The immunogenicity, safety, and efficacy of N8-GP in previously untreated patients with severe hemophilia A: pathfinder6 end-of-trial results

Kenet, Gili; Young, Guy; Chuansumrit, Ampaiwan; Matsushita, Tadashi; Yadav, Vandana; Zak, Marek; Male, Christoph

doi:10.1016/j.jtha.2023.07.030

Cited by 3 publications

(1 citation statement)

References 17 publications

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“…Within treatment‐related factors, specific types of FVIII products have been studied across trial designs, including individual product PUP trials, the SIPPET trial, and the RODIN study 5,13 . Although some variability in rates has been reported, all available FVIII products that differ in cell of origin, presence of B domain, and/or various modifications generate clinically significant rates of inhibitors; direct comparison of inhibitor incidence between products is limited, as most studies were single armed and non‐randomized 5,13,24–26 . Albeit not inclusive of EHL R‐FVIII products or R‐FVIII products produced in human cell lines, the SIPPET trial provided insight on how fixed patient‐related and environmental factors may interact, as in a secondary analysis the ‘benefit’ of PD‐FVIII was most evident in participants with low‐risk genetic variants 27 …”

Section: Discussionmentioning

confidence: 99%

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

Meeks,

Zimowski

2024

Haemophilia

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IntroductionThe advent of therapeutic recombinant factor VIII (FVIII) and factor IX (FIX) protein infusions revolutionized the care of persons with haemophilia in the 1990s. It kicked off an era with the increasing use of prophylactic factor infusions for patients and transformed conversations around the ideal trough activity levels as well as the ultimate goals in tailored, individualized care. Our knowledge surrounding the immunologic basis of inhibitor development and treatment derives from a time when patients were receiving frequent factor infusions and focused on immune tolerance induction following inhibitor development.DiscussionMore recently, care was revolutionized again in haemophilia A with the approval of emicizumab, a bispecific antibody mimicking activated FVIII function, to prevent bleeding. The use of emicizumab prophylaxis has resulted in a significantly slower accumulation of factor exposure days and continued effective prophylaxis in the case of inhibitor development. While emicizumab is effective at reducing the frequency of bleeding events in patients with haemophilia A, management of breakthrough bleeds, trauma, and surgeries still requires additional treatment. Ensuring that FVIII is a therapeutic option, particularly for life‐threatening bleeding events and major surgeries is critical to optimizing the care of persons with haemophilia A. Other novel non‐factor concentrate therapies, including rebalancing agents, will dramatically change the landscape for persons with haemophilia B with inhibitors.ConclusionThis review discusses the changing landscape regarding the timing of inhibitor development and management strategies after inhibitor development, stressing the importance of education across the community to continue to vigilantly monitor for inhibitors and be prepared to treat persons with inhibitors.

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Section: Discussionmentioning

confidence: 99%

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

Meeks,

Zimowski

2024

Haemophilia

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International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology

Rezende,

Neumann,

Angchaisuksiri

et al. 2024

Journal of Thrombosis and Haemostasis

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Simoctocog alfa (Nuwiq^®) in children: early steps in life’s journey for people with severe hemophilia A

Klukowska,

Sidonio,

Young

et al. 2024

Therapeutic Advances in Hematology

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People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent recurrent and potentially life-threatening bleeds that significantly impact day-to-day life. Factor VIII (FVIII) prophylaxis is well-established in children and has been shown to reduce the development of hemophilic arthropathy. However, a major challenge of FVIII therapy is the development of neutralizing anti-FVIII antibodies (FVIII inhibitors). Simoctocog alfa (Nuwiq®) is a human cell line-derived recombinant FVIII (rFVIII) whose immunogenicity, efficacy, and safety have been studied in 167 children with severe hemophilia A across two prospective clinical trials and their long-term extensions. In 105 previously untreated children, the inhibitor rate of 16.2% for high-titer inhibitors (26.7% for all inhibitors) was lower than published rates for hamster cell line-derived rFVIII products. There was no inhibitor development in previously untreated children with non-null F8 mutations and in previously treated children. In a case series of 10 inhibitor patients, 8 (80%) underwent successful immune tolerance induction with simoctocog alfa with a median time to undetectable inhibitor of 3.5 months. In an analysis of 96 children who enrolled in the extension studies and received long-term simoctocog alfa prophylaxis for up to 5 years, median spontaneous, joint, and total annualized bleeding rates were 0.3, 0.4, and 1.8, respectively. No thromboembolisms were reported in any of the 167 children, and there were no treatment-related deaths. Optimal care of children should consider several factors, including minimization of inhibitor development risk, maintaining tolerance to FVIII, highly effective bleed prevention and treatment, safety, and impact on long-term outcomes such as bone and joint health. In this context we review the pediatric clinical data and ongoing studies with simoctocog alfa.

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The immunogenicity, safety, and efficacy of N8-GP in previously untreated patients with severe hemophilia A: pathfinder6 end-of-trial results

Cited by 3 publications

References 17 publications

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology

Simoctocog alfa (Nuwiq^®) in children: early steps in life’s journey for people with severe hemophilia A

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The immunogenicity, safety, and efficacy of N8-GP in previously untreated patients with severe hemophilia A: pathfinder6 end-of-trial results

Cited by 3 publications

References 17 publications

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology

Simoctocog alfa (Nuwiq®) in children: early steps in life’s journey for people with severe hemophilia A

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Simoctocog alfa (Nuwiq^®) in children: early steps in life’s journey for people with severe hemophilia A