Nonacog beta pegol (N9-GP) in haemophilia B: A multinational phase III safety and efficacy extension trial (paradigm™4)

Young, Guy; Collins, Peter William; Colberg, T.; Chuansumrit, Ampaiwan; Hanabusa, Hideji; Lentz, Steven R.; Mahlangu, Johnny; Mauser‐Bunschoten, E. P.; Négrier, Claude; Oldenburg, Johannes; Patıroğlu, Türkan; Santagostino, Elena; Tehranchi, Ramin; Žák, Marek; Karim, Faraizah Abdul

doi:10.1016/j.thromres.2016.02.030

Cited by 51 publications

(95 citation statements)

References 12 publications

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“…7,8 Standard regimens require two or three intravenous infusions per week to maintain factor trough levels of more than 1 IU per deciliter, yet maintenance of higher levels may provide greater hemostatic protection. [9][10][11][12] The development of a new generation of factor concentrates with an extended half-life [13][14][15] has reduced the frequency of administration, most notably for factor IX products. [16][17][18] However, these products still require intravenous infusion.…”

Section: Resultsmentioning

confidence: 99%

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

et al. 2017

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BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. ( BACKGROUNDCurrent hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.

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Section: Resultsmentioning

confidence: 99%

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

et al. 2017

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“…However, the literature search identified little published data to strengthen the rather broad activity ranges and durations proposed. With some but not all of the EHL FIX products, factor levels in the range suggested by WFH might be obtained with a single dose for minor procedures over 2‐3 days, or the procedure may be planned around a standing prophylactic dose without the need for additional dosing …”

Section: Resultsmentioning

confidence: 99%

Perioperative management of haemophilia B: A critical appraisal of the evidence and current practices

et al. 2017

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The literature review revealed that documented experience in the perioperative management of bleeding risk in haemophilia B patients is relatively scarce. Therefore, the review was amended to provide a comprehensive overview of the perioperative management for haemophilia A and B patients; the expert panel applied a particular focus to haemophilia B. Several gaps were identified in the literature including the lack of consensus on defining surgery in terms of bleeding risk, optimal factor levels during surgery and lack of robust evidence on surgical outcomes. The ensuing discussions with the expert panel provided validation of some of the results from the systematic literature review and proposed future directions for perioperative management. Suggestions included collaboration with haemophilia treatment centres (HTCs) to collect real-world data on perioperative management, establishing the need for optimal factor level monitoring practice, and the appropriate adoption of extended half-life products in clinical settings.

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“…All patients were previously treated males with moderately severe or severe congenital haemophilia B and FIX activity ≤2%. In all trials, N9‐GP was administered intravenously (iv) as bolus injections . Additional information on the N9‐GP protein is provided in the Appendix .…”

Section: Methodsmentioning

confidence: 99%

“…Prophylaxis treatment regimens for adolescents and adults in paradigm™2 and paradigm™4 included N9‐GP 10 or 40 IU/kg once‐weekly. In paradigm™5, paediatric patients received prophylaxis with N9‐GP 40 IU/kg once‐weekly …”

Section: Methodsmentioning

confidence: 99%

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Once‐weekly prophylaxis with 40 IU/kg nonacog beta pegol (N9‐GP) achieves trough levels of >15% in patients with haemophilia B: Pooled data from the paradigm™ trials

Oldenburg¹,

Carção

Lentz

et al. 2018

Haemophilia

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Introduction Prophylaxis with replacement factor IX (FIX) reduces bleeding frequency and improves quality of life in haemophilia B patients. With prophylaxis, the likelihood of bleeding is lowered with increasing trough levels. New products with extended half‐life (EHL) can maintain high factor activity levels over prolonged periods, compared with standard FIX products. Aim To evaluate the safety, efficacy and pharmacokinetics of the new recombinant FIX EHL product, nonacog beta pegol (N9‐GP), using pooled data, with a focus on—but not limited to—prophylaxis at 40 IU/kg. Methods N9‐GP has been investigated in males with congenital haemophilia B and FIX activity ≤2% in the paradigm™ clinical trial programme. This analysis includes pooled data from five completed paradigm™ trials conducted in previously treated adults, adolescents and children, focusing on results of prophylaxis with 40 IU/kg once‐weekly intravenous dosing. Results In total, 115 previously treated patients were exposed to N9‐GP. Of 54 patients (47%) treated with N9‐GP 40 IU/kg once‐weekly prophylaxis, 72% experienced no spontaneous bleeds over 1 year. In all patients receiving 40 IU/kg once‐weekly, median overall annualized bleeding rate (ABR) was 1.03 (interquartile range 0.00; 2.89); median spontaneous ABR was 0.00 (0.00; 0.80). No patients developed inhibitors. Estimated mean steady‐state trough levels with N9‐GP 40 IU/kg once‐weekly were ≥15% overall; 27.3% in adolescents and adults. Conclusion N9‐GP 40 IU/kg once‐weekly was well tolerated and effective in preventing bleeding, maintaining mean FIX activity levels ≥15% across all age groups. N9‐GP may provide a new treatment option for preventing bleeding in haemophilia B patients.

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Nonacog beta pegol (N9-GP) in haemophilia B: A multinational phase III safety and efficacy extension trial (paradigm™4)

Cited by 51 publications

References 12 publications

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

Perioperative management of haemophilia B: A critical appraisal of the evidence and current practices

Once‐weekly prophylaxis with 40 IU/kg nonacog beta pegol (N9‐GP) achieves trough levels of >15% in patients with haemophilia B: Pooled data from the paradigm™ trials

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