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Timing and severity of inhibitor development in recombinant versus plasma-derived factor VIII concentrates: a SIPPET analysis
Peyvandi F, Cannavo A, Garagiola I, Palla R, Mannucci PM, Rosendaal FR
Journal of Thrombosis and Haemostasis : Jth. 2017;16((1):):39-43
Abstract
BACKGROUND The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is the most severe complication in the early phases of treatment of severe haemophilia A. Recently a randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) demonstrated a two-fold higher risk of inhibitors development in children treated with recombinant FVIII (rFVIII) products than with plasma-derived FVIII (pdFVIII) during the first 50 exposure days (EDs). OBJECTIVE/METHODS In this post-hoc SIPPET analysis we evaluated the rate of inhibitor incidence over time by every 5 EDs (from 0 to 50 EDs) in patients treated with different classes of FVIII product, made possible by a frequent testing regime. RESULTS The highest rate of inhibitor development occurred in the first 10 EDs with a large contrast between rFVIII and pdFVIII during the first 5 ED: hazard ratio 3.14 (CI95% 1.01-9.74) for all inhibitors and 4.19 (CI95% 1.18-14.8) for high-titre inhibitors. For patients treated with pdFVIII, the peak of inhibitor development occurred later (6-10 EDs) and lasted shorter. CONCLUSION These results emphasize the high immunologic vulnerability of patients during the earliest exposure to FVIII concentrates with the strongest response to recombinant FVIII products. This article is protected by copyright. All rights reserved.
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2.
A randomized trial of factor VIII and neutralizing antibodies in hemophilia A
Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V, Eshghi P, Hanagavadi S, Varadarajan R, Karimi M, et al
The New England Journal of Medicine. 2016;374((21)):2054-64.
Abstract
BACKGROUND The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).
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3.
Inhibitor development in relation to treatment duration in severe hemophilia A in previously untreated patients: results from the SIPPET trial
Peyvandi F, Mannucci PM, Garagiola I, Anzoletti MB, El-Beshlawy A, El-Alfy M, Madatha VR, Eshghi P, Varadarajan R, Hanagavadi S, et al
Journal of Thrombosis and Haemostasis. 2015;13((Suppl. 2)):321.. Abstract No. PO164-MON.
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Source of factor VIII replacement (PLASMATIC OR RECOMBINANT) and incidence of inhibitory alloantibodies in previously untreated patients with severe hemophilia a: the multicenter randomized sippet study
Peyvandi F, Mannucci PM, Garagiola I, Elalfy M, El-Beshlawy A, Ramanan MV, Eshghi P, Hanagavadi S, Varadarajan R, Karimi M, et al
Blood. 2015;126((23)): Abstract No. 5.
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5.
Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial
Mannucci PM, Kempton C, Millar C, Romond E, Shapiro A, Birschmann I, Ragni MV, Gill JC, Yee TT, Klamroth R, et al
Blood. 2013;122((5):):648-57.
Abstract
Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.
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6.
Pharmacokinetic properties of IB1001, an investigational recombinant factor IX, in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis
Martinowitz U, Shapiro A, Quon DV, Escobar M, Kempton C, Collins PW, Chowdary P, Makris M, Mannucci PM, Morfini M, et al
Haemophilia. 2012;18((6):):881-7.
Abstract
IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double-blind, non-inferiority, cross-over study conducted in participants aged >= 12 years weighing >= 40 kg, with severe or moderately severe haemophilia B (FIX activity <= 2 IU dL (-1) ). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4-18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8-59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg (-1) or nonacog alfa. The lower limit of the one-sided 95% confidence interval for the ratio of AUC (0-t) and AUC (0-) (IB1001/nonacog alfa) was 0.90, establishing non-inferiority. Terminal phase half-lives were similar (29.7 +/- 18.2 h for IB1001 and 33.4 +/- 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non-inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B. 2012 Blackwell Publishing Ltd.
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7.
A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study)
Gringeri A, Lundin B, Von Mackensen S, Mantovani L, Mannucci PM
Journal of Thrombosis and Haemostasis. 2011;9((4):):700-10.
Abstract
Background: Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia. Objective:This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period. Methods: Forty-five children with severe hemophilia A, aged 1-7years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25IUkg-1 3x week) or episodic therapy with >=25IUkg-1 every 12-24h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. Results:Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P<0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P< 0.05). Prophylaxis was more effective when started early (<=36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. Conclusion:This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life. 2011 International Society on Thrombosis and Haemostasis.
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8.
Pharmacokinetic behavior of IB1001, an investigational recombinant factor IX, in patients with hemophilia B: Repeat pharmacokinetic study and subgroup analysis
Martinowitz U, Shapiro AD, Quon DV, Escobar MA, Kempton CL, Collins P, Chowdary P, Makris M, Mannucci PM, Morfini M, et al
Blood. 2011;118((21):): Abstract No. 2267.
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9.
Recombinant human von Willebrand Factor (rhVWF): first-in-human study evaluating pharmacokinetics, demonstrating safety and tolerability in Type 3 von Willebrand Disease
Suiter T, Laffan M, Mannucci PM, Kempton CL, Romond EH, Shapiro AD, Birschmann I, Gill JC, Ragni MV, Turecek P, et al
Blood. 2010;116((21):): Abstract No. 237.
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10.
Primary and secondary prophylaxis in children with haemophilia A reduces bleeding frequency and arthropathy development compared to on-demand treatment: a 10-year, randomized, clinical trial
Gringeri A, Lundin B, von Mackensen S, Mantovani LG, Mannucci PM, Bianchi Bonomi A
ISTH Congress. 2009;: Abstract No. OC-MO-034.