Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial

Collins, Peter William; Young, Guy; Knobe, Karin; Karim, Faraizah Abdul; Angchaisuksiri, Pantep; Banner, Claus; Gürsel, Türkiz; Mahlangu, Johnny; Matsushita, Tadashi; Mauser‐Bunschoten, Eveline P.; Oldenburg, Johannes; Walsh, Christopher E.; Négrier, Claude

doi:10.1182/blood-2014-05-573055

Cited by 168 publications

(278 citation statements)

References 21 publications

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“…The patient population was geographically diverse and included patients from North America, Europe, Asia, and the Middle East (Table 1). More than half of the patients in both groups 1 and 2 reported chronic hemarthrosis or a target joint at the start of the study (see footnote of Table 1 for details 20 ). Group 2 patients (on-demand prior to study entry) reported a higher median nontrauma-induced bleeding rate than group 1 patients during the 12 months prior to study entry (21.0 vs 1.0).…”

Section: Patient Characteristicsmentioning

confidence: 96%

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Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

Santagostino

Martinowitz

Lissitchkov

et al. 2016

Blood

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176

284

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• rIX-FP maintains mean trough of 20 and 12 IU/dL FIX activity with 40 IU/kg weekly and 75 IU/kg every 2 weeks prophylaxis, respectively. • Weekly and 14-day prophylaxis regimens with rIX-FP were well tolerated and provided low bleeding rates and target joint improvement.A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity £2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P < .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as

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Section: Patient Characteristicsmentioning

confidence: 96%

“…20 ||Bleeding episodes in the 12 months prior to study entry. {Nontrauma defined as spontaneous and unknown cause bleeding episodes.…”

Section: Safetymentioning

confidence: 99%

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

Santagostino

Martinowitz

Lissitchkov

et al. 2016

Blood

Self Cite

176

284

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“…The conjugation of a 40-kDa branched polyethylene glycol (PEG) molecule to rFIX increases the half-life and enables once weekly prophylactic dosing instead of twice weekly dosing with unmodified rFIX (Collins et al 2014). Human coagulation factors are immunogenic in animals, precluding the possibility to conduct chronic toxicity studies (European Medicines Agency 2004b, 2005Ivens and Arora 2013;Kirschbaum and U.S. Food and Drug Administration 2014).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Nonacog Beta Pegol Long-term Safety in the Immune-deficient Rowett Nude Rat (Crl:NIH-Foxn1^rnu)

et al. 2016

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Nonacog beta pegol is a 40-kDa polyethylene glycosylated (PEGylated) human recombinant coagulation factor IX, intended for the treatment of hemophilia B. Human coagulation factors are immunogenic in animals; therefore, to evaluate the long-term toxicity of nonacog beta pegol, an immune-deficient, athymic rat (Rowett nude; Crl:NIH-Foxn1 rnu ) was used. Rats (n ¼ 216) were given intravenous nonacog beta pegol 0, 40, 150, 600, or 1,200 IU/kg every 5th day for 26 weeks. To avoid infections, the animals were housed in a full-barrier environment with sterilized food and bedding. Standard toxicity end points were unaffected by treatment. All treated animals were exposed to nonacog beta pegol throughout the study, and no animals developed antidrug antibodies. Immunohistochemical staining revealed PEG in choroid plexus epithelial cells in a dose-dependent manner. Transmission electron microscopy showed that PEG was distributed in cytoplasmic vesicles of these cells, with no apparent effect on cellular organelle structures. Fourteen (6.5%) animals were euthanized or died prematurely due to nontreatment-related infections in the urogenital system and skin. In conclusion, the athymic rat is a suitable model for testing chronic toxicity of human proteins that are immunogenic in animals. Nonacog beta pegol was generally well tolerated, with no adverse effect of PEG on choroid plexus epithelial cells.

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“…All approaches described above achieve only moderate increases of half-lives (1.5-to 2-fold compared to unmodified FVIII) [23]. This is in contrast to FIX where it was possible to increase the mean half-life 4-to 6-fold by different forms of bioengineering [24][25][26]. and pharmacokinetics in two pivotal phase 3 studies [27,28].…”

Section: Limitations Of Prolonging Half-life Of Fviiimentioning

confidence: 98%

“…Nonacog beta pegol (N9-GP; Refixia ® ) is a recombinant FIX product (Chinese hamster ovary cell line) linked to 40 kDa PEG moiety (attached to the FIX activation peptide) [26]. In a phase 3 study, 74 PTPs > 12 years with severe to moderately severe hemophilia B were randomized to either 10 (n = 30) or 40 IU/kg (n = 29) once-weekly prophylaxis or on demand treatment (n = 15) [26].…”

Section: Pegylated Fixmentioning

confidence: 99%

Extended Half-Life Factor VIII and Factor IX Preparations

Graf¹

2018

Transfus Med Hemother

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In the last couple of years, several extended half-life factor VIII and factor IX preparations were intensively studied and gained approval. In order to extend half-lives, techniques like fusion to protein conjugates (Fc part of IgG₁ or albumin), chemical modification (PEGylation), and protein sequence modification are implemented. With these techniques, it is possible to extend half-lives of factor IX products 4- to 6- fold, while half-life extension of factor VIII products is limited to 1.5- to 2-fold due to their interaction with von Willebrand factor. Nevertheless, both extended half-life factor VIII and IX products have improved and facilitated prophylactic factor replacement therapy in hemophilia A and B, respectively. Extended half-life factor concentrates pose challenges to coagulation laboratories because accurate therapy monitoring is not possible with all factor activity assays currently used.

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Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial

Abstract: Key Points Nonacog beta pegol, a recombinant glycoPEGylated FIX with extended half-life, was developed to improve care for patients with hemophilia B. Weekly prophylaxis with nonacog beta pegol was well tolerated and was associated with low bleeding rates and an improved quality of life.

Cited by 168 publications

References 21 publications

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

Evaluation of Nonacog Beta Pegol Long-term Safety in the Immune-deficient Rowett Nude Rat (Crl:NIH-Foxn1^rnu)

Extended Half-Life Factor VIII and Factor IX Preparations

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Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial

Abstract: Key Points Nonacog beta pegol, a recombinant glycoPEGylated FIX with extended half-life, was developed to improve care for patients with hemophilia B. Weekly prophylaxis with nonacog beta pegol was well tolerated and was associated with low bleeding rates and an improved quality of life.

Cited by 168 publications

References 21 publications

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

Evaluation of Nonacog Beta Pegol Long-term Safety in the Immune-deficient Rowett Nude Rat (Crl:NIH-Foxn1rnu)

Extended Half-Life Factor VIII and Factor IX Preparations

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Product

Resources

About

Evaluation of Nonacog Beta Pegol Long-term Safety in the Immune-deficient Rowett Nude Rat (Crl:NIH-Foxn1^rnu)