Clinical experience with polyelectrolyte-fractionated porcine factor VIII concentrate in the treatment of hemophiliacs with antibodies to factor VIII

Kernoff, P. B. A.; Thomas, ND; Lilley, PA; Matthews, Keith; Goldman, E; Tuddenham, Edward G. D.

doi:10.1182/blood.v63.1.31.bloodjournal63131

Cited by 3 publications

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“…Prior to this study, there had been reports of anamnesis following the use of pFVIII, although they were thought to occur less frequently than with hFVIII. 15,22,23 An open-label, phase 2 study of rpFVIII in patients with CHAWI that was published after this surgery study was designed and initiated reported a similar rate of anamnestic reactions as in this study. 16 The study sponsor, along with discussions with the health authorities (EMA), determined that the risks of anamnestic reactions associated with rpFVIII outweighed the benefits in patients with CHAWI who underwent surgery or other invasive procedures, and therefore this study was terminated early.…”

Section: Discussionsupporting

confidence: 54%

“…In this surgery study, good haemostasis was achieved with rpFVIII during the immediate perioperative period, but 5 of the 8 patients experienced anamnestic reactions. Prior to this study, there had been reports of anamnesis following the use of pFVIII, although they were thought to occur less frequently than with hFVIII 15,22,23 . An open‐label, phase 2 study of rpFVIII in patients with CHAWI that was published after this surgery study was designed and initiated reported a similar rate of anamnestic reactions as in this study 16 .…”

Section: Discussionmentioning

confidence: 66%

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Recombinant porcine factor VIII in patients with congenital haemophilia A with inhibitors undergoing surgery: Phase 3, single‐arm, open‐label study

Pfrepper,

Radossi,

Windyga

et al. 2024

Haemophilia

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IntroductionRecombinant porcine factor VIII (rpFVIII; susoctocog alfa) is predicted to provide functional FVIII activity in patients with congenital haemophilia A with inhibitors (CHAWI).AimsTo evaluate the efficacy and safety of rpFVIII in patients with CHAWI undergoing invasive procedures.MethodsThis phase 3, multicentre, single‐arm, open‐label study (NCT02895945) enrolled males aged 12–75 years with severe/moderately severe CHAWI who required surgical/invasive procedures. Patients received a loading dose of rpFVIII 1–2 h before surgery. The primary outcome was the proportion of all procedures with a ‘good’ or ‘excellent’ response (treatment success) on the global haemostatic efficacy assessment score.ResultsOf the eight dosed patients, five completed the study. Six of seven surgeries (85.7%; 95% confidence interval, 42.1–99.6) achieved treatment success; five were rated ‘excellent’, one was rated ‘good’. Seven surgery‐related bleeding episodes occurred in three patients during the study, with none requiring additional surgical intervention. Overall, six of eight patients experienced 17 treatment‐emergent adverse events. Three patients developed de novo inhibitors to rpFVIII. Five patients reported anamnestic reactions, three to both human (h) FVIII (i.e., alloantibodies to exogenous FVIII detected with anti‐hFVIII assays) and rpFVIII, and two to hFVIII only. Four serious adverse events were considered related to rpFVIII (three anti‐rpFVIII antibody positive; one anamnestic reaction to hFVIII and rpFVIII).ConclusionGood haemostasis was achieved with rpFVIII during the immediate perioperative period. The study was terminated early because the study sponsor and health authorities determined that the risk of anamnestic reactions outweighs the benefits in this study population.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 66%

Recombinant porcine factor VIII in patients with congenital haemophilia A with inhibitors undergoing surgery: Phase 3, single‐arm, open‐label study

Pfrepper,

Radossi,

Windyga

et al. 2024

Haemophilia

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“…Porcine (p)FVIII is known to be highly homologous to human (h)FVIII in terms of protein sequence and structure, 11,12 and has similar coagulation potential to hFVIII 11 . The cross‐reactivity of autoantibodies against pFVIII has been shown to be significantly lower (< 10%) in acquired PwHA 13–16 . Several reports have also indicated that inhibitor titers in congenital PwHA‐I are lower when measured against pFVIII than with hFVIII, 13–15,17,18 and clinical trials have demonstrated that recombinant(r) BDD‐pFVIII could be alternative agent to BPA for the treatment of bleeding events in PwHA‐I 19,20 …”

Section: Introductionmentioning

confidence: 99%

“…11 The cross-reactivity of autoantibodies against pFVIII has been shown to be significantly lower (< 10%) in acquired PwHA. [13][14][15][16] Several reports have also indicated that inhibitor titers in congenital PwHA-I are lower when measured against pFVIII than with hFVIII, [13][14][15]17,18 and clinical trials have demonstrated that recombinant(r) BDD-pFVIII could be alternative agent to BPA for the treatment of bleeding events in PwHA-I. 19,20 Most FVIII inhibitors bind to epitopes located in A2, C2 and/or A3-C1 domains of FVIII, [21][22][23][24][25] and mono-specific inhibitors associated with domains other than A2 and C2 are infrequent.…”

Section: Introductionmentioning

confidence: 99%

Hybrid human‐porcine factor VIII proteins partially escape the inhibitory effects of anti‐factor VIII inhibitor alloantibodies having A2 or C2 domain specificity

Mizumachi,

Nakajima,

Shimonishi

et al. 2023

Haemophilia

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IntroductionPorcine factor (pF)VIII has low cross‐reactivity with anti‐human (h)FVIII inhibitor alloantibodies. Clinical trials of pFVIII in congenital haemophilia A patients with inhibitor (PwHA‐I) are in progress. Most polyclonal anti‐hFVIII inhibitors recognize its A2 and/or C2 domain(s), and recombinant human‐porcine hybrid (hp)FVIII proteins may escape neutralization by these inhibitors.AimTo evaluate the ability of hpFVIII to limit the anti‐FVIII activity of inhibitor alloantibodies.MethodsThree hybrid proteins were created by substituting the hFVIII A2, C2 domain or both with the corresponding domains of pFVIII [termed hp(A2), hp(C2) and hp(A2/C2), respectively]. The reactivity of these hybrids was assessed by one‐stage clotting assays (OSA), thrombin generation assays (TGA) and rotational thromboelastometry (ROTEM) by adding them to FVIII‐deficient samples.ResultsOSA demonstrated that the hybrid proteins avoided neutralization by anti‐FVIII A2 or C2 monoclonal antibodies (mAb) and polyclonal inhibitor‐antibodies (polyAb) from PwHA‐I. In TGA, thrombin generation with hp(A2) and hp(A2/C2) was not attenuated in the presence of patient IgG recognizing anti‐A2 domain. In contrast, that with hFVIII and hp(C2) was suppressed by this IgG to levels equivalent to those of FVIII‐deficient plasma. With anti‐A2/C2 polyAb, the activity of hp(A2/C2) was unaffected. ROTEM demonstrated that the addition of hp(A2) or hp(A2/C2) to anti‐A2 polyAb shortened clot times/clot formation times, whilst hFVIII or hp(C2) were ineffective. Similarly with anti‐A2/C2 polyAb, hp(A2/C2) restored coagulation potential to a greater extent than hp(A2) and hp(C2).ConclusionHybrid FVIII proteins containing porcine FVIII A2 and/or C2 domain(s) could support effective therapy in PwHA‐I by avoiding neutralization.

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Acquired Factor VIII Inhibitors: Pathophysiology and Treatment

Alice¹,

Carrizosa²

2006

Hematology

152

198

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Hemophilia A is classically caused by a congenital deficiency of factor VIII, but an acquired form due to inhibitors to factor VIII (FVIII) typically presents later in life. Patients who develop such acquired factor VIII inhibitors may present with catastrophic bleeding episodes, despite having no prior history of a bleeding disorder. Though the disorder is rare, it is known to cause significant morbidity and mortality. This review will focus on what is currently known about acquired hemophilia A, its pathogenesis, its associated etiologies, and its treatment. Factor VIII and Acquired InhibitorsFactor VIII functions as a cofactor to factor IXa in the tenase complex, and a deficiency of factor VIII thus reduces the generation of thrombin on the surface of activated platelets. Factor VIII is synthesized as a 330-kDa precursor protein with an A 1 -a 1 -A 2 -a 2 -B-a 3 -A 3 -C 1 -C 2 domain structure. 1After proteolytic processing, FVIII associates with von Willebrand Factor (vWF) in heterodimers of a heavy (A 1 -a 1 -A 2 -a 2 ) and a light (a 3 -A 3 -C 1 -C 2 ) chain associated by a metal ion interaction. Most acquired FVIII inhibitors bind to the A2, A3 or C2 domains.2,3 Anti-C2 antibodies disrupt the binding of FVIII to phospholipid and vWF, while antibodies to A2 and A3 interfere with FVIII binding to factor X and factor IXa.In congenital hemophilia A patients treated with factor VIII, alloantibodies to FVIII develop in 20-40% of patients. By contrast, acquired inhibitors/autoantibodies against FVIII in nonhemophiliacs occur in only about one case per million per year. 4 In acquired hemophilia, autoantibodies are characteristically non-complement fixing, nonprecipitating immunoglobulins from the IgG family that bind FVIII in a time-and temperature-dependent manner. 5While most alloantibodies inactivate FVIII in direct proportion to their concentration (first-order kinetics), acquired inhibitors/autoantibodies show a non-linear inactivation pattern (type II or second-order kinetics). The kinetics plots in Figure 1 show a linear inactivation of FVIII by a type 1 alloantibody, with eventual complete inhibition of the FVIII activity. By contrast, the type 2 antibody shows a rapid initial inactivation phase followed by a slower phase of equilibrium where some factor VIII can usually be measured.

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Clinical experience with polyelectrolyte-fractionated porcine factor VIII concentrate in the treatment of hemophiliacs with antibodies to factor VIII

Cited by 3 publications

References 0 publications

Recombinant porcine factor VIII in patients with congenital haemophilia A with inhibitors undergoing surgery: Phase 3, single‐arm, open‐label study

Recombinant porcine factor VIII in patients with congenital haemophilia A with inhibitors undergoing surgery: Phase 3, single‐arm, open‐label study

Hybrid human‐porcine factor VIII proteins partially escape the inhibitory effects of anti‐factor VIII inhibitor alloantibodies having A2 or C2 domain specificity

Acquired Factor VIII Inhibitors: Pathophysiology and Treatment

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