BAY 94-9027 prophylaxis is efficacious and well tolerated for up to >5 years with extended dosing intervals: PROTECT VIII extension interim results

Abstract

Introduction: BAY 94-9027 is an extended-half-life, site-specifically PEGylated, B-domain-deleted recombinant factor VIII (FVIII). The PROTECT VIII main study demonstrated efficacy of bleed control using extended-interval prophylaxis with BAY 94-9027 for 36 weeks.

Aim: To report long-term efficacy and safety of prophylaxis with BAY 94-9027 in a descriptive analysis of the ongoing PROTECT VIII extension with a total treatment time of up to >5 years.

Methods: Previously treated males aged 12-65 years with severe haemophilia A who completed the PROTECT VIII main study were eligible for the open-label extension. Patients received on-demand treatment or prophylaxis (30-40 IU/kg twice weekly, 45-60 IU/kg every 5 days, or 60 IU/kg every 7 days) and could switch regimens as needed.

Results: Patients (N = 121; on demand, n = 14; prophylaxis, n = 107) accumulated a median (range) of 3.9 years (297-1965 days) and 223 (23-563) total exposure days by 31 January 2018. During the extension, median (quartile [Q]1; Q3) annualized bleeding rates (ABRs) for total bleeds were 1.6 (0.3; 4.6) for patients receiving prophylaxis and 34.1 (20.3; 36.6) for patients receiving on-demand treatment. ABRs for twice-weekly (n = 23), every-5-days (n = 33), every-7-days (n = 23) and variable frequency (n = 28) treatments were 1.7, 1.2, 0.7 and 3.1, respectively. Of prophylaxis patients, 20.6% were bleed-free throughout the extension (median time, 3.2 years), and 44.5% were bleed-free during the last 6 months. No patients developed FVIII inhibitors.

Conclusions: BAY 94-9027 prophylaxis was efficacious and well tolerated with dosing intervals up to every 7 days for a median (range) of 3.9 years (0.8-5.4 years).

Keywords: clinical trial; factor VIII; haemophilia A; intravenous infusions; recombinant proteins.

Conflict of interest statement

S. Lalezari: consultant for Bayer and Teva, has received honoraria/consultation fees from Teva, Pfizer and Bayer, and reimbursement for symposia/congresses from Bayer, Roche, Pfizer, Novo Nordisk, Alnylam/Sanofi, Grifols, Perrigo and Baxter.

M. T. Reding: has received honoraria for participation on advisory boards and/or speakers bureaus from Bayer, Bioverativ, Genentech, Novo Nordisk, Pfizer and Shire, and grant funding from Bayer and Biomarin.

I. Pabinger: has received honoraria for lectures and advisory board meetings from Bayer, CSL Behring, Pfizer, Novo Nordisk, Sobi and Shire, and has received unrestricted research grants from CSL Behring and Novo Nordisk.

P. A. Holme: has received grant/research support and speakers honorarium from Bayer.

C. Negrier: has received grant/research support, honoraria or consultation fees from Alnylam, Baxalta/Shire, Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Roche, Pfizer and Sobi.

P. Chalasani: has received research support from Pfizer, not related to any haematologic products.

H. Shin: has no disclosures to report.

M. Wang, D. Tseneklidou‐Stoeter and M. Maas Enriquez are employees of Bayer.

© 2019 The Authors. Haemophilia published by John Wiley & Sons Ltd.

Figures

Figure 1

Patient movement across treatment regimens during the extension study. *The variable frequency group included all patients depicted who finished with a different regimen than their initial regimen (n = 24) as well as 1 patient in the every‐7‐days group and 3 patients in the every‐5‐days group who switched twice (ending up back on their original treatment regimen). The analysis group at data cut‐off refers to the group in which patients were included for the statistical analysis [Colour figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

ABR by treatment regimen in the PROTECT VIII extension and negative binomial model. ABR = annualized bleeding rate; CI = confidence interval; Q, quartile; RR = rate ratio; *Patients who switched regimens during the extension (switched to a higher frequency, n = 20; switched to a lower frequency, n = 4; switched twice and were receiving their original frequency at interim analysis, n = 4). †P‐values were nominally derived from the negative binomial model, with no adjustments made for multiple comparisons [Colour figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Patients with 0 total bleeds and 0 joint bleeds during prophylaxis. *Median (range) time spent in the extension, 3.2 (0.1‒4.7) years. †Calculated for the subset of patients who spent ≥12 months in the extension. ‡Patients who switched regimens during the extension (switched to a higher frequency, n = 20; switched to a lower frequency, n = 4; switched twice and were receiving their original frequency at interim analysis, n = 4). §Patients who switched regimens during the last 6 months of the extension. ¶Patients who switched regimens during the last 12 months of the extension [Colour figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Assessment of response to treatment of bleeds and adequacy of haemostasis. *Patients who switched regimens during the extension (switched to a higher frequency, n = 20; switched to a lower frequency, n = 4; switched twice and were receiving their original frequency at interim analysis, n = 4) [Colour figure can be viewed at http://wileyonlinelibrary.com]