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Turoctocog alfa (NovoEight®)--from design to clinical proof of concept.

ABSTRACT: Turoctocog alfa (NovoEight®) is a recombinant factor VIII (rFVIII) with a truncated B-domain made from the sequence coding for 10 amino acids from the N-terminus and 11 amino acids from the C-terminus of the naturally occurring B-domain. Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without addition of any human- or animal-derived materials. During secretion, some rFVIII molecules are cleaved at the C-terminal of the heavy chain (HC) at amino acid 720, and a monoclonal antibody binding C-terminal to this position is used in the purification process allowing isolation of the intact rFVIII. Viral inactivation is ensured by a detergent inactivation step as well as a 20-nm nano-filtration step. Characterisation of the purified protein demonstrated that turoctocog alfa was fully sulphated at Tyr346 and Tyr1664, which is required for optimal proteolytic activation by thrombin. Kinetic assessments confirmed that turoctocog alfa was activated by thrombin at a similar rate as seen for other rFVIII products fully sulphated at these positions. Tyr1680 was also fully sulphated in turoctocog alfa resulting in strong affinity (low nm Kd ) for binding to von Willebrand factor (VWF). Half-lives of 7.2 ± 0.9 h in F8-KO mice and 8.9 ± 1.8 h haemophilia A dogs supported that turoctocog alfa bound to VWF after infusion. Functional studies including thromboelastography analysis of human haemophilia A whole blood with added turoctocog alfa and effect studies in mice bleeding models demonstrated a dose-dependent effect of turoctocog alfa. The non-clinical data thus confirm the haemostatic effect of turoctocog alfa and, together with the comprehensive clinical evaluation, support the use as FVIII replacement therapy in patients with haemophilia A.

SUBMITTER: Ezban M

PROVIDER: S-EPMC4232928 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Turoctocog alfa (NovoEight®)--from design to clinical proof of concept.

Ezban Mirella M Vad Knud K Kjalke Marianne M

European journal of haematology 20140528 5

Turoctocog alfa (NovoEight®) is a recombinant factor VIII (rFVIII) with a truncated B-domain made from the sequence coding for 10 amino acids from the N-terminus and 11 amino acids from the C-terminus of the naturally occurring B-domain. Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without addition of any human- or animal-derived materials. During secretion, some rFVIII molecules are cleaved at the C-terminal of the heavy chain (HC) at amino acid 720, and a monoclonal antibod ...[more]

PMID: 24797664

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Project description:PurposeTo illustrate the benefits of the extended half-life (EHL) recombinant factor VIII product N8-GP (Esperoct®, turoctocog alfa pegol) by describing individual cases of patients with severe hemophilia A treated with N8-GP in the pathfinder clinical trial program.Patients and methodsThis manuscript presents selected patient cases from the pivotal pathfinder clinical trial program, which included a number of clinical studies in adults (pathfinder 2 and 3) and children (pathfinder 5); overall results published previously. Clinical data and outcomes described in this manuscript are more detailed and derived from several interesting patient cases (five adults from pathfinder 2 and two children from pathfinder 5), who received N8-GP as prophylaxis (PPX) for their severe hemophilia A. Three of the five adults described here also underwent multiple major surgeries (for which they moved from pathfinder 2 into pathfinder 3 and later returned to pathfinder 2). New analyses on pediatric joint health from pathfinder 5 are also summarized here. Outcomes assessed included bleeding complications, improvements in quality of life, intraoperative hemostatic response, blood loss during surgery, number of blood transfusions, and annualized bleeding rates. For the pediatric patients, target joint resolution, adverse events, and annualized joint bleeding rate were also assessed, all by the treating physician.ResultsConsiderable improvements in treatment adherence, bleeding rates, and overall physical activity levels were demonstrated in two adult cases from the pathfinder 2 trial. N8-GP demonstrated good or excellent hemostatic coverage in three adult patients undergoing multiple major surgeries. The benefits of N8-GP for joint health and in support of children and adolescents with evolving active lifestyles were reported for several pediatric cases.ConclusionThese patient cases highlight the benefits of EHL products, such as N8-GP, for patients with severe hemophilia A. They include more challenging scenarios relating to improvements in previously poor adherence to PPX, children with active sporting lifestyles, and patients requiring multiple major surgeries.

Project description:Molecular breast imaging (MBI) is a dedicated nuclear medicine breast imaging modality that employs dual-head cadmium zinc telluride (CZT) gamma cameras to functionally detect breast cancer. MBI has been shown to detect breast cancers otherwise occult on mammography and ultrasound. Currently, a MBI-guided biopsy system does not exist to biopsy such lesions. Our objective was to consider the utility of a novel conical slant-hole (CSH) collimator for rapid (<1 min) and accurate monitoring of lesion position to serve as part of a MBI-guided biopsy system.An initial CSH collimator design was derived from the dimensions of a parallel-hole collimator optimized for MBI performed with dual-head CZT gamma cameras. The parameters of the CSH collimator included the collimator height, cone slant angle, thickness of septa and cones of the collimator, and the annular areas exposed at the base of the cones. These parameters were varied within the geometric constraints of the MBI system to create several potential CSH collimator designs. The CSH collimator designs were evaluated using Monte Carlo simulations. The model included a breast compressed to a thickness of 6 cm with a 1-cm diameter lesion located 3 cm from the collimator face. The number of particles simulated was chosen to represent the count density of a low-dose, screening MBI study acquired with the parallel-hole collimator for 10 min after a ∼150 MBq (4 mCi) injection of Tc-99m sestamibi. The same number of particles was used for the CSH collimator simulations. In the resulting simulated images, the count sensitivity, spatial resolution, and accuracy of the lesion depth determined from the lesion profile width were evaluated.The CSH collimator design with default parameters derived from the optimal parallel-hole collimator provided 1-min images with error in the lesion depth estimation of 1.1 ± 0.7 mm and over 21 times the lesion count sensitivity relative to 1-min images acquired with the current parallel-hole collimator. Sensitivity was increased via more vertical cone slant angles, larger annular areas, thinner cone walls, shorter cone heights, and thinner radiating septa. Full width at half maximum trended in the opposite direction as sensitivity for all parameters. There was less error in the depth estimates for less vertical slant angles, smaller annular areas, thinner cone walls, cone heights near 1 cm, and generally thinner radiating septa.A Monte Carlo model was used to demonstrate the feasibility of a CSH collimator design for rapid biopsy application in molecular breast imaging. Specifically, lesion depth of a 1-cm diameter lesion positioned in the center of a typical breast can be estimated with error of less than 2 mm using circumferential count profiles of images acquired in 1 min.

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Turoctocog alfa (NovoEight®)--from design to clinical proof of concept.

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Turoctocog alfa (NovoEight®)--from design to clinical proof of concept.

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