Association of bullous pemphigoid with acquired hemophilia A: a case report.

Acquired hemophilia A, a rare condition resulting in spontaneous bleeding without prior bleeding disorders, arises due to autoantibody-mediated inhibition of coagulation factor VIII and is typically associated with autoimmune, neoplastic, drug, or obstetric factors. We present the case of a 31-year-old woman with bullous pemphigoid, managed with corticosteroids since 2013, who presented spontaneous hemorrhagic manifestations. Upon admission, laboratory tests revealed hypochromic microcytic anemia, prolonged activated partial thromboplastin time, and a factor VIII level < 1%, indicative of acquired hemophilia A. Further assessments showed elevated Ristocetin cofactor activity, von Willebrand factor antigen, and a factor VIII inhibitor level of 665 BU. This underscores the importance of considering acquired hemophilia A in autoimmune dermatological conditions like bullous pemphigoid, highlighting the association between autoimmune disorders and coagulation abnormalities, particularly in cases of spontaneous hemorrhagic events.

Blunting specific T-dependent antibody responses with engineered "decoy" B cells.

Antibody inhibitors pose an ongoing challenge to the treatment of subjects with inherited protein deficiency disorders, limiting the efficacy of both protein replacement therapy and corrective gene therapy. Beyond their central role as producers of serum antibody, B cells also exhibit many unique properties that could be exploited in cell therapy applications, notably including antigen-specific recognition and the linked capacity for antigen presentation. Here we employed CRISPR-Cas9 to demonstrate that ex vivo antigen-primed Blimp1-knockout "decoy" B cells, incapable of differentiation into plasma cells, participated in and downregulated host antigen-specific humoral responses after adoptive transfer. Following ex vivo antigen pulse, adoptively transferred high-affinity antigen-specific decoy B cells were diverted into germinal centers en masse, thereby reducing participation by endogenous antigen-specific B cells in T-dependent humoral responses and suppressing both cognate and linked antigen-specific immunoglobulin (Ig)G following immunization with conjugated antigen. This effect was dose-dependent and, importantly, did not impact concurrent unrelated antibody responses. We demonstrated the therapeutic potential of this approach by treating factor VIII (FVIII)-knockout mice with antigen-pulsed decoy B cells prior to immunization with an FVIII conjugate protein, thereby blunting the production of serum FVIII-specific IgG by an order of magnitude as well as reducing the proportion of animals exhibiting functional FVIII inhibition by 6-fold.

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.

[Acquired hemophilia A and emicizumab for the treatment of bleeding: two case report and a literature review]. / Hémophilie A acquise, le traitement par emicizumab peut relayer les agents by-passant : à propos de deux cas et une revue de la littérature.

Emicizumab is a bispecific antibody that mimics the function of factor VIII (FVIII) and is indicated for prophylactic use in patients with congenital hemophilia A with or without inhibitors. Acquired hemophilia A (AHA) is a rare and severe disorder causes by autoantibodies that inhibit FVIII. In AHA, acute bleeding are managed with bypassing agents but several reports described the off-label use of emicizumab. The aim of this article is to describe two cases of AHA treated with emicizumab and a review of the scientific littérature. Reports indicate that the use of emicizumab is efficacious to treat acute bleeding with less thrombotic events thant with bypassing agents and with a reduced hospitalisation duration. Nevertheless biological monitoring is more complicated with assay interferences and a persistent circulation more than 6 months after the last injection was observed for our two patients.

Evaluating clinically translatable conditioning for platelet gene therapy in murine hemophilia A with inhibitors.

BACKGROUND: Platelet gene therapy is effective in hemophilia A (HA) mice even with inhibitors. Fludarabine (Flu), along with busulfan (Bu) or melphalan (Mel), preconditioning has been shown to be highly effective for hematopoietic stem cell transplantation in the clinic. OBJECTIVES: To evaluate the efficacy of Bu-Flu and Mel-Flu preconditioning in platelet gene therapy of HA with inhibitors. METHODS: Bu-Flu and Mel-Flu were used to condition HA mice preimmunized with recombinant human factor (F)VIII. An optimal 660 centigray total body irradiation was used as a control regimen in parallel. Platelet-FVIII expression was introduced by transplantation of 2bF8 lentivirus (LV)-transduced hematopoietic stem cells. Animals were analyzed by fluorescence-activated cell sorting, quantitative polymerase chain reaction, FVIII assays, and tail bleeding tests. RESULTS: Bu-Flu, but not Mel-Flu, enabled successful 2bF8 gene therapy. All recipients achieved >55% chimerism post hematopoietic stem cell transplantation in both Bu-Flu and 660 centigray groups, with comparable copy numbers of 2bF8 cassette and the platelet-FVIII levels. The bleeding phenotype was rescued in 2bF8LV-transduced recipients. FVIII inhibitor titers declined with time, with comparable disappearance time of inhibitors between the 2 groups. When animals were rechallenged with recombinant human FVIII after the titers dropped to undetectable levels, no inhibitors were detected in 2bF8LV-transduced recipients. In contrast, all untransduced transplanted control mice produced inhibitors. These data demonstrate that immune tolerance was established in 2bF8LV-transduced primed HA mice under Bu-Flu conditioning. CONCLUSION: Bu-Flu preconditioning allows for successfully introducing platelet-FVIII expression to restore hemostasis and induce immune tolerance in primed HA mice, suggesting that this approach is a promising clinically translatable strategy for gene therapy of HA with inhibitors.

Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors.

INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

Peripheral Blood Lymphocyte Subsets in Factor VIII Inhibitor-Positive Patients with Severe Hemophilia A: A Case-Control Study.

INTRODUCTION AND OBJECTIVES: The present study aimed to investigate different peripheral lymphocyte subsets in patients with severe hemophilia A (HA) and factor VIII (FVIII) inhibitor production. For this, age-matched cases of 19 FVIII inhibitor-positive (IP), 21 FVIII inhibitor-negative (IN) and 45 healthy controls were selected for study. METHODS: Flow cytometry was used to analyze the peripheral lymphocyte subsets, including T, B, natural killer (NK) and NKT cells. The T cell subsets included CD3 + CD4-CD8- [double negative T (DNT)], CD3 + CD4 + CD8+ [double-positive T (DPT)], CD3 + CD4 + CD8- and CD3 + CD4-CD8+ T cells. Pairwise comparisons of absolute lymphocyte subset values were conducted among the three groups. The cut-off value for absolute lymphocyte counts was determined using receiver operating characteristic curve analysis. RESULTS: The results demonstrated that the absolute values of DPT cells in the IN and IP groups were significantly lower than those in the healthy control group (P = 0.007). The DNT values were also lower in severe HA patients with or without inhibitor than those in healthy subjects, but these differences were not statistically significant (P = 0.053). In addition, the absolute value of CD4+ Th cells in the IP group was lower than that in the healthy controls (P = 0.013). Although not statistically significant (P = 0.064), the absolute values of NKT cells were higher in the IN group compared with the IP group, and higher in the IP group compared with the healthy control group. There were no statistically significant differences in total T, B, CD8 + and NK cells among the IN, IP and healthy control groups. The cut-off value for absolute CD4+ Th cells in the IN group was < 598/µl. CONCLUSION: The decrease in absolute values of CD4+ Th cells in severe HA patients may contribute to the establishment of infused FVIII immune tolerance. If the CD4+ Th value remains > 598/µl, clinicians should be vigilant for possible FVIII inhibitor production, especially on days prior to FVIII exposure.

Anti-mCD20 in combination with α-mCXCL13 monoclonal antibody inhibits anti-FVIII antibody development in hemophilia A mice.

Anti-factor VIII (FVIII) antibody development poses a significant challenge in hemophilia A (HA) patients receiving FVIII protein replacement therapy. There is an urgent need for novel therapeutic strategies to inhibit the production of anti-FVIII inhibitory antibodies (inhibitors) in HA. This study aimed to investigate a combination monoclonal antibody (mAb) therapy targeting CXCL13 and CD20 on the development of anti-FVIII antibodies in a HA murine model, along with the underlying mechanisms involved. Specifically, mAbs targeting mouse CD20 (18B12) with an IgG2a backbone and mouse CXCL13 (2C4) with an IgG1 backbone were synthesized. HA mice with FVIII inhibitors were established, and the results revealed that the combination therapy of anti-mCD20 with α-mCXCL13 significantly suppressed anti-FVIII antibody development and induced FVIII tolerance. Furthermore, this combination therapy led to a marked reduction of peripheral and splenic follicular helper T cells and an enhancement of regulatory T cell induction, along with sustained depletion of bone marrow and splenic plasma cells in HA mice with preexisting FVIII immunity. Thus, the concurrence of blockage of CD20 and neutralization of CXCL13 hold promise as a therapeutic strategy for HA patients with inhibitors.

Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A.

BACKGROUND: Once-weekly efanesoctocog alfa provides high sustained factor VIII activity with superior bleeding prevention as compared with prestudy factor VIII prophylaxis in previously treated patients 12 years of age or older with severe hemophilia A. Data on outcomes of efanesoctocog alfa treatment in children younger than 12 years of age with severe hemophilia A are limited. METHODS: We conducted a phase 3, open-label study involving previously treated patients younger than 12 years of age with severe hemophilia A. Patients received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. The primary end point was the occurrence of factor VIII inhibitors (neutralizing antibodies against factor VIII). Secondary end points included annualized rates of treated bleeding episodes, bleeding treatment, safety, and pharmacokinetics. RESULTS: A total of 74 male patients were enrolled (38 with an age of <6 years and 36 with an age of 6 to <12 years). No factor VIII inhibitors developed. Most adverse events were nonserious. No serious adverse events that were assessed by the investigator as being related to efanesoctocog alfa were reported. In the 73 patients treated according to the protocol, the median and model-based mean annualized bleeding rates were 0.00 (interquartile range, 0.00 to 1.02) and 0.61 (95% confidence interval, 0.42 to 0.90), respectively. A total of 47 patients (64%) had no treated bleeding episodes, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints. A total of 41 of 43 bleeding episodes (95%) resolved with one injection of efanesoctocog alfa. Mean factor VIII activity at steady state was more than 40 IU per deciliter for 3 days and more than 10 IU per deciliter for almost 7 days after dose administration. The geometric mean terminal half-life was 40.0 hours. CONCLUSIONS: In children with severe hemophilia A, once-weekly prophylaxis with efanesoctocog alfa provided high sustained factor VIII activity in the normal to near-normal range (>40 IU per deciliter) for 3 days and more than 10 IU per deciliter for almost 7 days after administration, leading to effective bleeding prevention. Efanesoctocog alfa was associated with mainly nonserious adverse events. (Funded by Sanofi and Sobi; XTEND-Kids ClinicalTrials.gov number, NCT04759131.).

Acid Treatment of FVIII-Containing Plasma Samples Unmasks a Broad Spectrum of FVIII-Specific Antibodies in ELISA.

During routine treatment, plasma samples of patients with hemophilia A or acquired hemophilia A are frequently analyzed for the presence of FVIII-specific antibodies. While only inhibitory antibodies can be detected by the Bethesda assay, inhibitory and non-inhibitory antibodies can be detected by ELISA. However, plasma samples of patients frequently contain endogenous or substituted FVIII, hence interfering with both types of analyses. One option for the inactivation of FVIII is heat denaturation, which unfortunately has been shown to lead to high background signals complicating the discrimination of negative and positive plasma samples. In the current study, we developed a method of acid denaturation for FVIII-containing plasma samples that can help identify samples containing FVIII-specific antibodies and compared the effects of heat and acid denaturation on the detection of FVIII-antibody interactions in a monoclonal setting. The aim of our study was to establish an analysis that allows safer treatment decisions in the context of tolerance to FVIII.

Emicizumab versus immunosuppressive therapy for the management of acquired hemophilia A.

BACKGROUND: Acquired hemophilia A (AHA) is an autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII. Immunosuppressive therapy (IST) is standard of care to eradicate autoantibody production and protect from further bleeding but carries a risk of severe infection and mortality in frail patients with AHA. Recently, emicizumab has been studied for its potential to reduce the need for early and aggressive IST. OBJECTIVES: To compare outcomes of 2 studies that used either IST (GTH-AH 01/2010; N = 101) or prophylaxis with emicizumab (GTH-AHA-EMI; N = 47) early after diagnosis of AHA. METHODS: Baseline characteristics were balanced by propensity score matching. Primary endpoint was the rate of clinically relevant new bleeds during the first 12 weeks; secondary endpoints were adverse events and overall survival. RESULTS: The negative binominal model-based bleeding rate was 68% lower with emicizumab as compared with IST (incident rate ratio, 0.325; 95% CI, 0.182-0.581). No difference was apparent in the overall frequency of infections (emicizumab 21%, IST 29%) during the first 12 weeks, but infections were less often fatal in emicizumab-treated patients (0%) compared with IST-treated patients (11%). Thromboembolic events occurred less often with emicizumab (2%) than with IST (7%). Overall survival after 24 weeks was better with emicizumab (90% vs 76%; hazard ratio, 0.44; 95%, CI, 0.24-0.81). CONCLUSION: Using emicizumab instead of IST in the early phase after initial diagnosis of AHA reduced bleeding and fatal infections and improved overall survival.

Structural basis for inhibition of coagulation factor VIII reveals a shared antigenic hotspot on the C1 domain.

BACKGROUND: Hemophilia A arises from dysfunctional or deficient coagulation factor (F)VIII and leads to inefficient fibrin clot formation and uncontrolled bleeding events. The development of antibody inhibitors is a clinical complication in hemophilia A patients receiving FVIII replacement therapy. LE2E9 is an anti-C1 domain inhibitor previously isolated from a mild/moderate hemophilia A patient and disrupts FVIII interactions with von Willebrand factor and FIXa, though the intermolecular contacts that underpin LE2E9-mediated FVIII neutralization are undefined. OBJECTIVES: To determine the structure of the complex between FVIII and LE2E9 and characterize its mechanism of inhibition. METHODS: FVIII was bound to the antigen binding fragment (Fab) of NB2E9, a recombinant construct of LE2E9, and its structure was determined by cryogenic electron microscopy. RESULTS: This report communicates the 3.46 Å structure of FVIII bound to NB2E9, with its epitope comprising FVIII residues S2040 to Y2043, K2065 to W2070, and R2150 to H2155. Structural analysis reveals that the LE2E9 epitope overlaps with portions of the epitope for 2A9, a murine-derived inhibitor, suggesting that these residues represent a shared antigenic region on the C1 domain between FVIII-/- mice and hemophilia A patients. Furthermore, the FVIII:NB2E9 structure elucidates the orientation of the LE2E9 glycan, illustrating how the glycan sterically blocks interactions between the FVIII C1 domain and the von Willebrand factor D' domain. A putative model of the FVIIIa:FIXa complex suggests potential clashing between the NB2E9 glycan and FIXa light chain. CONCLUSION: These results describe an antigenic "hotspot" on the FVIII C1 domain and provide a structural basis for engineering FVIII replacement therapeutics with reduced antigenicity.

Clinical immunogenicity outcomes from GENEr8-1, a phase 3 study of valoctocogene roxaparvovec, an AAV5-vectored gene therapy for hemophilia A.

Gene transfer therapies utilizing adeno-associated virus (AAV) vectors involve a complex drug design with multiple components that may impact immunogenicity. Valoctocogene roxaparvovec is an AAV serotype 5 (AAV5)-vectored gene therapy for the treatment of hemophilia A that encodes a B-domain-deleted human factor VIII (FVIII) protein controlled by a hepatocyte-selective promoter. Following previous results from the first-in-human phase 1/2 clinical trial, we assessed AAV5-capsid- and transgene-derived FVIII-specific immune responses with 2 years of follow-up data from GENEr8-1, a phase 3, single-arm, open-label study in 134 adult men with severe hemophilia A. No FVIII inhibitors were detected following administration of valoctocogene roxaparvovec. Immune responses were predominantly directed toward the AAV5 capsid, with all participants developing durable anti-AAV5 antibodies. Cellular immune responses specific for the AAV5 capsid were detected in most participants by interferon-γ enzyme-linked immunosorbent spot assay 2 weeks following dose administration and declined or reverted to negative over the first 52 weeks. These responses were weakly correlated with alanine aminotransferase elevations and showed no association with changes in FVIII activity. FVIII-specific cellular immune responses were less frequent and more sporadic compared with those specific for AAV5 and showed no association with safety or efficacy parameters.

Emicizumab as a Promising Form of Therapy for Type A Hemophilia - A Review of Current Knowledge from Clinical Trials.

Hemophilia is a plasma bleeding disorder characterized by a deficiency of certain blood clotting factors. The most common forms of this disease, i.e., type A and type B, affect approximately 400,000 people worldwide. Without appropriate treatment ensuring the proper coagulation cascade, this disease may lead to serious disability. Minimizing patient discomfort is possible via replacement therapy, consisting of the substitution of a missing coagulation factor via intravenous administration. Frequent medication and the risk related to factor inhibitors are significant disadvantages, necessitating the improvement of current therapies or the development of novel ones. This review examines the humanized bispecific antibody Emicizumab which ensures hemostasis by mimicking the action of the coagulation factor VIII, a deficiency of which causes type A hemophilia. The paper outlines the topic and then summarizes available clinical trials on Emicizumab in type A hemophilia. Several interventional clinical trials have found Emicizumab to be effective in decreasing bleeding episodes and raising patient satisfaction among various hemophilia A populations. Current Emicizumab-related trials are forecast to be completed between 2024 and 2030, and in addition to congenital hemophilia A, the trials cover acquired hemophilia A and patients playing sports. Providing a more comprehensive understanding of Emicizumab may revolutionize the management of hemophilia type A and improve quality of life. Conclusively, Emicizumab is a gentler therapy owing to subcutaneous delivery and fewer injections, which reduces injection-site reactions and makes therapy less burdensome, ultimately decreasing hospital visits and indirect costs.

Inhibitor eradication and treatment for acquired hemophilia A.

INTRODUCTION: Acquired hemophilia A (AHA) is a rare hemorrhagic autoimmune disorder characterized by autoantibodies against coagulation factor VIII (FVIII). In approximately half of the cases AHA does not recognize any cause (idiopathic form), while in the other cases it may be triggered by autoimmune disorders, cancers, drugs, infections, or pregnancy. Besides treating the underlying disorder, specific AHA treatment includes management of bleeding, if necessary, and inhibitor eradication. AREAS COVERED: This narrative review summarizes the main epidemiological, clinical, laboratory, and therapeutic characteristics of AHA. In particular, it is focused on the current therapeutic options for the inhibitor eradication, also showing the latest findings on the innovative therapies. A literature search strategy was performed, without temporal limits, through Medline and PubMed electronic databases. EXPERT OPINION: Various first-line and second-line immunosuppressive agents are currently available for the management of AHA. Among the latter, the anti-CD20 monoclonal antibody rituximab has been the object of intense research during the last years from investigators as innovative promising eradicating therapy for AHA. Preliminary data from the studies support the use of this drug as a first-line option for newly diagnosed AHA cases.

The use of Bacillus subtilis as a cost-effective expression system for production of Cholera Toxin B fused factor VIII epitope regions applicable for inducing oral immune tolerance.

Coagulation factor replacement therapy for the X-linked bleeding disorder Haemophilia, characterized by a deficiency of coagulation protein factor VIII (FVIII), is severely complicated by antibody (inhibitors) formation. The development of FVIII inhibitors drastically alters the quality of life of the patients and is associated with a tremendous increase in morbidity as well as treatment costs. The ultimate goal of inhibitor control is antibody elimination. Immune tolerance induction (ITI) is the only clinically established approach for developing antigen-specific tolerance to FVIII. This work aims to establish a novel cost-effective strategy to produce FVIII molecules in fusion with cholera toxin B (CTB) subunit at the N terminus using the Bacillus subtilis expression system for oral tolerance, as the current clinical immune tolerance protocols are expensive. Regions of B-Domain Deleted (BDD)-FVIII that have potential epitopes were identified by employing Bepipred linear epitope prediction; 2 or more epitopes in each domain were combined and cDNA encoding these regions were fused with CTB and cloned in the Bacillus subtilis expression vector pHT43 and expression analysis was carried out. The expressed CTB-fused FVIII epitope domains showed strong binding affinity towards the CTB-receptor GM1 ganglioside. To conclude, Bacillus subtilis expressing FVIII molecules might be a promising candidate for exploring for the induction of oral immune tolerance.

Predicting inhibitor development using a random peptide phage-display library approach in the SIPPET cohort.

ABSTRACT: Inhibitor development is the most severe complication of hemophilia A (HA) care and is associated with increased morbidity and mortality. This study aimed to use a novel immunoglobulin G epitope mapping method to explore the factor VIII (FVIII)-specific epitope profile in the SIPPET cohort population and to develop an epitope mapping-based inhibitor prediction model. The population consisted of 122 previously untreated patients with severe HA who were followed up for 50 days of exposure to FVIII or 3 years, whichever occurred first. Sampling was performed before FVIII treatment and at the end of the follow-up. The outcome was inhibitor development. The FVIII epitope repertoire was assessed by means of a novel random peptide phage-display assay. A least absolute shrinkage and selection operator (LASSO) regression model and a random forest model were fitted on posttreatment sample data and validated in pretreatment sample data. The predictive performance of these models was assessed by the C-statistic and a calibration plot. We identified 27 775 peptides putatively directed against FVIII, which were used as input for the statistical models. The C-statistic of the LASSO and random forest models were good at 0.78 (95% confidence interval [CI], 0.69-0.86) and 0.80 (95% CI, 0.72-0.89). Model calibration of both models was moderately good. Two statistical models, developed on data from a novel random peptide phage display assay, were used to predict inhibitor development before exposure to exogenous FVIII. These models can be used to set up diagnostic tests that predict the risk of inhibitor development before starting treatment with FVIII.

Immunogenicity profile of rurioctocog alfa pegol in previously treated patients with severe congenital hemophilia A.

ABSTRACT: Rurioctocog alfa pegol is an extended-half-life full-length recombinant factor VIII (FVIII) bound to 20-kDa polyethylene glycol (PEG) that has been shown to be well tolerated and efficacious in the treatment and prevention of bleeding events in previously treated patients with severe hemophilia A. Here, we present a comprehensive analysis of immunogenicity data collected during 6 clinical studies of rurioctocog alfa pegol, including a total of 360 unique previously treated patients with severe hemophilia A. The analysis included treatment-emerging FVIII-neutralizing antibodies (FVIII inhibitors); preexisting and treatment-emerging antibodies binding to FVIII, PEG-FVIII, or PEG; and treatment-emerging antibodies binding to Chinese hamster ovary host cell proteins. Moreover, the potential association between the presence of these binding antibodies and adverse events (AEs) observed in patients was investigated, and the potential impact of these antibodies on the incremental recovery of rurioctocog alfa pegol in patients was analyzed. Overall, the data indicate that rurioctocog alfa pegol is not associated with any unexpected immunogenicity characteristics. Of 360 patients, 1 patient developed a transient FVIII inhibitor with a titer of 0.6 Bethesda units per mL, which was not associated with any serious AEs. Antibodies binding to FVIII, PEG-FVIII, or PEG were not detected at the time when the inhibitor was present. Moreover, 54 of 360 patients either entered the clinical studies with preexisting binding antibodies or developed these antibodies after exposure to rurioctocog alfa pegol. These antibodies were transient in most patients and did not show any causal relationship to either AEs or spontaneous bleeding episodes.