Therapeutic and routine prophylactic properties of rFactor VIII Fc (efraloctocog alfa, Eloctate^®) in hemophilia A

Figures & data

Figure 1 Study flowchart for adults and adolescents enrolled into A-Long studies.

Note: The disposition of patients in the trials along with details of dose adjustments that could be undertaken during the trial are shown.
Abbreviation: PK, pharmacokinetic.

Figure 2 Study flowchart for children enrolled into A-Long studies.

Note: The disposition of patients in the trials along with details of dose adjustments that could be undertaken during the trial are shown.
Abbreviation: PK, pharmacokinetic.

Table 1 Sampling schedule used across different arms of the study

rFVIIIFc study	Arm/cohort	Dose of rFVIIIFc (IU/kg)	Number of patients	Sampling schedule
Phase I/IIa	Cohort A – crossover full PKa	25	6	0, 0.167, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, and 168 h
Phase I/IIa	Cohort B – crossover full PKa	65	10	As above +192, 216, and 240 h
Phase III	Arm 1 – crossover full PKa	50	28	0, 0.5, 1, 6, 24, 72, 96, and 120 h
Phase III	Arm 1 – abbreviated PK groups	50	155	0, 0.5, 3, 72, and 96 h
Pediatric study	Majority of patients	50	37	0, 0.5, 3, 24, 48, and 72 h

Notes:

a The comparator for the crossover PK was rAHF-PFM (Advate^®). The data for this table has been taken from published manuscripts related to Phase 1, Phase III, and pediatric studies of rFVIIFc.^33–35,38 Adapted from Nestorov I, Neelakantan S, Ludden TM, et al. Population pharmacokinetics of recombinant factor VIII Fc fusion protein. Clin Pharmacol Drug Dev. 2015;4(3):163–174. © 2014, The American College of Clinical Pharmacology.³⁸

Abbreviations: PK, pharmacokinetic; rFVIIIFc, recombinant FVIII Fc fusion protein; rAHF-PFM, recombinant anti-hemophilic factor – protein-free medium; h, hours.

Table 2 PK results of rFVIIIFc (efraloctocog alfa, Eloctate®) and rAHF-PFM (Advate®)

Parameter	rFVIIIFc – pediatric study		rFVIIIFc – Phase III pivotal study, abbreviated PK arm		rFVIIIFc –Phase III full crossover PK	rAHF-PFM –Phase III full crossover PK	rAHF-PFM pivotal study
Age (years)	2 to <6	6 to <12	12–17	≥18	≥12	≥12	10–65
Number of patients (n)	10	27	11	144	28	28	30
IR (IU/dL per IU/kg)	1.9 (1.7, 2.0)	2.4 (2.0, 2.9)	1.8 (1.6, 2.1)	2.0 (1.9, 2.1)	2.3 (2.1, 2.4)	2.35 (2.2, 2.5)	2.4±0.5
t1/2 (h)	12.0 (9.5, 14.4)	14.6 (11.5, 17.7)	16.4 (14.1, 18.6)	17.8 (16.9, 18.7)	19.7 (17, 22)	12.4 (11.1, 13.9)	12.0±4.3
MRT (h)	16.4 (13.0, 19.7)	21.1 (16.8, 25.5)	23.1 (19.9, 26.4)	25.3 (24.1, 26.6)	26.1 (23, 29)	16.8 (15.2, 18.6)	15.69±6.21
CL (mL/h/kg)	3.9 (2.9, 4.8)	2.7 (2.3, 3.1)	2.7 (2.3, 3.0)	2.5 (2.3, 2.6)	2.06 (1.8, 2.3)	3.04 (2.7, 3.4)	3.0±1.0
VSS mL/kg	58.7(54.7, 62.6)	49.9 (44.4, 55.3)	60.3 (32.3, 67.3)	57.5 (55.4, 59.5)	49.1 (46.6, 51.7)	51.2 (47.2, 55.5)	47.0±1.0
Mean relative change in t1/2 (h)a	−33%	−18%	−8%	100%	NA	NA	NA
Mean relative change in CL (mL/h/kg)a	+58%	+9%	+8%	100%	NA	NA	NA

Notes: Data presented as mean (95% CI) and the Advate^® data from pivotal studies are presented as mean ± SD. Data have been taken from published Phase I, Phase III, and pediatric studies and US FDA submission^33–35,39 and rounded off to the nearest decimal for simplicity.

a The mean relative change compared to adult values (10%). Adapted with permission of American Society of Hematology, from Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Powell JS, Josephson NC, Quon D, et al. Blood. 2012;119(13):3031–3037; permission conveyed through Copyright Clearance Center, Inc.³³ Adapted with permission of American Society of Hematology, from Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Mahlangu J, Powell JS, Ragni MV, et al. Blood. 2014;123(3):317–325; permission conveyed through Copyright Clearance Center, Inc.³⁴ Adapted from Young G, Mahlangu J, Kulkarni R, et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost. 2015;13(6):967–977. © 2015 Young et al. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.³⁵ Adapted from Tarantino MD, Collins PW, Hay CR, et al. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia. 2004;10(5):428–437. With permission from John Wiley and Sons.³⁹

Abbreviations: PK, pharmacokinetics; IR, incremental recovery, the% rise in activity seen with an infusion of 1 IU/Kg of factor concentrate; t_1/2, terminal half-life; MRT, mean residence time; CL, systemic clearance; V_SS, volume of distribution at steady state; NA, not available; rFVIIIFc, recombinant FVIII Fc fusion protein; rAHF-PFM, recombinant anti-hemophilic factor – protein-free medium; SD, standard deviation; CI, confidence interval.

Figure 3 Comparison of rFVIIIFc and prestudy rFVIII PK parameters in pediatric study.

Notes: A comparison of the FVIII PK parameters for rFVIIIFc versus prestudy FVIII was performed for 46 subjects (<6 years of age, n=19; 6 to <12 years of age, n=27) with the one-stage clotting assay, and the ratio of rFVIIIFc PK to the PK of the prior FVIII for each subject was calculated. Representative summaries from subjects who received prestudy therapy with the most common prestudy treatments, Advate^® (antihemophilic factor [recombinant]) (A) or Helixate/Kogenate (B), are shown. Each box represents the median and interquartile range, the “whiskers” represent the minimum and maximum, and the reference unity line marks the point at which PK parameters for rFVIIIFc and prestudy FVIII are the same. For all subjects in the PK subgroup an intrasubject comparison of rFVIIIFc and prestudy FVIII PK was performed; data for the half-life comparison are shown by age cohort and prestudy FVIII product (C, D). Reproduced from Young G, Mahlangu J, Kulkarni R, et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost. 2015;13(6):967–977. © 2015 Young et al. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.³⁵
Abbreviations: PK, pharmacokinetic; rFVIIIFc, recombinant FVIII Fc fusion protein; CL, clearance; IR, incremental recovery; t_½, half-life; pdFVIII, plasma-derived FVIII; V_ss, volume of distribution at steady state.

Table 3 Key outcome data relating to bleeding episodes and weekly consumption of rFVIIIFc

Outcome	Pivotal study arm 1 N=117	Pivotal study arm 2 N=23	Pivotal study arm 3 N=23	Pediatric study 2 to <6 yr N=35	Pediatric study 6 to <12 yr N=34
ABR, negative binomial model (95% CI)	2.9 (2.3–3.7)	8.9 (5.5–14.5)	37.3 (24.0–57.7)	NA	NA
Observed ABRa (all bleeds) Median (IQR) [range]	1.6 (0, 4.7)	3.6 (1.9, 8.4)	33.6 (21.1, 48.7)	0 (0, 3.9) [0–0.5]	2 (0, 4) [0–27.2]
Overall bleeds (spontaneous) Median (IQR) [range]	0 (0, 2)	1.9 (0, 4.8)	20.2 (12.2, 36.8)	0 (0, 0) [0.0–7.9]	0 (0, 0) [0.0–19.8]
Joint bleeds (spontaneous) Median (IQR) [range]	0 (0, 1.7)	0 (0, 3.8)	18.6 (7.6, 29.6)	0 (0, 0) [0.0–6.0]	0 (0, 0) [0.0–14.8]
Joint bleeds (traumatic) Median (IQR) [range]	0 (0, 1.2)	0 (0, 1.2)	3.9 (0.0, 8.6)	0 (0, 0) [0.0–6.5]	0 (0, 0) [0.0–7.9]
Muscle bleeds (spontaneous) Median (IQR)	0 (0, 0)	0 (0, 0)	5.1 (1.8, 6.8)	NA	NA
Muscle bleeds (traumatic) Median (IQR)	0 (0, 0)	0 (0, 0)	0 (0, 2)	NA	NA
Patients with no bleeding episodes, n (%)	53 (45%)	4 (17%)	0		46%
Weekly dose IU/kg, median (min, max for adults; IQR for pediatric patients)	77.9 (54.0, 141.5)	65.6 (59.4, 70.7)	NA	91.6 (84.7, 104.6)	86.9 (79.1, 103.1)

Notes:

a In the extension study, the median (IQR) overall ABR in the arm 1 – 0.66 (0.22, 2.63), arm 2 – 2.03 (0.60, 4.39), 2–6 years group – 0.00 (0.00, 2.00), and 6–12 years group – 1.54 (0.00, 3.41).⁴² Adapted with permission of American Society of Hematology, from Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Mahlangu J, Powell JS, Ragni MV, et al. Blood. 2014;123(3):317–325; permission conveyed through Copyright Clearance Center, Inc.³⁴ Adapted from Young G, Mahlangu J, Kulkarni R, et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost. 2015;13(6):967–977. © 2015 Young et al. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.³⁵ Adapted from Nolan B, Mahlangu J, Perry D, et al. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A. Haemophilia. 2016;22(1):72–80. © 2015 The Authors. Haemophilia Published by John Wiley & Sons Ltd.⁴²

Abbreviations: rFVIIIFc, recombinant FVIII Fc fusion protein; ABR annualized bleed rate; CI, confidence interval; IQR, interquartile range; NA, not available; yr, years.

Table 4 Final dosing schedule at end of Phase III pivotal study illustrating the interindividual variability in prophylactic dosing regimensa

Dosing frequency, n (%)	rFVIIIFc dose IU/kg									All patients – frequency of infusion
	25	30	35	25/50	40	45	50	60	65
Twice weekly	–	–	–	34 (29.1)	–	1 (0.9)	–	–	–	35 (29.9)
Every 3 days	3 (2.6)	2 (1.7)	1 (0.9)	0 (0)	2 (1.7)	0 (0)	20 (17.1)	1 (0.9)	10 (8.5)	39 (33.3)
Every 4 days	–	–	–	–	–	–	2 (1.7)	–	2 (1.7)	4 (3.4)
Every 5 days	–	–	–	–	–	–	34 (29.1)	1 (0.9)	4 (3.4)	39 (33.3)
All patients – rFVIIIFc dose	3 (2.6)	2 (1.7)	1 (0.9)	34 (29.1)	2 (1.7)	1 (0.9)	56 (47.9)	2 (1.7)	16 (13.7)	117 (100)

Note:

a Adapted with permission of American Society of Hematology, from Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Mahlangu J, Powell JS, Ragni MV, et al. Blood. 2014;123(3):317–325; permission conveyed through Copyright Clearance Center, Inc.³⁴

Abbreviation: rFVIIIFc, recombinant FVIII Fc fusion protein.

PowellJSJosephsonNCQuonDSafety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patientsBlood2012119133031303722223821

 PubMed Web of Science ®Google Scholar

YoungGMahlanguJKulkarniRRecombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia AJ Thromb Haemost201513696797725912075

 PubMed Web of Science ®Google Scholar

NestorovINeelakantanSLuddenTMLiSJiangHRoggeMPopulation pharmacokinetics of recombinant factor VIII Fc fusion proteinClin Pharmacol Drug Dev20154316317427140796

 PubMed Web of Science ®Google Scholar

TarantinoMDCollinsPWHayCRClinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia AHaemophilia200410542843715357767

 PubMed Web of Science ®Google Scholar

MahlanguJPowellJSRagniMVPhase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia ABlood2014123331732524227821

 PubMed Web of Science ®Google Scholar

NolanBMahlanguJPerryDLong-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia AHaemophilia2016221728026218032

 PubMed Web of Science ®Google Scholar