Matching-adjusted indirect comparisons of annualized bleeding rate and utilization of BAY 94-9027 versus three recombinant factor VIII agents for prophylaxis in patients with severe hemophilia A

Figures & data

Figure 1 Comparison of ABR and proportion of patients with zero bleeds between BAY 94-9027 and (A) rFVIIIFc; (B) BAX 855; (C) rAHF-PFM-2004; (D) rAHF-PFM-2012. *P<0.05.

Abbreviations: ABR, annualized bleeding rate; rAHF-PFM, recombinant antihemophilic factor–plasma/albumin-free method; rFVIIIFc, recombinant factor VIII–Fc fusion protein.

Table 1 Observed baseline characteristics of patients treated with BAY 94-9027 and rFVIIIFc, before and after matching

Baseline characteristics^b	Before matching			After matching^a
	BAY 94-9027	rFVIIIFc	P	BAY 94-9027	rFVIIIFc	P
	N=103	N=140		N=103	N=140
Age ≤29.4 years	33 (32.0%)	70 (50.0%)	<0.01*	50.0%	50.0%	1.00
Weight ≤72.4 kg	49 (47.6%)	70 (50.0%)	0.81	50.0%	50.0%	1.00
Ethnicity
White	73 (70.9%)	90 (64.1%)	0.35	64.1%	64.1%	1.00
Asian	26 (25.2%)	38 (26.8%)	0.85	26.8%	26.8%	1.00
Region
Europe	37 (35.9%)	37 (26.1%)	0.15	26.1%	26.1%	1.00
North America	23 (22.3%)	48 (34.5%)	0.06	34.5%	34.5%	1.00
Prior treatment type
Prophylactic	83 (80.6%)	86 (61.3%)	<0.01*	61.3%	61.3%	1.00
On-demand	20 (19.4%)	54 (38.7%)	<0.01*	38.7%	38.7%	1.00
Number of bleeding events in the prior year
Prior prophylactic: >6.0	31 (30.1%)	43 (30.6%)	1.00	30.6%	30.6%	1.00
Prior on-demand: >27.4	14 (13.6%)	27 (19.4%)	0.32	19.4%	19.4%	1.00
Presence of target joint(s)
Prior prophylactic	61 (59.2%)	46 (33.1%)	<0.001*	33.1%	33.1%	1.00
Prior on-demand	16 (15.5%)	47 (33.8%)	<0.01*	33.8%	33.8%	1.00

Notes: ^aThe effective sample size of the BAY 94-9027 overall group after matching was 44.60. ^bThe median of age, weight, and estimated bleeding events in the prior year in the pooled rFVIIIFc group was approximated using the weighted sum of corresponding medians in the individualized and the weekly prophylaxis arms in A-LONG. *P<0.05.

Abbreviation: rFVIIIFc, recombinant human factor VIII–Fc fusion protein.

Table 2 Observed baseline characteristics of patients treated with BAY 94-9027 and BAX 855, before and after matching

Baseline characteristics	Before matching			After matching^a
	BAY 94-9027	BAX 855	P	BAY 94-9027	BAX 855	P
	N=104	N=101		N=104	N=101
Age ≤28 years	34 (32.7%)	50 (50.0%)	<0.05*	50.0%	50.0%	1.00
Weight ≤73 kg	51 (49.0%)	50 (50.0%)	1.00	50.0%	50.0%	1.00
Ethnicity
White	73 (70.2%)	77 (76.7%)	0.41	76.7%	76.7%	1.00
Asian	27 (26.0%)	23 (22.5%)	0.71	22.5%	22.5%	1.00
Prior treatment type
Prophylactic	84 (80.8%)	83 (82.5%)	0.94	82.5%	82.5%	1.00
On-demand	20 (19.2%)	18 (17.5%)	0.94	17.5%	17.5%	1.00
Presence of target joint(s)	78 (75.0%)	66 (65.0%)	0.17	65.0%	65.0%	1.00

Notes: ^aThe effective sample size of the BAY 94-9027 overall group after matching was 78.30. *P<0.05.

Table 3 Observed baseline characteristics of patients treated with BAY 94-9027 and rAHF-PFM

Baseline characteristics^b	Before matching			After matching^a
	BAY 94-9027	rAHF-PFM (2004 study)^a	P	BAY94-9027	rAHF-PFM (2004 study)^a	P
	N=104	N=107		N=104	N=107
Age ≤18 years	13 (12.5%)	54 (50.0%)	<0.001*	50.0%	50.0%	1.00
Ethnicity
White	73 (70.2%)	99 (92.8%)	<0.001*	92.8%	92.8%	1.00
Asian	27 (26.0%)	1 (0.9%)	<0.001*	0.9%	0.9%	1.00
Prior treatment type^a
Prophylactic	84 (80.8%)	78 (73.0%)	0.23	73.0%	73.0%	1.00
On-demand	20 (19.2%)	29 (27.0%)	0.23	27.0%	27.0%	1.00
Baseline characteristics^b	BAY 94-9027	rAHF-PFM (2012 study)	P	BAY 94-9027	rAHF-PFM (2012 study)	P
	N=104	N=66		N=104	N=66
Age <16 years	9 (8.7%)	9 (13.6%)	0.44	13.6%	13.6%	1.00
Ethnicity
White	73 (70.2%)	58 (87.9%)	<0.05*	87.9%	87.9%	1.00
Asian	27 (26.0%)	1 (1.5%)	<0.001*	1.5%	1.5%	1.00
Presence of target joint(s)	78 (75.0%)	63 (95.5%)	<0.001*	95.5%	95.5%	1.00

Notes: ^aThe effective sample size of the BAY 94-9027 overall group was 25.32 after matching with the 2004 study and 55.33 after matching with the 2012 study. ^bPatients on both prior prophylactic and on-demand treatment in the 2004 study were categorized as being on “prior prophylactic treatment” to be consistent with the definition in the PROTECT VIII trial. *P<0.05.

Abbreviation: rAHF-PFM, recombinant antihemophilic factor–plasma/albumin-free method.

Figure 2 Comparison of weekly rFVIII utilization between BAY 94-9027 and (A) rFVIIIFc; (B) BAX 855; (C) rAHF-PFM-2004; (D) rAHF-PFM-2012. Median weekly rFVIII utilization of prophylactic BAX 855 was estimated using the median dose per infusion (44.6 IU/kg) multiplied by the median of prophylaxis infusions per week (1.96). Median weekly rFVIII utilization of rAHF-PFM-2004 was estimated using the median annualized consumption (5,733.3 IU/kg/year) multiplied by 7/365.25. Median weekly rFVIII utilization of rAHF-PFM-2012 was estimated using the median dose per infusion (30.7 IU/kg) multiplied by the protocol-specified number of prophylaxis infusions per week (ie, every other day). *P<0.05.

Abbreviations: rAHF-PFM, recombinant antihemophilic factor–plasma/albumin-free method; rFVIIIFc, recombinant human factor VIII–Fc fusion protein.

Figure 3 Relative reduction in annual IU utilization and incremental ABR and percentage of patients with zero bleeds, BAY 94-9027 vs rFVIIIFc, BAX 855, rAHF-PFM-2004, or rAHF-PFM-2012. *P<0.05.

Abbreviations: ABR, annualized bleeding rate; rAHF-PFM, recombinant antihemophilic factor–plasma/albumin-free method; rFVIIIFc, recombinant human factor VIII–Fc fusion protein.

Figure S1 PRISMA flow diagram.

Table S1 Inclusion and exclusion criteria for the SLR

Inclusion criteria	Exclusion criteria
Language
Studies in English	Studies not in English
Study design and publication type
RCTs	Reviews (SLR and narrative reviews)
Single-arm trials	Observational studies
	Case reports
	Commentaries and letters
	Recommendations/guidelines
Study population
Adult and adolescent patients with severe hemophilia A	Non-human studies
	Studies focusing on pediatric patients (<12 years old)
	Not hemophilia A
	Not severe hemophilia A patients^a
Study interventions
rFVIIIFc, BAX 855, or rAHF-PFM	Studies that did not include rFVIIIFc, BAX 855, or rAHF-PFM
Outcomes of interest
Studies that included outcomes	Studies that did not include outcomes

Note: ^aStudies with mixed severe and moderately severe hemophilia A patients may be included.

Abbreviations: rAHF-PFM, recombinant antihemophilic factor/plasma/albumin-free method; RCT, randomized controlled trial; rFVIIIFc, recombinant factor VIII–Fc fusion protein; SLR, systematic literature review.

Table S2 Summary of clinical trials used in the analysis

Study	Study drug	Design	Patients	N	Regimen	Outcome Endpoint
PROTECT VIII^a	BAY 94-9027	Phase II/III, multinational, partially randomized, open-label trial	Men aged 12–65 years with FVIII <1% and ≥150 ED to FVIII	132	10-week run-in period: 25 IU/kg twice weekly (on-demand or prophylaxis) Randomization period: twice weekly (30–40 IU/kg), every 5 days (45–60 IU/kg), or every 7 days (60 IU/kg) prophylaxis for 36 weeks	ABR (primary)
A-LONG^b	rFVIIIFc	Phase III open-label, multicenter, partially randomized trial	Previously treated males aged ≥12 years with severe hemophilia A (FVIII <1%)	165	Three treatment arms: 1) individualized prophylaxis (25–65 IU/kg every 3–5 days); 2) weekly prophylaxis (65 IU/kg); 3) episodic (10–50 IU/kg)^f	ABR (primary)
PROLONG-ATE^c	BAX 855	Phase II/III multicenter, open-label study	Subjects aged 12–65 years with severe hemophilia A (FVIII <1%) and ≥150 ED to FVIII	138	Prophylaxis regimen: 45±5 IU/kg twice weekly for ≥50 ED On-demand regimen: 10–60±5 IU/kg for 6 months±2 days	ABR (primary)
rAHF-PFM-2004^d	rAHF-PFM	Three-part study; open-label, uncontrolled, prophylactic study (part 2) and two PK studies	Subjects aged ≥10 years with FVIII ≤2%, weight >35 kg, and ≥150 ED to FVIII	111	Prophylactic regimen: 25–40 IU/kg three times per week or every other day for ≥75 ED (PK regimens: 50±5 IU/kg, two infusions 72 h to 4 weeks apart)	ABR (post hoc)
rAHF-PFM-2012^e	rAHF-PFM	Open-label, multicenter study	Subjects aged 7–65 years with FVIII ≤2% and ≥150 ED to FVIII	66	Standard prophylaxis: 20–40 IU/kg every 48±6 h for 12 months^g PK-tailored prophylaxis: 20–80 IU/kg every 72±6 h for 12 months^g	ABR (primary)

Notes: ^aReding et al (2017)¹; ^bMahlangu et al (2014)²; ^cKonkle et al (2015)³; ^dTarantino et al (2004)⁴; ^dValentino et al (2012)⁵. ^fTreatment was terminated upon completion of pharmacokinetic assessments and achievement of prespecified rFVIIIFc exposure to ensure acceptable inhibitor detection. Median duration of treatment was 32.1 and 28.0 days for prophylaxis arms 1 and 2, respectively. ^gRandomization to standard or PK-tailored prophylaxis occurred after 6 months of on-demand treatment at 50±6 IU/kg.

Abbreviations: ABR, annualized bleeding rate; ED, exposure days; FVIII, factor VIII; PK, pharmacokinetic; rAHF-PFM, recombinant antihemophilic factor–plasma/albumin-free method; rFVIIIFc, recombinant factor VIII–Fc fusion protein.