post-authorisation safety study investigating the long-term safety and efficacy of turoctocog alfa in routine clinical practice (NCT02035384).
The study design followed European Medicines Agency guideline recommendations for FVIII product investigation. 15

Participants
Patients were considered for inclusion if it had already been decided that they would switch from their previous FVIII product to turoc- Patients with a history of FVIII inhibitors were eligible for inclusion.
Patients who had previously participated in any clinical study with turoctocog alfa were not eligible.

Treatment
Product usage was in accordance with clinical daily practice and generally in agreement with the approved product label and national guidelines. 10 Commercially available product was used as part of this study.

Study endpoints and clinical assessments
The primary endpoint was the proportion of patients developing FVIII inhibitors (≥.6 BU, or above the specific local laboratory reference range). The physician was encouraged to perform clinical evaluation and blood testing for FVIII inhibitors during visits to the clinic or when there was a lack of therapeutic effect. Inhibitor testing was in accordance with the local practice and not mandatory, due to the noninterventional nature of the study. Secondary safety endpoint was the number of adverse reactions reported during the study period. Secondary efficacy endpoints included haemostatic effect of turoctocog alfa in the treatment of bleeds and during surgical procedures, annualised bleeding rate (ABR) for preventive and on-demand treatment, and consumption of turoctocog alfa.
Detailed information related to treatment and bleeding episodes was captured in a paper patient diary by the patient or parent/caregiver. If a patient was unable to enter a treatment or bleeding episode in the diary, or was hospitalised, information was reported by the physician. It was possible to use the patient's own diary to capture details of bleeding episodes (e.g. location, type, date of occurrence), where some of the data points (haemostatic response and severity of bleed) were not captured.

Statistical methods
Data evaluation was mainly based upon descriptive statistics. The pro-

Patient disposition and baseline characteristics
In total, 70 patients were screened for this study (see Figure 1); 68 patients were exposed to FVIII during study participation and therefore included in the full analysis set and safety analysis set. One patient with FVIII level > 2% at inclusion could not be classified into 'severe haemophilia (FVIII level < 1%)' or 'moderately severe haemophilia (FVIII level 1-2%)' categories; however, this patient was included in the total number of patients in the analyses by severity of haemophilia A to represent the full analysis set.
During the study, 68 patients were exposed to turoctocog alfa for a total of 87.8 patient-years and 8967 EDs. The mean EDs (standard deviation [SD]) per patient was 131.9 (99.0) days/patient; 50 patients reported 100 EDs. Of the 68 exposed patients, 63 patients were on a prophylaxis regimen (14 patients < 12 years; 49 patients ≥ 12 years) and five patients received on-demand treatment (all patients ≥ 12 years). No patients switched from on-demand to prophylaxis (or F I G U R E 1 Participant flow. FAS, full analysis set; SAS, safety analysis set. a Patient forgot diary and did not wish to continue in study. b Evaluations until the moment of withdrawal were included in the analyses. c 8 patients were considered as study completers without recording a minimum of 100 EDs but confirmed by the physician as completers. vice versa) after entering the study. A total of 58 (84.1%) patients (9 patients < 12 years; 49 patients ≥ 12 years) completed the study, of which eight patients (all ≥ 12 years) were considered as study completers without recording a minimum of 100 EDs but confirmed by the physician as completers.
The study population, disposition and baseline demographics are shown in Table 1. The study population included 14 paediatric patients (< 12 years) and 55 adolescent/adult patients (≥ 12 years), of which one patient was not exposed to turoctocog alfa. Before study entry, five patients (all ≥ 12 years) received an on-demand regimen. Overall, 63 patients (14 patients < 12 years; 49 patients ≥ 12 years) were on a prophylaxis regimen. Historical frequency of dosing for prophylaxis is reported in Table 1; prophylaxis dose before the trial was not collected.
Six patients (one patient < 12 years; five patients ≥ 12 years [oldest patient: 41 years old]) reported a history of clinical suspicion of inhibitors. Information on the historical inhibitor titre, duration and treatment was not consistently captured. Five of the six patients were tested for FVIII inhibitors during the study; one patient (< 12 years) was not tested. In total, 41 (60.3%) patients had a family history of haemophilia A. Fifty-one patients had a history of switching FVIII products.

FVIII inhibitor development
None of the 68 exposed patients was reported to be positive for FVIII inhibitor during treatment with turoctocog alfa (proportion of patients: 0%; 97.5% upper confidence limit: 6.5). Of the 68 exposed patients, 55 had at least one inhibitor test post-baseline; all of them reported negative FVIII inhibitor test results.

Surgery
Eight patients underwent 11 surgeries. Haemostatic response was available for seven surgeries (four surgeries in three patients with severe haemophilia, two surgeries in two patients with moderately severe haemophilia and one surgery in a patient with FVIII level > 2%).
Of these surgeries, haemostatic response for five surgeries was rated as 'Excellent' and for two surgeries was rated as 'Good' . Overall TA B L E 3 Details of bleeding episodes and haemostatic response to turoctocog alfa treatment

Age at inclusion, N (%)
Haemophilia severity at inclusion, N (%) Severe: FVIII level < 1%, Moderately Severe: FVIII level 1-2%. FVIII, factor VIII. a Haemostatic response was calculated for 37 patients with bleeding episodes for whom there was diary data. b One patient with FVIII activity > 2% at inclusion is included in the 'Total' column to represent the full analysis set. c Haemostatic response for the treatment of bleeds was evaluated on a four-point scale where 'excellent' (abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection) and 'good' (definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection for complete resolution) responses were classified as successful, and responses rated as 'moderate' (probable or slight beneficial effect within approximately 8 hours after the first injection; usually requiring more than one injection), 'none' (no improvement, or worsening of symptoms within approximately 8 hours after the first injection; usually requiring more than one injection) or 'missing' were classified as failure.
success rate for haemostatic effect during surgical procedures was 100%. Details of surgeries and invasive procedures with haemostatic response are shown in Supplementary Table 3.

Consumption of turoctocog alfa for prophylaxis
The mean (SD) average dose of turoctocog alfa for prophylaxis reg-

DISCUSSION
During guardian 5, turoctocog alfa was well tolerated and no inhibitors against turoctocog alfa were detected during the study period. Turoctocog alfa was effective for the prevention and treatment of bleeding episodes, and for haemostatic management during surgery in patients with severe and moderately severe haemophilia A.
The development of inhibitors against FVIII remains a major complication of haemophilia A treatment. 2 Importantly, guardian 5 is one of the first clinical studies to include patients with a history of inhibitors switching to a new recombinant FVIII concentrate (turoctocog alfa).
In this study, 55 of 68 exposed patients were tested for an inhibitor post-baseline; none of these patients reported FVIII inhibitor development (≥.6 BU) during treatment with turoctocog alfa. This included six patients with history of inhibitors. The real-world data reported here are consistent with clinical study data of PTPs without a history of inhibitor development, in the guardian 1, 2 and 3 studies, where turoctocog alfa was well tolerated and no patients developed inhibitors. 6,7,11 One patient in guardian 5 had a history of a high-titre inhibitor (30 BU) successfully treated with an immune tolerance induction with plasma-derived FVIII (personal communication). Due to fear of relapse, the patient was kept on plasma-derived FVIII until study start when he was switched to turoctocog alfa. Regular inhibitor tests performed during the study were negative and a FVIII half-life of slightly more than 6 hours was maintained.
One patient with multiple cardiovascular risk factors developed angina pectoris 2 hours after turoctocog alfa injection and was sub-sequently diagnosed with a myocardial infarction. Cases of myocardial infarction and acute coronary syndromes in patients with haemophilia occurring during or immediately after the administration of coagulation factor have been reported previously, 19 including one case of myocardial infarction from a clinical trial with turoctocog alfa. 20 Conditions predisposing to arterial occlusion, such as obesity, hypertension and hypercholesterolemia as observed in this patient, play an important role in the pathogenesis of myocardial infarction. It is noteworthy that the patient continued treatment with turoctocog alfa after the event.
The overall estimated negative binomial ABR for patients on prophylaxis regimen was 3.65 bleeds/patient/year, which was lower than the reported historical ABR (4.8 bleeds/patient/year). The overall success rate for the treatment of bleeds reported in the guardian 5 study was comparable to the reported success rate in previous guardian studies. 6,7,11,13 Despite advances in treatment of haemophilia A with the development of novel non-factor replacement therapies, 21  inhibitor testing was done only when there was a suspicion of inhibitor development and not as a routine practice. As a result, 13 patients were excluded from the primary analysis because they were not tested for inhibitors. It is likely that these patients were not tested because there was no clinical suspicion of an inhibitor; however, this cannot be confirmed. The study ended when 50 patients were exposed for 100 EDs to study product; therefore, some patients were observed for less than 100 EDs.
In conclusion, the safety of turoctocog alfa in PTPs with haemophilia A in routine clinical practice has been demonstrated in this study.
The reported ABR, surgical procedure outcomes, bleed resolution and monthly consumption data are supportive of the efficacy profile of turoctocog alfa. Turoctocog alfa remains an effective treatment option for patients with haemophilia A in the rapidly evolving treatment landscape.

ACKNOWLEDGEMENTS
This study and editorial support for the article were funded by Novo Nordisk A/S, Denmark. stated that they had no interests which might be perceived as posing a conflict or bias.

AUTHOR CONTRIBUTIONS
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

DATA AVAILABILITY STATEMENT
Data sets from Novo Nordisk-sponsored clinical research completed after 2001 for product indications approved in both the EU and US will be shared with bona fide researchers submitting a research proposal requesting access to data. The access request proposal form and the access criteria can be found at novonordisk-trials.com. Data will be available permanently after research completion and approval of product and product use in both the EU and US on a specialised Statistical Analysis System data platform. The analyses available for use will be those as approved by the Independent Review Board according to the IRB Charter (see novonordisk-trials.com). Individual participant data will be shared in data sets in a de-identified/-anonymised format. In addition, the study protocol and redacted Clinical Study Report will be available according to Novo Nordisk data sharing commitments.