Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post-treatment.

Introduction: Valoctocogene roxaparvovec uses an adeno-associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe haemophilia A, providing bleeding protection.

Aim: To assess safety and efficacy of valoctocogene roxaparvovec 5-6 years post-treatment.

Methods: In a phase 1/2 trial, adult male participants with severe haemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec and were followed for 6 (6 × 10 vg/kg; n = 7) and 5 (4 × 10 vg/kg; n = 6) years.

Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1.

Background: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL).

Objectives: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1.

Methods: Participant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS).

Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A.

Background: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously.

Methods: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×10 vector genomes of valoctocogene roxaparvovec per kilogram of body weight.

Psychometric Validation of the Haemo-QOL-A in Participants with Hemophilia A Treated with Gene Therapy.

Purpose: The hemophilia-specific health-related quality of life (HRQOL) questionnaire (Haemo-QOL-A) is validated for detecting QOL changes following standard therapy for hemophilia A, but has not been rigorously evaluated after gene therapy. This post hoc analysis evaluated the psychometric properties of Haemo-QOL-A in adult people with severe hemophilia A (PWSHA) receiving valoctocogene roxaparvovec (AAV5-hFVIII-SQ) in 2 clinical trials (phase 1/2, NCT02576795; phase 3, NCT03370913).

Patients And Methods: Adult PWSHA (factor VIII levels ≤1 IU/dL) received 1 AAV5-hFVIII-SQ infusion (6×10 vg/kg).

Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A.

Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial ( NCT02576795 ), liver biopsy samples were collected 2.

Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A.

Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited.

Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A.

Introduction: Valoctocogene roxaparvovec is an investigational AAV5-based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A.

Aim: To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795).

Methods: Men ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti-AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 10 vg/kg dose, n = 7) and 4 years (4 × 10 vg/kg dose, n = 6).

Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A.

Evaluation of immune responses to adeno-associated virus (AAV)-mediated gene therapies prior to and following dose administration plays a key role in determining therapeutic safety and efficacy. This report describes up to 3 years of immunogenicity data following administration of valoctocogene roxaparvovec (BMN 270), an AAV5-mediated gene therapy encoding human B domain-deleted FVIII (hFVIII-SQ) in a phase 1/2 clinical study of adult males with severe hemophilia A. Patients with pre-existing humoral immunity to AAV5 or with a history of FVIII inhibitors were excluded from the trial.

Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial.

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII.

Pediatric patients with intravascular devices: polymicrobial bloodstream infections and risk factors.

A retrospective study was conducted, including 61 patients with long-term intravascular devices (IVDs) admitted to the Childrens Hospital Los Angeles with diverse underlying diseases, different types of catheters, and culture-proven catheter-related bloodstream infections (BSIs). Within these patients, 125 catheter-related BSIs occurred, and the incidence of monomicrobial and polymicrobial BSIs was evaluated. Risk factors for polymicrobial BSIs were determined.

Severe congenital protein C deficiency: description of a new mutation and prophylactic protein C therapy and in vivo pharmacokinetics.

Severe congenital protein C deficiency is a rare life-threatening disorder that presents with purpura fulminans, disseminated intravascular coagulation, and thrombotic complications during the neonatal period. Affected children require acute replacement therapy with fresh frozen plasma or protein C concentrate, for example, Ceprotin (Baxter AG, Vienna). Long-term management and outcome is dependent on effective anticoagulation with warfarin, low-molecular weight heparin, or protein C concentrate.

Overt and incomplete (silent) cerebral infarction in sickle cell anemia: diagnosis and management.

Cerebral vasculopathy in sickle cell anemia (HbSS) is manifest clinically as cerebral infarction and intracranial hemorrhage. The type of stroke, ischemic or hemorrhagic, is age specific with distinct differences in outcomes. Cerebral infarction with or without clinical stroke begins during early childhood and rarely causes death immediately.

Ethanol-lock technique for persistent bacteremia of long-term intravascular devices in pediatric patients.

Objectives: To use the ethanol-lock technique (in conjunction with systemic antibiotics) to salvage central lines from removal and to prevent persistence of catheter-related infections among pediatric patients with long-term intravascular devices.

Design: Medical records of patients treated with ethanol locks were retrospectively reviewed from June 1, 2004, through June 22, 2005.

Setting: Childrens Hospital Los Angeles, Los Angeles, Calif, a tertiary care pediatric hospital.

The next generation of hemophilia treatment specialists.

We currently are witnessing a serious attrition of physicians specializing in hemophilia treatment in Europe and the United States while most physicians who complete training in hematology-oncology choose oncology practice as their career. Nevertheless, recent therapeutic developments, including advances in prophylaxis and inhibitor management, have renewed the demand for experts in hemophilia and related disorders. To meet this demand, several specialty training programs have been developed in the United States and Europe, specifically the International Course in Hemophilia in Malmö, Sweden, the Children's Hospital of Los Angeles International Pediatric Hemostasis and Thrombosis Program, and the Baxter/National Hemophilia Foundation Fellowship Programs.

Overt and incomplete (silent) cerebral infarction in sickle cell anemia: diagnosis and management.

Regional complete infarctions in children with sickle cell anemia (HbSS) are often associated with stenosis of the large intracranial arteries and result in lifetime disability. Incomplete infarction occurs more frequently than previously recognized and has far-reaching effects on neurocognitive development and the risk for overt secondary strokes into adulthood. Clinical and neuroimaging modalities have been highlighted in an algorithmic approach, with the studies giving the highest yield in results and most likely to be available listed in sequential order.

Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination.

Rates and severity of pneumococcal infections in children with sickle cell disease were examined before licensure of pneumococcal-conjugated vaccine (PVC). Rates of peak invasive infection rates in 1-year-old children with hemoglobin SS and mortality in those 0 to 10 years of age were 36.5 to 63.

Cardiac abnormalities in children with sickle cell anemia.

Sickle cell anemia (SCA) results in chronic volume overload of the heart due to hemodilution. Previous echocardiographic studies of cardiac function in children with SCA have not accounted for these abnormal loading conditions. The objectives of this study were to (1) determine how the degree of anemia and transfusion status relate to cardiac findings and (2) evaluate cardiac function using load-independent parameters of function.