Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients

Shapiro, Amy D.; Ragni, Margaret V.; Valentino, Leonard A.; Key, Nigel S.; Josephson, Neil C.; Powell, Jerry S.; Cheng, Gregory; Thompson, Arthur R.; Goyal, Jaya; Tubridy, Karen L; Peters, Robert; Dumont, Jennifer; Euwart, Donald; Lian, Li; Hallén, B; Gozzi, Peter; Bitonti, Alan J.; Jiang, Haiyan; Luk, Alvin; Pierce, Glenn F.

doi:10.1182/blood-2011-07-367003

Cited by 164 publications

(159 citation statements)

References 24 publications

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“…The strategy might also serve as gene therapy approach for hemophilia A which could be easily adapted from the current FIX gene transfer approaches which have been developed for hemophilia B [61]. preclinical [62] and clinical trials [63]. Similarly the pharmacokinetic properties of FIX could be also improved by genetic fusion to albumin via cleavable peptides derived from the FIX activation sequence [64].…”

Section: Engineering Fix Variants To Bypass Fviiimentioning

confidence: 99%

Engineered Factor VII, Factor IX, and Factor X Variants for Hemophilia Gene Therapy

2012

J Genet Syndr Gene Ther

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FVII/FVIIaPatients with hemophilia A and B have deficient protein concentrations of FVIII and FIX, respectively and therefore are treated by protein substitution with plasma-derived or recombinant factor FVIII or FIX concentrates. In about 20-30% of the patients with hemophilia A and in 3-5% of those with hemophilia B this can lead to the development of neutralizing antibodies against the infused proteins which makes therapy inefficient [1,2]. Recombinant activated factor VII (rFVIIa) protein is currently an alternative therapy available for inhibitor patients to treat excessive bleeding. However, supraphysiological concentrations and repeated administration are required to induce hemostasis [3].Consequently, FVIIa analogs were created for future protein replacement therapy or gene delivery approaches based on crystalline structure analysis of free and TF-bound FVIIa or on sequence homology of other more potent proteases [4,5].Like the other vitamin K dependent coagulation factors, FVII is physiologically synthesized in the liver. FVII is secreted into the circulation as a 406-residue single-chain polypeptide which contains an N-terminal γ-carboxyglutamic acid (Gla) domain in which all ten Glu residues are post-translationally carboxylated followed by two regions homologous to epidermal growth factor domains and a serine protease domain [3,6,7]. Upon vascular injury, the cofactor tissue factor (TF) is exposed to FVII and triggers the extrinsic pathway of the coagulation cascade by activation of FIX, factor X and FVII auto-activation on the TF-bearing cells resulting in large-scale thrombin generation and a fibrin clot. FVII is activated to FVIIa by internal proteolysis due to a cleavage of a single Arg152-Ile153 peptide bond. The physiological plasma concentration of FVII is around 10 nM, however, only about 1% of FVII is circulating in its free and active form. FVIIa has a plasma halflife of approximately 2.5 hours [8]. FVII activation results in connected FVII light and heavy chains which form a one-to-one complex with TF in the presence of Ca 2+ ions. The complex formation is an essential process in which TF allosterically leads to a fully active FVIIa [9]. The cleavage alone leaves FVIIa in a zymogen-like conformation of quite low specific activity [3,10]. Several residues in the first EGF-like domain of FVII and in the protease domain, especially methionine at position 306, seem to be pivotal for the cofactor-mediated allosteric stimulation [11]. TF stabilizes the active conformation of FVIIa for accelerated activation of its substrates FIX and FX [12,13] by inducing a conformational change and establishing a stable salt bridge between the residues Ile153 and Asp343 [14] and stabilization of the interaction between the residues Leu305 and Phe374 which in turn stabilizes S 1 and S 3 substrate pocket and the activation pocket [15]. These findings contributed to the development of FVIIa variants with enhanced TFindependent (intrinsic) specific activity by mimicking the effect of TF binding [16]. Additional fin...

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Section: Engineering Fix Variants To Bypass Fviiimentioning

confidence: 99%

Engineered Factor VII, Factor IX, and Factor X Variants for Hemophilia Gene Therapy

2012

J Genet Syndr Gene Ther

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“…A decision tree to account for the baseline and residual drug level. Note: The decision tree presented here is only for demonstration purpose and may be different from the one that was actually used in the real study (4) additional column in the dataset (e.g., INDX), if the value in the column of INDX is 1, the data record in the same row is the dummy observation record, otherwise, the true observation data record. Alternatively, the dummy observation records with large time point can be inserted into the dataset for each PK profile at the very beginning to avoid the "check and refresh" procedure.…”

Section: Case 1: Using Dta Variable To Calculate User-defined Parametersmentioning

confidence: 99%

Using DTA and DTAARRAY Variables and Programming in WinNonlin ASCII Models to Streamline User-Defined Calculation and Data Analysis

Shen

Bowsher

et al. 2015

AAPS J

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Abstract. In pharmacokinetic (PK) analysis, there are many occasions where user-defined calculations need to be performed before or after the primary PK modeling/analysis. Conventionally, these calculations are often executed outside of the primary PK analysis by pre-or post-processing data from multiple sources, manually entering formulas and multiple additional set-ups. Such analysis approaches increase the risk of generating data defects and can employ software that is not fully compliant. We propose a method of leveraging DTA and DTAARRAY variables plus simple programming techniques in an ASCII model to automate these user-defined calculations in WinNonlin and eliminate the need for manual handling of data outside of the primary analysis. We demonstrated the application of this strategy through three case study examples. In case 1 (post-processing data), DTA variables were used to calculate three user-defined parameters in the primary PK model. In case 2 (pre-processing data), a baseline correction decision tree was programmed into the PK model to account for both the endogenous baseline level as well as the presence of residual drug. In case 3, DTAARRAY variables were used to perform a looping operation to calculate the difference factor (F1) and the similarity factor (F2) in support of in vitro bioequivalence evaluations.

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“…Для снижения вероятности кровоточивости, учитывая относительно короткий период полужиз-ни препаратов фактора IX, их назначение требуется 2-3 раза в неделю. Современные биоинженерные технологии позволяют разрабатывать новые моди-фицированные рекомбинантные препараты факто-ров свертывания крови с более продолжительным периодом полужизни [3,4].…”

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Renal Allogeneic Transplantation in Patient With Haemophilia B

Пурло¹,

Akhmetshin²,

Буланов³

et al. 2015

Russian Journal of Transplantology and Artificial Organs

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ВВЕДЕНИЕГемофилия В (болезнь Кристмаса) -наследс-твенное, сцепленное с полом заболевание крови, обусловленное недостаточностью коагуляционно-DOI: 10.15825/1995-1191-2014-4-111-116 We report the case of successful renal allogeneic transplantation and treatment in a 56-year-old patient with haemophilia B at Hematology Research Center. He has received replacement therapy by factor IX since 2010. The transplant is marked with good renal function during 13 post-transplant months without episodes of rejection or bleeding complications. The complicated surgical interventions are possible in patients with haemophilia В аnd end-stage chronic renal failure in the presence of replacement therapy of IX factor for the purpose of achievement of optimum hemostasis.

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Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients

Cited by 164 publications

References 24 publications

Engineered Factor VII, Factor IX, and Factor X Variants for Hemophilia Gene Therapy

Engineered Factor VII, Factor IX, and Factor X Variants for Hemophilia Gene Therapy

Using DTA and DTAARRAY Variables and Programming in WinNonlin ASCII Models to Streamline User-Defined Calculation and Data Analysis

Renal Allogeneic Transplantation in Patient With Haemophilia B

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