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

Previous studies reported the efficacy and safety profile of extended half‐life PEGylated recombinant factor VIII (FVIII) rurioctocog alfa pegol (TAK‐660, SHP660, BAX 855) in preventing bleeding in haemophilia A patients.


| INTRODUC TI ON
Patients with severe haemophilia A, a rare inherited deficiency of coagulation factor VIII (FVIII), typically experience high morbidity associated with spontaneous and traumatic bleeding episodes. 1,2 Standard of care for severe haemophilia A is intravenous administration of regular prophylactic FVIII replacement therapy. 1,3 Timely use of prophylaxis can prevent bleeding episodes, development of target joints and the ensuing arthropathy. Prophylactic FVIII replacement therapy is thus recommended to maintain joint health and health-related quality of life (HRQoL). 1,[3][4][5][6][7] Standard half-life FVIII products require regular infusions up to every other day, and some patients remain at considerable risk for bleeding events despite this frequency. 8,9 Use of extended half-life products and prophylaxis personalized to the individual's FVIII pharmacokinetic profile may benefit patients by reducing the treatment burden while maintaining or even improving treatment efficacy. 9 (recombinant). 11 The safety and efficacy profile of rurioctocog alfa pegol has been reported previously in several studies in paediatric and/or adult patients with haemophilia A. [11][12][13] The Continuation study was conducted to collect long-term safety and efficacy data of rurioctocog alfa pegol for prophylaxis and treatment of bleeding episodes in previously treated paediatric and adult patients with severe haemophilia A who either transitioned from other rurioctocog alfa pegol studies or were newly recruited patients naïve to rurioctocog alfa pegol.

K E Y W O R D S
adverse effects, haemophilia A, long-term outcomes, patient-reported outcome measures, prophylaxis, recombinant factor VIII, rurioctocog alfa pegol F I G U R E 1 Patient disposition and study design. A total of 218 patients enrolled in the study: 2 patients failed screening and 216 patients received at least 1 dose of rurioctocog alfa pegol in any prophylactic regimen. FD, fixed dose; FVIII, factor VIII; PK, pharmacokinetic; q5d, every 5 d; q7d, every 7 d. a These patient numbers total > 216 because some patients received multiple regimens, as they were able to switch from twiceweekly FD to q5d FD, q7d FD and/or PKtailored treatment; 186 patients received only FD prophylaxis. b This patient death was considered unrelated to treatment with rurioctocog alfa pegol Any FD prophylaxis (n = 215) a FD options: • Twice-weekly FD prophylaxis (n = 191) a • q5d FD prophylaxis (n = 57) a • q7d FD prophylaxis (n = 15) a Previously treated with plasma-derived or recombinant FVIII (n = 10) Previously completed a rurioctocog alfa pegol study (n = 206)

Optional switch to
Completed (n = 187) Enrolled patients dosed at least once (n = 216)

PK-tailored prophylaxis (n = 25) a
Discontinued (n = 29): • Adverse event (n = 5) • Physician decision (n = 2) • Withdrawal by patient (n = 6) • Protocol deviation (n = 6) • Death (n = 1) b • Other (n = 9) After protocol amendment 2 | MATERIAL S AND ME THODS Patients who developed a high-titre inhibitor (>5 BU), or a low-titre inhibitor (between 0.6 and 5 BU) that could not be managed with the study's prophylaxis regimen, were discontinued from the study. Patients who required elective major or minor surgical or dental procedures or minor emergency surgical or dental procedures could enrol in the surgery study (NCT01913405) and

| Study design, conduct and patients
could return to the Continuation study after completion of the surgery study.  FD or PK-tailored dose regimen; those already receiving q5d or q7d FD prophylaxis could remain on those regimens or switch to PK-tailored prophylaxis. Details of PK assessment methods are provided in Appendix S1. There was no assignment to the various prophylactic regimens. Rurioctocog alfa pegol was used to treat breakthrough bleeds according to bleed severity and per European

| Treatment
Medicines Agency guidelines, with doses generally between 10 and 60 IU/kg ± 5 IU/kg (Table S2). Study participation was to continue until the patient had achieved ≥100 exposure days to rurioctocog alfa pegol across all studies.

| Study endpoints and outcome measures
The co-primary endpoints were incidence of confirmed FVIII in-

| Patients
A total of 216 patients received at least one dose of rurioctocog alfa pegol, and 187 patients completed the study (Figure 1). Most patients TA B L E 2 Point estimates of mean spontaneous, joint and total ABRs (using a generalised linear model)

| Secondary efficacy outcomes
Total ABR in all patients receiving any prophylaxis regimen with rurioctocog alfa pegol was mean (SD) 2.49 (3.12) and median (Q1, Q3) Patients receiving PK-tailored prophylaxis, n 4 6 6 9 25 Patients receiving PK-tailored prophylaxis who experienced a bleed, n    bleeding episodes in a non-target joint within any 2-month period).

| Safety
Overall, 838 AEs were reported in 174 (80.6%) patients (Table 5), of which 20 AEs in 11 (5.1%) patients were considered related to treatment ( Table 6). All treatment-related AEs were mild or moderate in severity. There were no treatment-related serious AEs (SAEs). Only one treatment-related allergic or hypersensitivity reaction was reported: a non-serious mild AE of drug eruption that developed 1.1 days after exposure to rurioctocog alfa pegol. Subsequent prophylactic infusions of rurioctocog alfa pegol were administered as planned without any further reported drug eruption or hypersensitivity reactions, and this AE subsequently resolved.
Fifty-two SAEs (all considered not related to study drug) occurred in 33 (15.3%) patients (Table S4)

| Patient-reported outcomes
Most patients aged ≥18 years who completed the Haemo-SYM questionnaire (55/91; 60.4%; Figure 3A) had significant improvement from baseline in the total score (P = .0023). A clinically meaningful change from baseline to end-of-study improvement in SF-36 physical component score ( Figure 3B had clinically meaningful change from baseline to end-of-study improvement on the PedsQL total score, no statistically significant improvement was observed for mean improvement in PedsQL total score (P = .0829; Figure 3C).

| D ISCUSS I ON
This phase 3b Continuation study in 216 children and adults with severe haemophilia A revealed long-term safety and efficacy consistent with previous rurioctocog alfa pegol studies 11,12,20 and previous studies with the parent molecule, antihemophilic factor (recombinant). [21][22][23][24][25][26] It is noteworthy that no patients developed confirmed inhibitory antibodies to PEGylated FVIII during the study, given a mean observation period per patient of 2.2 years. The proportion of patients (13.4%) who discontinued prematurely from this long-term study is within the range reported for other FVIII replacement therapy studies (4.7% to 20%) and may be higher than some studies owing to the long-term nature of this study. 21,23,[27][28][29][30] The Limitations associated with extension studies should be taken into consideration when interpreting the final results of this study. Importantly, as this study was designed in accordance with regulatory guidance on the evaluation of FVIII in children aged <12 years, 31 comparison with a control group receiving prophylaxis with a conventional FVIII product was not possible. As patients were not assigned randomly to the different prophylaxis regimens, but instead allowed to switch from twice-weekly FD rurioctocog alfa pegol to less frequent FD or PK-tailored dosing, and because patient numbers varied across treatment and age groups, robust comparisons between the prophylaxis regimens were not possible. These limitations were offset in part by the long follow-up period and representativeness of the haemophilia A population across a wide age range.

| CON CLUS IONS
In previously treated children and adults with severe haemophilia A in the Continuation study, long-term prophylaxis with rurioctocog alfa pegol was efficacious. The safety and immunogenicity profile was similar to that observed in previous studies 11,12,20 and consistent with that reported for the non-PEGylated parent molecule, antihemophilic factor (recombinant), 32 indicating that PEGylation did not have an effect on product safety. No patients developed FVIII inhibitory antibodies, and the observed spontaneous and total ABRs were lower at the end of study than at baseline.

ACK N OWLED G EM ENTS
The authors would like to thank all patients and their caregivers who took part in the Continuation study, as well as the

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results reported in this article, will be made available within 3 months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.