Pharmacokinetics and pharmacodynamics of SCT800, a new recombinant FVIII, in hemophilia A mice

Gu, Ruixia; Liu, Liang; Xie, Liangzhi; Gai, Wenlin; Cao, Si-shuo; Zhang, Meng; Gan, Hui; Wu, Zhiyong; Li, Jian; Zheng, Ying; Zhu, Xue-Ming; Dou, Guifang

doi:10.1038/aps.2015.121

Cited by 3 publications

(1 citation statement)

References 36 publications

(31 reference statements)

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“…Moreover, viral removal/inactivation steps (such as nanofiltration) were added to ensure higher safety. Results from preclinical studies, 10 a phase I pharmacokinetic (PK) study, and a phase III on‐demand efficacy‐safety study [unpublished data] have confirmed that SCT800 has PK profiles similar to those of Xyntha ® , and exhibits high in vivo recovery (IVR), effective haemostatic response, good safety and high tolerability. The primary purpose of this study was to evaluate the repeat PKs, efficacy and safety of SCT800 in the prophylaxis and treatment of bleeding episodes in adolescents and adults with severe haemophilia A who have previously received FVIII therapy (NCT03815318).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic, efficacy and safety evaluation of B‐domain‐deleted recombinant FVIII (SCT800) for prophylactic treatment in adolescent and adult patients with severe haemophilia A

et al. 2021

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Introduction SCT800 is a recombinant human B‐domain‐deleted coagulation factor VIII (BDDrFVIII) developed in China. Aim To evaluate the repeat pharmacokinetics (PKs), efficacy, and safety of SCT800 in previously treated Chinese adolescent and adult patients with severe haemophilia A. Methods A phase III, multicentre, prospective, open‐label, single‐arm trial was conducted at 12 medical centres. Subjects received treatment for 24 weeks. PKs were assessed at the initial and repeated dosing 24 weeks later. The primary endpoint was annualized bleeding rate (ABR). Breakthrough bleeding episodes and inhibitor development were assessed. Results A total of 71 of 73 patients completed the study, and 18 were enrolled for the repeat PK investigation. Total exposure was 5643 exposure days. Overall, SCT800 showed comparable repeat PK profiles. The total ABR was 2.82 (95% confidence interval 2.01‐3.96). During prophylaxis, 43.8% of patients had no bleeding episodes. The majority (89.4%) of bleeding episodes were controlled with 1–2 injections of SCT800, the success rate (defined as ‘excellent’ or ‘good’ haemostatic response) for the treatment of bleeding episodes was 92.6%. The incidence of treatment‐related adverse events was 53.4%. Drug‐related AE incidence was 4.1%. The observed AEs were similar to those of other coagulation factor VIII, but lower in frequency. No subject developed an inhibitor, and no other safety concerns were identified. Conclusions SCT800 has robust PK characteristics, and is safe and efficacious for the prophylaxis and treatment of bleeding episodes in previously treated adolescent and adult patients with severe haemophilia A.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetic, efficacy and safety evaluation of B‐domain‐deleted recombinant FVIII (SCT800) for prophylactic treatment in adolescent and adult patients with severe haemophilia A

et al. 2021

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Mouse models of hemostasis

Mohammed

Monroe²,

Gailani

2020

Platelets

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Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice

et al. 2022

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Advances in the development of novel treatment options for hemophilia A are prevalent. However, the anti-FVIII neutralizing antibody (inhibitor) response to existing FVIII products remains a major treatment challenge. While some novel products are designed to function in the presence of inhibitors, they do not specific address the immunogenicity risk or mechanistic causes of inhibitor development, which remain unclear. Furthermore, most preclinical studies supporting clinical gene therapy programs have reported immunogenicity signals in animal models, especially at higher vector doses and sometimes using multiple vector designs. In these settings, immunogenicity risk factor determination, comparative immunogenicity of competing vector designs, and the potential for obtaining meaningful prognostic data remain relatively unexplored. Additionally, there remains the opportunity to investigate clinical gene therapy as an alternative to standard immune tolerance induction therapy. The current study was designed to address these issues through longitudinal dose-response evaluation of four AAV vector candidates encoding two different FVIII transgenes in a murine model of hemophilia A. Plasma FVIII activity and anti-FVIII antibody data were used to generate a pharmacokinetic model that 1) identifies initial FVIII expression kinetics as the dominant risk factor for inhibitor development, 2) predicts a therapeutic window where immune tolerance is achieved, and 3) demonstrates evidence of gene therapy-based immune tolerance induction. While there are known limitations to the predictive value of preclinical immunogenicity testing, these studies can uncover or support the development of design principles that can guide the development of safe and effective genetic medicines.

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Pharmacokinetics and pharmacodynamics of SCT800, a new recombinant FVIII, in hemophilia A mice

Abstract: In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties.

Cited by 3 publications

References 36 publications

Pharmacokinetic, efficacy and safety evaluation of B‐domain‐deleted recombinant FVIII (SCT800) for prophylactic treatment in adolescent and adult patients with severe haemophilia A

Pharmacokinetic, efficacy and safety evaluation of B‐domain‐deleted recombinant FVIII (SCT800) for prophylactic treatment in adolescent and adult patients with severe haemophilia A

Mouse models of hemostasis

Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice

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