Thalidomide for the treatment of gastrointestinal bleeding due to angiodysplasia in a patient with Glanzmann’s thrombasthenia

Angiodysplasia is a frequent cause of persistent gastrointestinal (GI) hemorrhage in elderly patients. Although GI bleeding isn’t the most common manifestation in patients with bleeding disorders, when present, it represents a challenging complication. We describe a 62-year-old patient with Glanzmann’s thrombasthenia, who used thalidomide for severe and recurrent GI bleeding. For 6 months, the patient experienced temporary control of GI bleeding with thalidomide in a daily oral dose of 100 mg. The anti-angiogenic effects of thalidomide have recently been explored by several groups, particularly in the management of bleeding from angiodysplasia, including cases with von Willebrand disease. Here, we review the relevant descriptions of the use of thalidomide in this situation, and also discuss potential reasons why we observed only a temporary control of the GI bleeding in our patient, such as the use of low-dose regimen due to limitations posed by thalidomide side effects

Updates From Guardian (tm): A Comprehensive Registration Programme

Turoctocog alfa is an approved B-domain truncated recombinant factor VIII concentrate for adults and children with haemophilia A. Clinical data for turoctocog alfa have been reported from the guardian1, guardian2 and guardian3 phase III trials. guardian1 and guardian3 phase III trials enrolled 150 adolescents/adults (12yr), and 63 children (200 patients treated for a cumulative total of >54000 exposure days in the phase III trials. Pooled efficacy data show a favourable long-term effect of turoctocog alfa on annualised bleeding rate and a success rate for haemostatic response of 86%; 90% of bleeds were resolved with 1-2 doses. This article reviews the clinical development of turoctocog alfa with reference to the guardian clinical programme, describing results obtained to date and ongoing trials.95812229Novo Nordisk Health Care AG (Zurich, Switzerland

Updates from guardian™: a comprehensive registration programme

Turoctocog alfa is an approved B‐domain truncated recombinant factor VIII concentrate for adults and children with haemophilia A. Clinical data for turoctocog alfa have been reported from the guardian™1, guardian™2 and guardian™3 phase III trials. guardian™1 and guardian™3 phase III trials enrolled 150 adolescents/adults (≥12 yr), and 63 children (200 patients treated for a cumulative total of >54 000 exposure days in the phase III trials. Pooled efficacy data show a favourable long‐term effect of turoctocog alfa on annualised bleeding rate and a success rate for haemostatic response of 86%; 90% of bleeds were resolved with 1–2 doses. This article reviews the clinical development of turoctocog alfa with reference to the guardian™ clinical programme, describing results obtained to date and ongoing trials95S81Special Issue: 12th Novo Nordisk Symposium on Haemostasis Management, Vienna, Austria, 4–6 June 201422Medical writing support was provided by Andy Lockley of Bioscript Medical Ltd (Macclesfield, UK) and funded by Novo Nordisk Health Care AG (Zurich, Switzerland

Gene therapy: paving new roads in the treatment of hemophilia

Hemophilia is a monogenic disease with robust clinicolaboratory correlations of severity. These attributes coupled with the availability of experimental animal models have made it an attractive model for gene therapy. The road from animal models to human clinical studies has heralded significant successes, but major issues concerning a previous immunity against adeno-associated virus and transgene optimization remain to be fully resolved. Despite significant advances in gene therapy application, many questions remain pertaining to its use in specific populations such as those with factor inhibitors, those with underlying liver disease, and pediatric patients. Here, the authors provide an update on viral vector and transgene improvements, review the results of recently published gene therapy clinical trials for hemophilia, and discuss the main challenges facing investigators in the field457743750sem informaçãosem informaçãoDr. Yamaguti-Hayakawa reports personal fees and non-financial support from Roche outside the submitted work. Dr. Ozelo reports grants from BioMarin, Pfizer, during theconduct of the study and grants from Novo Nordisk, Shire,Bioverativ, and Roche outside the submitted wor

Haemophilia experiences, results and opportunities (HERO study) in Brazil : assessment of the psychosocial effects of haemophilia in patients and caregivers

The international Haemophilia Experiences, Results and Opportunities (HERO) study assessed the psychosocial aspects of life for people with haemophilia (PWH) and their caregivers in several countries. Brazil was not included in this initiative. An observational, multicentre, cross-sectional study was performed involving PWH (moderate-to-severe haemophilia) and their caregivers, from November 2014 to July 2015. The primary objective was to quantify the extent of the primary psychosocial factors affecting PWH in their everyday life. Descriptive statistics and comparisons between Brazilian and global respondents are presented. A total of 100 adult male PWH and 100 caregivers (responding on behalf of their oldest affected child aged <18 years) completed the survey. Sixty-eight per cent of the PWH had haemophilia A without inhibitors. Chronic pain and hepatitis C were the most common conditions related to haemophilia. On the EQ-5D assessment, 64% of PWH reported extreme/moderate pain. Treatment for depression or anxiety was reported by 18% of PWH and by 29% of caregivers. There was a lower employment rate for PWH in Brazil, compared to the countries included in the original HERO survey (51% vs 60%); 71% of PWH stated that haemophilia has a negative impact on their work. Over the previous 5 years, 58% of PWH and 68% of caregivers did not have difficulties in obtaining the concentrated factor for treatment. Our study presents an overview of the psychosocial aspects of life with haemophilia in Brazil, providing a basis for health policy decisions and may further improve comprehensive care for PWH254640650GF is the author of the study protocol and responsible for reporting the results. CL and MO were the principal investigators. CL, RB, GF and MO interpreted data and reviewed the manuscript. All authors read and approved the final version of the paper. Cristiane Aoqui Guenoub provided medical writing on behalf of Springer Healthcare. This manuscript was prepared according to the International Society for Medical Publication Professionals' Good Publication Practice for Communicating Company‐Sponsored Medical Research: the GPP3 Guideline

Immunogenicity of Current and New Therapies for Hemophilia A

Anti-drug antibody (ADA) development is a significant complication in the treatment of several conditions. For decades, the mainstay of hemophilia A treatment was the replacement of deficient coagulation factor VIII (FVIII) to restore hemostasis, control, and prevent bleeding events. Recently, new products have emerged for hemophilia A replacement therapy, including bioengineered FVIII molecules with enhanced pharmacokinetic profiles: the extended half-life (EHL) recombinant FVIII products. However, the main complication resulting from replacement treatment in hemophilia A is the development of anti-FVIII neutralizing alloantibodies, known as inhibitors, affecting approximately 25&ndash;30% of severe hemophilia A patients. Therefore, the immunogenicity of each FVIII product and the mechanisms that could help increase the tolerance to these products have become important research topics in hemophilia A. Furthermore, patients with inhibitors continue to require effective treatment for breakthrough bleedings and procedures, despite the availability of non-replacement therapy, such as emicizumab. Herein, we discuss the currently licensed treatments available for hemophilia A and the immunogenicity of new therapies, such as EHL-rFVIII products, compared to other products available

The effectiveness and safety of octocog alfa in patients with hemophilia A: up to 7-year follow-up of the real-world AHEAD international study

Background: Real-world data assessing treatment outcomes in patients with hemophilia A in routine clinical practice are limited. Objective: To evaluate the effectiveness and safety of octocog alfa in patients with moderate/severe hemophilia A receiving treatment in clinical practice. Design: The international Antihemophilic Factor Hemophilia A Outcome Database study is an observational, noninterventional, prospective, multicenter study. Methods: This planned interim data read-out was conducted following 7 years of observation of patients receiving octocog alfa (cut-off, 30 June 2020). The primary endpoint was joint health status, assessed by the Gilbert Score. Secondary endpoints included annualized bleeding rates (ABRs), Hemophilia Joint Health Score (HJHS), health-related quality of life, consumption, and safety. This post hoc analysis stratified data by hemophilia severity at baseline [moderate, factor VIII (FVIII) 1–5%; severe, FVIII <1%]. Results: Of the 711 patients in this analysis, 582 (82%) were receiving prophylaxis with octocog alfa at enrollment, and 498 (70%) had severe disease. Median Gilbert Scores were higher with on-demand therapy versus prophylaxis and scores were comparable in moderate and severe disease. In patients receiving prophylaxis, there was an improvement in HJHS Global Gait Score over 7 years of follow-up overall and in patients with severe disease. ABRs and annualized joint bleeding rates were low across all 7 years. An ABR of zero was reported in 34–56% of prophylaxis patients versus 20–40% in the on-demand group. ABRs were similar in severe and moderate disease. In total, 13/702 (1.9%) patients experienced 18 treatment-related adverse events. Conclusion: These data demonstrate the long-term effectiveness and safety of octocog alfa in patients with moderate and severe hemophilia A, especially in those receiving prophylaxis. The high number of patients receiving on-demand treatment experiencing zero bleeds could be due to selection bias within the study, with patients with less severe disease more likely to be receiving on-demand treatment. Trial registration: ClinicalTrials.gov: NCT02078427

Transgene-host Cell Interactions Mediate Significant Influences On The Production, Stability, And Function Of Recombinant Canine Fviii.

Recombinant FVIII manufacturing is characterized by poor product stability and low yields. Codon-optimization of transgenes accelerates translation by exploiting the synonymous codon usage bias of a species. However, this can alter the performance of the final product. Additionally, the effects of transgene design across diverse cell types are not well understood and are of interest for next-generation protein and gene therapies. To investigate the effects of transgene design across different host cells, B-domain-deleted (BDD) and modified codon-optimized (CO-N6) transgenes were inserted via lentiviral delivery into cBOECs, HEK293T, and MDCK cells. The CO-N6 cFVIII transgene produced threefold more protein per transgene in HEK293T cells, and sixfold more protein in the two canine cell lines. However, pharmacokinetic analysis in hemophilia A dogs demonstrated that cFVIII produced from cBOECs transduced with the CO-N6 transgene had significantly reduced in vivo recovery. Furthermore, this product showed reduced in vitro stability and activity on thrombin activation versus the BDD product. This trend was reversed in HEK293T lines. Overall, our results demonstrate the need for an integrated approach that not only assesses protein expression levels but also considers the influence that host-cells have on preserving the molecular and biochemical properties of the naturally occurring FVIII