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Reipert B.M.,Baxalta Innovations GmbH
Cellular Immunology | Year: 2016

The development of persistent neutralizing antibodies against factor VIII (FVIII) is the most severe complication in the treatment of congenital hemophilia A patients with FVIII replacement therapies. Recently, we presented data which indicate that neutralizing antibodies are high-affinity antibodies which are mostly of the IgG1 and IgG4 subclasses. However, there are also FVIII-specific antibodies of low to moderate affinity which are found in some patients without neutralizing antibodies and in some healthy individuals. The underlying immune mechanisms which regulate the development of these different populations of FVIII-specific antibodies are poorly understood.In this review, we discuss potential mechanisms for the development of low-affinity and high-affinity antibodies. In particular, we discuss the role of memory B cells which are essential in maintaining long-lasting antibody responses and in driving the rapid anamnestic antibody response after re-exposure to the same antigen. We also present available data on the potential role of FVIII-specific memory B cells in the maintenance of neutralizing antibodies against FVIII. © 2016 Elsevier Inc.

Nikolov N.,Baxalta GmbH | Reisinger J.,Clinical Innovations | Schwarz H.P.,Baxalta Innovations GmbH
Immunotherapy | Year: 2016

Intravenous immunoglobulins have been used to treat autoimmune disorders (ADs) for over 50 years. The etiologies of various ADs are not fully understood and although intravenous immunoglobulin treatment has proved its immunomodulatory properties, the roles of proposed mechanisms of action also remain a matter of speculation. A systemic search of the literature regarding KIOVIG® (Baxalta US, Inc., MA, USA) use in clinical trials on patients with ADs and a detailed review of retrieved articles revealed eight relevant publications. These articles reported KIOVIG use in multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy, idiopathic thrombocytopenic purpura, Kawasaki disease, Guillain-Barre syndrome and other autoimmune and neurologic disorders and showed that KIOVIG is an effective, safe and well-tolerated treatment in the studied populations. Nevertheless, further studies on larger patient cohorts are needed. © 2016 Future Medicine Ltd.

Manco-Johnson M.J.,Aurora University | Bomgaars L.,Baylor College of Medicine | Palascak J.,University of Cincinnati | Shapiro A.,Indiana Hemophilia and Thrombosis Center | And 4 more authors.
Thrombosis and Haemostasis | Year: 2016

Severe congenital protein C (PC) deficiency (SCPCD) is associated with disseminated intravascular coagulation (DIC), purpura fulminans (PF), and vascular thromboembolic events (TE), often leading to organ failure and death. PC replacement therapy offers a safe, effective treatment for thromboembolic complications of SCPCD and secondary prophylaxis for recurrent DIC, PF, and TEs. A prospective, multi-centre, open-label, phase 2/3 study was conducted to demonstrate the safety and efficacy of protein C concentrate for treatment of PF and acute TEs. Fifteen enrolled patients with SCPCD received protein C concentrate; 11 received treatment for acute TEs (PF, 18 events; PF and other coumarin-related vascular thromboembolic events [coumarin-induced skin necrosis; CISN], 1 event; venous thrombosis, 5 events). Predefined efficacy criteria for treatment of acute TEs were compared with a historical control arm (i. e. patients receiving conventional therapy without protein C replacement). PF/CISN was demonstrated by pre-defined primary and secondary efficacy ratings. Primary ratings of protein C concentrate-treated episodes were significantly higher (p=0.0032) than in the historical control. For 19 PF/CISN episodes in 11 patients, 94.7 % of treatments were rated effective and 5.3 % effective with complications (not related to protein C concentrate). In a secondary efficacy rating, all treatments were rated effective (68.4 % excellent; 21.1 % good; 10.5 % fair). For 5/24 vascular thrombosis episodes, 80 % of treatments were rated excellent and 20 % were rated good. No treatment-related adverse events or serious adverse events occurred. In conclusion, protein C concentrate provides an efficacious, safe treatment for PF, CISN, and other TEs in SCPCD patients. © Schattauer 2016.

Gill J.C.,Medical College of Wisconsin | Castaman G.,San Bortolo Hospital | Castaman G.,University of Florence | Windyga J.,Institute of Hematology and Transfusion Medicine | And 10 more authors.
Blood | Year: 2015

This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatmentof bleedsinsevere von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, aslong ashemostatic factor VIII activity (FVIII:C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIIIat50IUVWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 5 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = 5 none to 1 = 5 excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII:C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII:C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227. © 2015 by The American Society of Hematology.

Blau I.-W.,Charite - Medical University of Berlin | Conlon N.,St Jamess Hospital | Petermann R.,Baxalta Innovations GmbH | Nikolov N.,Baxalta GmbH | Plesner T.,Vejle Hospital
Expert Review of Clinical Immunology | Year: 2016

The number of patients with secondary immune deficiencies (SID) is on the rise, mostly since the arrival on the market of novel targeted therapies that have increased the survival rates of patients with hematological malignancies. The recent changes in the SID landscape have brought with them new and diverse medical needs that treatments for SID management should strive to meet. In this special report, we study the opportunities provided by facilitated subcutaneous immunoglobulin administration (fSCIg) to treat patients for whom the conventional routes (intravenous and subcutaneous) are sub-optimal. Experts in the treatment of SID describe real-life cases from their daily practice, in which fSCIg has led to reducing the burden of treatment and increasing the treatment satisfaction. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

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