Molecular design and downstream processing of turoctocog alfa (NovoEight), a B-domain truncated factor VIII molecule

Ahmadian, Haleh; Hansen, Ernst Broberg; Faber, Johan H.; Sejergaard, Lars; Karlsson, Johan; Bolt, Gert; Hansen, Jens; Thim, Lars

doi:10.1097/mbc.0000000000000477

Cited by 15 publications

(10 citation statements)

References 18 publications

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“…Turoctocog alfa is a third‐generation, recombinant, B domain‐truncated human coagulation factor VIII (FVIII): the molecule has been discussed in detail elsewhere . Truncation of the B domain relative to endogenous FVIII has not been associated with any impact on the safety or efficacy of turoctocog alfa, which has demonstrated efficacy and safety in Phase 3 trials in previously treated children, adolescents and adults (guardian 1, 2 and 3 clinical trials).…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial

et al. 2019

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Introduction: Turoctocog alfa is a recombinant, B domain-truncated factor VIII (FVIII) approved for patients with haemophilia A. Aim: To evaluate the safety and efficacy of turoctocog alfa in previously untreated patients (PUPs) with severe haemophilia A. Methods: Guardian 4 was a multicentre, multinational, non-randomized, openlabel phase 3 trial comprising a main and extension phase. The former concluded once ≥ 50 patients had received treatment for ≥ 50 exposure days (EDs) or developed inhibitors. Patients received turoctocog alfa intravenously for prevention and treatment of bleeds. The primary endpoint was the incidence rate of FVIII inhibitors (≥0.6 Bethesda Units) reported during the first 50 EDs. Results: Of the 58 patients who completed the main phase, 25 (43.1%) patients developed inhibitors (detected within 6-24 [mean: 14.2] EDs from treatment start).High-risk mutations were identified in 60% of patients who developed inhibitors in the main phase and were a significant predictor of inhibitor development (P = .003).Of the 21 patients who started immune tolerance induction therapy, 85.7% completed treatment with a negative inhibitor test (note that data on the last 3 patients completing ITI are based on information collated from sites prior to the final database lock). Haemostatic response (including missing values as failure) was rated as 'excellent' or 'good' for 86.1% of bleeds occurring during prophylaxis. The estimated mean annualized bleeding rate for patients on prophylaxis was 4.26 bleeds/patient/year (95% CI: 3.34 − 5.44).Conclusions: Turoctocog alfa was effective at preventing and stopping bleeds and was well tolerated. Inhibitor development was within the expected range for this PUP population.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: Introductionmentioning

confidence: 99%

Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial

et al. 2019

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“…Turoctocog alfa has a robust and reliable manufacturing process, resulting in a product with high purity and homogeneity [23, 24]. This purification process may be important for the observed stability of turoctocog alfa when stored at high temperatures and variable conditions.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Fluctuating Temperature on the Stability of Turoctocog Alfa for Hemophilia A

Napolitano¹,

Nøhr

2019

Drugs R D

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Background and objectiveFactor VIII (FVIII) is indicated for the prevention or treatment of bleeding in patients with hemophilia A. FVIII product stability under high and fluctuating temperatures is important, particularly for patients who reside in, or travel to, regions with high ambient temperatures, as they may remove their product from the refrigerator and return it, unused, multiple times. We evaluated the effect of variable temperature storage conditions, including up to 40 °C, on the stability of the recombinant FVIII product, turoctocog alfa.MethodsTuroctocog alfa dry powder stability was assessed when moved between storage conditions of 5 °C (ambient humidity) and 40 °C (75% relative humidity) multiple times over a 2-month period, followed by long-term storage at 40 °C for 3 months and 5 °C for 1 month. Three product strengths (250, 1500, and 3000 IU), including the lowest and highest doses, were evaluated. Stability assessments included potency, purity, oxidized forms, high molecular weight protein (HMWP), and water content.ResultsOverall, the three doses of turoctocog alfa tested remained stable under varying temperature conditions, without any potency or purity impairment, nor were any major increases in oxidized forms, HMWP, or water content observed. All results were within shelf-life specification limits.ConclusionThe results demonstrated that turoctocog alfa can be subjected to variable storage conditions, including cycling between 5 °C and ≤ 40 °C, and subsequent storage for 3 months up to 40 °C, without loss of stability. This suggests that turoctocog alfa may offer greater product storage flexibility for patients in everyday practice, with a potential reduction in wastage.

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“…The manufacturing process includes several successive chromatography steps for capture of the FVIII product and its purification whose virus clearance capacity has been evaluated by Ellgaard et al [217]. In particular, MMC with Capto MMC resin was used for FVIII capture and anti-FVIII IAC using rF25 mAb [237] coupled to Seph was used as purification step. In the initial capture step, the MMC resin with adsorbed FVIII was washed with detergent and virus inactivation significantly contributed to the resulting viral clearance.…”

Section: Mab Ligands: Anti-fviii Immunoaffinity Chromatography (Iac)mentioning

confidence: 99%

Polysaccharide-based chromatographic adsorbents for virus purification and viral clearance

Junter

Lebrun

2020

Journal of Pharmaceutical Analysis

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Molecular design and downstream processing of turoctocog alfa (NovoEight), a B-domain truncated factor VIII molecule

Cited by 15 publications

References 18 publications

Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial

Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial

The Effect of Fluctuating Temperature on the Stability of Turoctocog Alfa for Hemophilia A

Polysaccharide-based chromatographic adsorbents for virus purification and viral clearance

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