Efficacy and safety of recombinant porcine factor VIII in Japanese patients with acquired hemophilia A.

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies inhibiting human factor VIII (hFVIII). This phase II/III open-label study evaluated the safety and efficacy of recombinant porcine factor VIII (rpFVIII, susoctocog alfa) in adults with AHA and severe bleeding episodes in Japan (NCT04580407). The initial rpFVIII dose was 200 U/kg, with subsequent doses based on clinical measures including plasma FVIII activity. The primary efficacy endpoint was the proportion of severe bleeding episodes with a positive response to rpFVIII therapy 24 h after treatment initiation. Five patients were eligible for, and completed, rpFVIII treatment (age group: 60s-80s; median hFVIII inhibitor: 52 BU/mL; porcine FVIII [pFVIII] inhibitor: 3/5 patients). The median (range) total dose/patient was 548.4 (198-1803) U/kg with a median 3.0 infusions/patient. All patients responded positively to rpFVIII therapy at 24 h regardless of baseline pFVIII inhibitor status. rpFVIII treatment was well tolerated with no adverse events of special interest such as thromboembolic events or de novo pFVIII inhibitors. This study supports the use of rpFVIII as a novel therapy in the clinical management of patients with AHA in Japan. rpFVIII was approved for treating bleeding episodes in adults with AHA in Japan in 2024.

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

INTRODUCTION: Porcine 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. AIM: To evaluate the ability of hpFVIII to limit the anti-FVIII activity of inhibitor alloantibodies. METHODS: Three 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. RESULTS: OSA 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). CONCLUSION: Hybrid FVIII proteins containing porcine FVIII A2 and/or C2 domain(s) could support effective therapy in PwHA-I by avoiding neutralization.

Acquired Hemophilia A: Bleeding Pattern and Hemostatic Therapeutic Strategies.

Acquired Hemophilia A (AHA) is a rare autoimmune disorder characterized by the onset of a sudden and unexpected bleeding episode in a patient with no personal or family history of bleeding diathesis, and with a typical laboratory feature, i.e., a prolonged activated partial thromboplastin time that is not otherwise explained. This bleeding disorder is caused by autoantibodies directed against the coagulation factor VIII (FVIII). AHA is idiopathic in 50% of cases and is secondary to well-defined diseases in the remaining 50%. AHA affects elderly patients although it has also been observed in the post-partum period. Bleeding manifestations are heterogeneous, ranging from mild to life-threatening bleeds involving limbs and organs. Severe bleeding with a significant decrease in hemoglobin levels must be promptly and adequately treated in order to avoid a worsening of the hemorrhages and their complications. According to international recommendations, the bypass agents (i.e., activated prothrombin complex concentrate and activated recombinant factor VII) and the replacement therapy with recombinant porcine FVIII are considered as the first-line therapy for bleeding control, due to their proven clinical efficacy. Plasma-derived or recombinant FVIII concentrates could be used as second-line treatments. Emicizumab may represent a valid and interesting therapeutic option for prophylaxis of bleeding recurrences.

Acquired Hemophilia A After SARS-CoV-2 Infection: A Case Report.

Acquired hemophilia A is a rare autoimmune coagulation disorder associated to the development of neutralizing antibodies directed towards coagulation factor VIII, known as factor VIII inhibitors, in subjects with previous normal clotting system homeostasis and personal and family history negative for bleeding episodes. This condition, although variable in severity and clinical presentation, may lead to severe and life-threatening hemorrhages which can be either spontaneous or associated with traumatic events and invasive procedures. Here we report the case of a 53-year-old woman who was admitted to our Internal Medicine Unit "Cesare Frugoni", Policlinico di Bari, in July 2021, and diagnosed with acquired hemophilia A. We aim to raise awareness about this rare condition, its clinical presentation and therapeutic management options in order to obtain a quick diagnosis and an effective therapeutic intervention.

Recombinant porcine factor VIII corrects thrombin generation in vitro in plasma from patients with congenital hemophilia A and inhibitors.

Background: Neutralizing factor VIII (FVIII) antibodies are a major complication in hemophilia A. Antihemophilic factor VIII (recombinant), porcine sequence (rpFVIII; susoctocog alfa; Baxalta US Inc., a Takeda company) has low cross-reactivity to anti-human FVIII antibodies and can provide functional FVIII activity in the presence of FVIII inhibitors. Objectives: Evaluate in vitro thrombin generation and clot formation responses to rpFVIII in blood from patients with congenital hemophilia A. Methods: In this multicenter study, blood was obtained for in vitro analyses that included human and porcine FVIII inhibitors, low <5 Bethesda units (BU)/ml or high ≥5 BU/ml titer (Nijmegen-modified Bethesda assay); thrombin generation assay (TGA), clot viscoelasticity (thromboelastography), fibrin clot structure analysis (scanning electron microscopy), and epitope mapping. Results: Blood samples were from 20 patients with congenital hemophilia A (FVIII activity <1%, mean [range] inhibitor titers: anti-human FVIII, 14 [1-427] BU/ml [n = 13 high, n = 6 low, n = 1 data unavailable]); anti-porcine FVIII, 12 (0-886) BU/ml (n = 11 high, n = 8 low, n = 1 data unavailable). Porcine inhibitor titer and TGA response measured by endogenous thrombin potential showed an inverse correlation (2.7-10.8 U/ml rpFVIII Spearman correlation coefficient: -0.594 to -0.773; p < 0.01). Clot structures in low anti-porcine inhibitor titer plasmas were similar to those in noninhibitor plasma. Conclusions: Recombinant porcine factor VIII demonstrated a dose-dependent correction of thrombin generation and clot formation in vitro, dependent on the anti-porcine FVIII inhibitor titer. Procoagulant responses to rpFVIII occurred in plasma containing FVIII inhibitors.

Recombinant porcine factor VIII: Lessons from the past and place in the management of hemophilia A with inhibitors in 2021.

The most serious complication of factor VIII (FVIII) replacement therapy is the occurrence of anti-FVIII alloantibodies that can strongly reduce or abolish the effect of human FVIII products. Bypassing agents to control bleeding episodes are recommended for these patients, but their efficacy is difficult to predict and monitor. FVIII products derived from porcine plasma had an important role in the treatment of hemophilia A for 50 years, from 1954 to 2004. Indeed, porcine FVIII could achieve hemostasis in patients in whom human FVIII products were ineffective. A recombinant porcine FVIII product is now available. This highly purified protein has the same biochemical and hemostatic properties, but much lower risks of infection and toxicity compared with plasma-derived porcine FVIII. The product is licensed in the United States and Europe for the treatment of acquired hemophilia A. However, this recombinant molecule could also be of clinical interest for people with inherited hemophilia A and inhibitors, particularly for the management of bleeding episodes in people receiving emicizumab as prophylactic treatment in the absence of anti-porcine FVIII antibodies.

Acquired haemophilia and haemostatic control with recombinant porcine factor VIII: case series.

BACKGROUND: Acquired haemophilia A (AHA) is a rare acquired bleeding disorder that can present with life-threatening bleeding. AIMS: To describe recent Australian use of recombinant porcine factor VIII (rpFVIII) replacement therapy as a haemostatic agent in patients with acquired haemophilia. METHODS: Four patients with acquired haemophilia treated in three different institutions around Australia in the past 12 months were included in the study. Haemostatic efficacy of Obizur (Takeda) was assigned by the treating haematologist according to previously published criteria. RESULTS: Six bleeds were treated with rpFVIII, three of which were initially refractory to treatment with recombinant VIIa. rpFVIII was rated efficacious in 100% of bleeds by 24 h. rpFVIII loading dose was 100 U/kg (100-120 U kg-1 ) and this increased the factor VIII level (via one-stage FVIII assay) from <1-1.2% to 54-306% taken 0.5-1.5 h post-infusion. Subsequent doses ranged from 40 to 60 U/kg twice daily or daily for 3 to 13 days. No rpFVIII related adverse events occurred. Three of the four patients achieved complete remission and were weaned from immunosuppression. One patient died prior to achieving partial remission, secondary to an arterial ischaemic event. CONCLUSION: This case series demonstrates that recombinant porcine FVIII is efficacious to treat acute bleeds in acquired haemophilia, including in those who are refractory to bypassing agents. Doses of rpFVIII were able to be titrated based on FVIII level and clinical response.

Cross-reacting inhibitors against recombinant porcine factor VIII in acquired hemophilia A: Data from the GTH-AH 01/2010 Study.

BACKGROUND: Recombinant porcine factor VIII (rpFVIII, OBI-1, susoctocog alfa) is used for the treatment of acute bleeds in patients with acquired hemophilia A (AHA). Inhibitors in AHA can sometimes cross-react with rpFVIII. OBJECTIVES: To assess the frequency, strength, and determinants of cross-reactivity. PATIENTS/METHODS: Baseline samples from 70 patients of the prospective, observational cohort study GTH-AH 01/2010 were assessed for anti-human FVIII and anti-rpFVIII inhibitors using modified Nijmegen-Bethesda assays, as well as anti-human FVIII domain reactivity using enzyme-linked immunoassay (ELISA). RESULTS: Anti-human FVIII inhibitors were present in all samples ranging between 0.7 and 3891 Bethesda Units (BU)/mL. Inhibitors from 31 of 70 patients (44%) partially inhibited rpFVIII with anti-rpFVIII titers ranging between 0.5 and 471 BU/mL. Anti-rpFVIII titers were ≤5 BU in most patients. Patients with cross-reacting inhibitors, as compared to patients without, had significantly higher anti-human FVIII titers (27.8 versus 5.4 BU/mL) and lower baseline FVIII activity (<1 versus 2.6 IU/dL). The ratio between anti-rpFVIII to anti-human titers was highest for inhibitors involving the C1 domain. Cross-reactivity was very rare, if inhibitors reacted only with the C2 domain of FVIII (6%). An anti-human FVIII titer of >100 BU/mL predicted cross-reactivity with 97% likelihood, whereas an anti-human FVIII titer of <3.8 BU/mL predicted absent cross-reactivity with 90% likelihood. CONCLUSION: Cross-reacting inhibitors should be considered when choosing a treatment for bleeding patients with AHA. Cross-reactivity is frequent in patients with anti-human FVIII titers of >100 BU/mL.

[Successful treatment of acquired hemophilia A with recombinant porcine factor VIII]. / Erfolgreiche Behandlung einer erworbenen Hemmkörperhämophilie A mit rekombinantem porcinem Faktor VIII.

Acquired hemophilia A is a rare, potentially life-threatening disease resulting from autoantibodies against coagulation factor VIII. We report the case of a patient with acquired hemophilia A and severe bleeding after incision of a peritonsillar abscess. Treatment with high dose factor VIII and recombinant activated factor VII failed to control bleeding. However, a single infusion of recombinant porcine factor VIII stopped bleeding efficiently and resulted in measurable factor VIII levels.

Management of acquired hemophilia A: Review of current evidence.

Acquired hemophilia A (AHA) is a rare acquired bleeding disorder caused by autoantibodies against autologous factor VIII (FVIII). It is a disease that most commonly affects the elderly, but it has been described in children and during the post-partum period. It is idiopathic in 50% of cases and is associated with autoimmune disease, malignancy, pregnancy, infection or certain medications in the other 50%. The diagnosis should be suspected in patients with an isolated prolonged aPPT without previous personal or familial bleeding history. Treating the bleeding and eradication of the inhibitor is the mainstay of treatment. The first line of treatment for acute bleeding is the use of bypassing agents. The most commonly used method for eradicating the inhibitor is immunosuppression, namely corticosteroids alone or in combination with cyclophosphamide. This review summarises current knowledge and reviews management options and guidelines.

Review of recombinant anti-haemophilic porcine sequence factor VIII in adults with acquired haemophilia A.

Acquired haemophilia A (AHA) is a rare, serious bleeding disorder most often encountered in elderly patients. The mainstay of haemostatic management is with bypassing agents (BPAs) including recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCCs). Their major limitation is incomplete efficacy, potential risk for thrombosis and the lack of routine laboratory assays for monitoring treatment response. Plasma-derived porcine FVIII (pd-pFVIII, Hyate C®), first used in the 1950s for the management of congenital haemophilia, has sufficient sequence homology to be haemostatic in humans, but the lack of complete homology facilitates efficacy even in the presence of human allo- and autoantibodies against human FVIII (hFVIII). In a small phase II/III study, recombinant porcine FVIII (rpFVIII, Obizur®, OBI-1, susoctocog alfa) was shown to be safe and effective for the management of bleeding episodes in patients with AHA with anti-porcine FVIII (anti-pFVIII) antibody levels of 20 BU/ml or less. Treatment outcome was judged on clinical response and FVIII levels after an initial fixed dose of 200 IU/kg. The rise in FVIII levels showed considerable inter-individual variability and was significantly influenced by the presence of anti-pFVIII antibodies. Based on the baseline levels of anti-pFVIII antibodies and response to treatment, three potential patient groups were identifiable. In the first group, the absence of cross-reacting antibodies was associated with supra-therapeutic FVIII levels, fewer infusions and lower rpFVIII utilization per treatment episode. The second group had patients with low levels of cross-reacting anti-pFVIII antibodies (0.8-5 BU/ml) with near-normal response to rpFVIII. The last group had higher titres of anti-pFVIII antibody (10-30 BU/ml) associated with lower FVIII levels, more infusions and higher consumption of rpFVIII. We propose a new treatment algorithm for the haemostatic management of AHA that includes the potential first-line clinical use of rpFVIII that takes into account availability of anti-pFVIII antibody results, titre of anti-pFVIII antibodies and severity of bleeding episode.

Recombinant porcine factor VIII for high-risk surgery in paediatric congenital haemophilia A with high-titre inhibitor.

INTRODUCTION: High-titre factor VIII (FVIII) inhibitors complicate peri-operative haemostasis. Recombinant porcine FVIII (r-pFVIII) may provide an alternative haemostatic agent for high-risk procedures and allow FVIII activity monitoring. AIM: Devise an effective haemostatic plan for repair of a progressively symptomatic aortic coarctation in a 5-year-old male with immune tolerance induction (ITI) refractory high-titre FVIII inhibitors. METHODS: Preprocedure human FVIII inhibitor titre was 58 Bethesda Units mL-1 (BU) and cross-reacted to neutralize porcine FVIII at 30 BU. Daily ITI with plasma-derived FVIII concentrate was supplemented with anti-B-cell and anti-plasma cell immunotherapy to reduce FVIII inhibitor titres. Potential haemostatic agents were evaluated in comparative ex vivo thrombin generation assays (TGA). RESULTS: Four weeks after immunosuppression, human and porcine inhibitor titres declined to 16 and 2 BU respectively. TGA with r-pFVIII was less robust than with activated prothrombin complex concentrate (aPCC); however, r-pFVIII was selected for cardiac surgery to secure the ability to assay FVIII levels throughout this high-bleeding risk procedure. Haemostasis with r-pFVIII was excellent; initial trough FVIII activity levels ranged from 0.81-1.17 IU mL-1 . On postoperative day 3, peak and trough levels markedly declined suggesting a rising porcine inhibitor titre. Postprocedure prophylaxis was transitioned to aPCC, informed by TGA. CONCLUSIONS: R-pFVIII provided effective peri-procedural haemostasis with no adverse events. Rapid neutralization of r-pFVIII after the first 60 hours, despite intensive immune suppression, accentuates the importance of careful monitoring. Use of TGA can support bypassing agent selection for convalescence. The comparative cost of r-pFVIII may limit its use to high morbidity clinical scenarios.

Recombinant porcine sequence factor VIII (rpFVIII) for acquired haemophilia A: practical clinical experience of its use in seven patients.

INTRODUCTION: A recombinant porcine factor VIII B-domain-deleted product (rpFVIII; OBIZUR, Baxalta Incorporated, Deerfield, IL 60015, USA) was recently approved for treatment of bleeding episodes in adults with acquired haemophilia A (AHA) in the United States. To date, no clinical experience outside the registration study has been reported. AIM: To describe early clinical experience using rpFVIII for AHA. METHODS: A retrospective chart review of seven patients with AHA treated with rpFVIII at four institutions from November 2014 to October 2015. RESULTS: The time to diagnosis of AHA ranged from 5 days to 6 weeks. Six major and one other bleed were treated with rpFVIII following unsatisfactory bypassing agent (BPA) therapy. Good haemostatic efficacy was seen in five of seven cases. rpFVIII loading doses of 100 (n = 6) or 200 U kg-1 (n = 1) increased FVIII activity from <1 to 9% at baseline to 109-650% within 0.25-7 h in six of seven cases. Subsequent median doses ranged from 30 to 100 U kg-1 for 3-26 days. No rpFVIII-related adverse events were reported. Three patients survived with inhibitor eradication, one with persistent inhibitor, two died with inhibitors present and one was discharged and later died from unrelated causes. CONCLUSIONS: rpFVIII showed good haemostatic efficacy with no recurrences in most cases, with consumption substantially less than in the registration study. Treatment decisions were based on FVIII activity levels and clinical assessment. The ability to titrate rpFVIII dose using FVIII activity was considered advantageous compared with BPA therapy. Notable delays in diagnosis were observed.

Acquired haemophilia: experience of two Italian centres with 17 new cases.

Acquired haemophilia is a rare but often catastrophic haemorrhagic disorder associated with a high mortality rate. No single therapeutic approach has been consistently successful and clinical experience remains mainly anecdotal. This report describes 17 new cases diagnosed at two Italian haemophilia centres between 1979 and 1995. There was no difference in sex distribution. Mean age at diagnosis was 50 years. Fifty-nine per cent of cases had associated disorders and 29% developed an inhibitor post-partum. Eleven (64%) patients required substitutive therapy. Desmopressin was successfully used in five cases for minor bleeding. Immunosuppressive drugs (steroid, cyclophosphamide or experimental therapy) were used in 14 (82%) cases. Eight of 15 (52%) evaluable cases achieved complete remission (four post-partum). Fatal haemorrhage occurred in 2/15 (13%) of patients within 2 days from diagnosis. Acquired haemophilia is a severe coagulopathy. Prompt diagnosis with characterization and intensive treatment is usually required. However, particular subsets of patients such as those with inhibitor occurring post-partum or with low inhibitor titre at diagnosis usually show a more favourable clinical outcome.

Porcine factor VIII (Hyate: C®): in vitro stability, microbiological safety and effect of heparin.

The in vitro stability of porcine factor VIII (PF VIII) was evaluated when it was reconstituted with sterile water (PF VIIISW ) to ≈ 30 U PFVIII mL(-1) , as per the manufacturer's recommendations, and stored in plastic syringes at room temperature, with and without heparin and at four different dilutions. PF VIII was prepared antiseptically without laminar airflow and remained sterile at room temperature for 1 week. PF VIIISW retained at least 88% of baseline activity for 48 h and 74-86% for 72 h. Addition of heparin 1 unit mL(-1) solution resulted in a decrease in the stability of PF VIIISW to 72-74 % of baseline values by 24 h. Reconstituted PF VIIISW , further diluted with normal saline to 10-24 U PF VIII mL(-1) , retained 98% of baseline activity for 48 h and 84% of baseline for 72 h. PF VIII diluted to 6 U mL(-1) , however, retained 100% baseline activity for only 24 h, and declined to 71% and 64 % of baseline by 48 and 72 h, respectively. PF VIII reconstituted with normal saline, instead of sterile water, retained 90% or more of baseline activity for a minimum of 4 days. Once reconstituted, PF VIII appeared to be more stable at room temperature than when stored in the refrigerator. These in vitro stability studies confirm that PF VIII (30 U mL(-1) ) can be given effectively by prolonged continuous infusion, since it retains 88% baseline activity at room temperature in a plastic syringe for a minimum of 48 h, remains sterile and will maintain baseline PF VIII levels when further diluted with saline.