Advancing personalized care in hemophilia A: ten years’ experience with an advanced category antihemophilic factor prepared using a plasma/albumin-free method

Figures & data

Figure 1 Chronology of observations from studies of rAHF-PFM leading toward personalized care for patients with hemophilia A.

Abbreviations: ABR, annual bleed rate (bleeds/patient/year); HRQOL, health-related quality of life; M-W-F, Monday-Wednesday-Friday; PK, pharmacokinetic; Tx, therapy; FVIII, factor VIII; rAHF-PFM, recombinant antihemophilic factor produced using a plasma/albumin-free method.

Table 1 Summary of clinical registration studies of rAHF-PFM

Study	Population	Design	Treatment	Endpoints	Efficacy results
Pivotal^Citation16	Criteria: FVIII ≤2 IU/dL; age ≥ 10 years; PTP (≥ 150 EDs) Enrolled • N=111 • Median age: 18 years • 96% FVIII <1 IU/dL • 108 treated Per-protocol • N=30	Parts 1 and 3: PK Part 2: open label, uncontrolled determination of hemostatic efficacy of prophylaxis for ≥75 EDs	Prophylaxis: 3 to 4×/week at 25 to 40 IU/kg for ≥ 75 EDs	Bioequivalence of rAHF-PFM relative to RECOMBINATEa PK Hemostatic efficacy	Treatment of bleeds • 93% of bleeds (473/510) required 1 or 2 infusions • Excellent or good for 439/510 (86%) • Excellent or good for 80% of spontaneous • Excellent or good for 87% of trauma-related ABRb • Overall: 6.3 bleeds/pt/y • Nonadherent vs adherent:c  ○ Mean of 9.9 vs 4.4 (P<0.03). • 32 patients (30%) did not bleed during prophylaxis
Continuation^Citation21	Criteria: completion of pivotal study Enrolled: N=81 Per-protocol • N=22 ITT • N=34	Open-label, uncontrolled Part 1: PK Part 2: hemostatic efficacy during prophylaxis or episodic treatment	a. 3 to 4× per week at 25–40 IU/kg for ≥75 EDs b. Investigator-modified prophylaxis for ≥75 EDs c. Episodic therapy	PK after 75 EDs Hemostatic efficacy	Treatment of bleeds • 88.5% of treated bleeds (726/820) required 1 or 2 infusions ABR, mean, by regimen • Standard prophylaxis: 6.0 • Modified prophylaxis: 4.8 • Episodic: 18.5. • Adherent vs nonadherentc  ○ Mean of 7.9 vs 4.5 • 11 of 81 patients (14%) did not bleed during prophylaxis
Pediatric^Citation14	Criteria: FVIII ≤2 IU/dL; age <6 years; PTP (≥50 EDs) Enrolled • N=53 (1 female) • Age: 1–5 years; mean 3.1 years • Treated: N=53	As described for continuation study	Planned: as described for continuation study except that standard prophylaxis was 3–4 times/week at 25–50 IU/kg and duration of prophylaxis was ≥46 weeks/year	Hemostatic efficacy	Treatment of bleeds • 90.1% (42/354) required 1 or 2 infusions • Excellent or good for 332/354 (93.8%) ABR, median, by regimen • Standard prophylaxis: 4.0 • Modified prophylaxis: 4.4 • Episodic: 24.4 • 9 patients (8 on prophylaxis; 1 on episodic tx) did not have a bleeding episode during the study Joint ABR, median by regimen • Prophylaxis: 0 • Modified prophylaxis: 0 • Episodic: 14.2

Notes:

a RECOMBINATE is manufactured by Baxter Healthcare, Westlake Village, CA, USA

b ABR is given in units of bleeds/patient/year

c adherent was defined as 25–40 IU/kg per infusion for >80% of the prophylactic infusions at a frequency of 3–4 times per week for 80% of the time on study.

Abbreviations: N, number; ABR, annual bleed rate; ED, exposure day; FVIII, factor VIM; PK, pharmacokinetic; pt, patient; PTP, previously treated patient; RECOMBINATE, Recombinate rAHF; SD, standard deviation; tx, therapy; wk, week; y, year; ITT, intent-to-treat; vs, versus; rAHF-PFM, recombinant antihemophilic factor produced using a plasma/albumin-free method.

Table 2 Efficacy ratings for treatment of bleeding in studies of rAHF-PFM

Rating	Definition
Excellent	Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single infusion
Good	Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an infusion, but possibly requiring more than one infusion for complete resolution
Fair	Probable or slight beneficial effect within approximately 8 hours after the first infusion, and usually requiring more than one infusion
None	No improvement, or worsening of symptoms

Abbreviation: rAHF-PFM, recombinant antihemophilic factor produced using a plasma/albumin-free method.

Figure 2 Predicted annual joint bleed rate as a function of time spent with factor (F)VIII <1 IU/dL. Negative binomial linear model with joint bleed rate as the dependent variable, and time with FVIII <1 IU/dL, age, and body weight as independent variables. The figure shows the predicted probability of having no bleeds per year dependent on time per week spent with an FVIII <1 IU/dL.

Notes: Open circles (○) represent patients aged 1–6 years; asterisks (*) represent patients aged 10–65 years. Reprinted with permission from John Wiley and Sons. Collins PW, Blanchette VS, Fischer K, et al; rAHF-PFM Study Group. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost. 2009;7(3):413–420.³³ Copyright © International Society on Thrombosis and Haemostasis.

Figure 3 Study design for comparison of standard prophylaxis, PK-guided prophylaxis, and episodic treatment with rAHF-PFM.

Abbreviations: ABR, annual bleed rate (bleeds/patient/year); EDs, exposure days; HRQOL, health-related quality of life; PK, pharmacokinetic; FVIII, factor VIII; rAHF-PFM, recombinant antihemophilic factor produced using a plasma/albumin-free method; q, every.

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

ShapiroADAnti-hemophilic factor (recombinant), plasma/albumin-free method (octocog-alpha; ADVATE) in the management of hemophilia AVasc Health Risk Manag20073555556518078007

 PubMedGoogle Scholar

BlanchetteVSShapiroADLiesnerRJPlasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patientsJ Thromb Haemost2008681319132618503631

 PubMed Web of Science ®Google Scholar

CollinsPWBlanchetteVSFischerKrAHF-PFM Study GroupBreak-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia AJ Thromb Haemost20097341342019143924

 PubMed Web of Science ®Google Scholar