Defining extended half‐life <scp>rFVIII</scp>—A critical review of the evidence

Mahlangu, Johnny; Young, Guy; Hermans, Cédric; Blanchette, Victor S.; Berntorp, Erik; Santagostino, Elena

doi:10.1111/hae.13438

Cited by 67 publications

(100 citation statements)

References 41 publications

(83 reference statements)

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“…Empirically, rFVIII products that employ technologies to extend half‐life, such as PEGylation (BAX 855, BAY 94‐9027 and N8‐GP) and Fc fusion (rFVIIIFc), have half‐life extension ratios of 1.4‐1.6 in well‐designed PK studies . These empirical observations are above the minimal half‐life extension ratio of 1.3 shown in our investigation .…”

Section: Discussionsupporting

confidence: 47%

“…In the example, using a 2×/wk regimen with a weekly dose of 90 IU/kg, FVIII levels >1 IU/dL were maintained in 56.6% of patients (matching 3×/wk dosing at 100 IU/kg/wk, benchmark 2) when the halflife extension ratio reached 1.26. Using an every 72-hour dosing regimen and increasing the half-life extension ratio to 1.33-more similar to the minimum extension ratio observed in currently available EHL products 25 -was predicted to result in 92.8% of patients maintaining rFVIII >1 IU/dL ( Figure 3 and Table 1).…”

Section: Extending 3×/wk Dosing (Benchmarks 1-3) By 24 Hours To a 2mentioning

confidence: 90%

“…For these explorations, we should draw from clinical studies which use the number of total and index joint bleeds (ABR and AJBR) as outcomes, are of sufficient length to have collected robust data (ie minimum of 1 year) and employ accurate definitions of a clinical bleed (particularly for children, adults and those with joint damage). In addition to the minimum cut‐off for half‐life extension ratio, there may be other criteria that need to be met for an rFVIII to be classified as an EHL …”

Section: Discussionmentioning

confidence: 99%

“…Rather, these products should be evaluated by measuring a half‐life extension ratio compared with a benchmark standard half‐life product tested in the same individual, using the same assays to measure FVIII levels and the same methods for calculating PK parameters . The utility of looking at the ratios of other pharmacokinetic parameters, such as clearance and area under the curve (AUC), is reviewed by Mahlangu J et al …”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20] Rather, these products should be evaluated by measuring a half-life extension ratio compared with a benchmark standard half-life product tested in the same individual, using the same assays to measure FVIII levels and the same methods for calculating PK parameters. 21 The utility of looking at the ratios of other pharmacokinetic parameters, such as clearance and area under the curve (AUC), is reviewed by Mahlangu J et al 25 A pragmatic definition of an EHL rFVIII should be based on a half-life extension ratio that enables fewer rFVIII infusions in most patients while maintaining or improving trough levels, thus reducing the burden of infusions without increasing the weekly dose and without compromising bleed prevention compared with standard products. We sought to identify the half-life extension ratio required to meet this requirement, thereby contributing to the objective description of a rFVIII product as an EHL; we have not sought to recommend one EHL regimen over another.…”

mentioning

confidence: 99%

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Pharmacokinetic modelling and validation of the half‐life extension needed to reduce the burden of infusions compared with standard factor VIII

et al. 2018

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Introduction Currently, no universally accepted definition of extended half‐life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half‐life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII. Aim To identify the half‐life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose. Methods A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels always >1 IU/dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half‐life was extended until the percentage of patients with FVIII >1 IU/dL equalled that of the benchmark regimen. Results Benchmark 3×/wk dosing totalling 100 IU/kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always >1 IU/dL. With 2×/wk dosing, totalling 80 or 90 IU/kg/wk, half‐life extensions required to maintain 56.6% of patients at FVIII levels >1 IU/dL were 1.30 and 1.26, respectively. A half‐life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU/kg/wk) while maintaining 92.8% of patients with FVIII >1 IU/dL. Conclusion Based on this investigation, EHL rFVIII products should have a minimum half‐life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.

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Section: Discussionsupporting

confidence: 47%

Section: Extending 3×/wk Dosing (Benchmarks 1-3) By 24 Hours To a 2mentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetic modelling and validation of the half‐life extension needed to reduce the burden of infusions compared with standard factor VIII

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Bispecific Antibodies and Advances in Non–Gene Therapy Options in Hemophilia

Shima

2020

Research and Practice in Thrombosis and Haemostasis

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Regular prophylaxis has markedly improved the treatment for patients with hemophilia A, especially after the introduction of highly purified factor VIII (FVIII) concentrates. However, frequent intravenous infusions and the development of FVIII inhibitors remain as unsolved difficulties. To overcome these unmet needs, a bispecific antibody mimicking activated FVIII has been developed in Japan. This bispecific antibody, emicizumab, recognizes activated factor IX (FIXa) and activated factor X (FXa), and promotes FIXa‐catalyzed activation of FX in the absence of FVIII. Emicizumab initially reacts with FIXa generated by the action of factor VIIa/tissue factor complexes. Subsequently, thrombin generation is enhanced in the presence of higher amounts of FIXa derived from FXIa‐dependent mechanisms. Hence, emicizumab‐driven FXa and thrombin generation is maintained by a FXI activation loop in the intrinsic coagulation pathway. Reactions downstream of emicizumab are regulated by natural anticoagulants including activated protein C, antithrombin, and tissue factor pathway inhibitor. Phase 3 studies (HAVEN 1‐4 and HOHOEMI studies) demonstrated a remarkable reduction in bleeding rates together with a high percentage of patients with zero treated bleeds irrespective of the presence of inhibitors. In general, emicizumab proved to be well tolerated, although isolated thromboembolic and thrombotic microangiopathic complications were observed in the HAVEN 1 studies, and 3 out of a total of 400 patients developed neutralizing antidrug antibodies. In addition, several questions remain to be discussed with respect to open‐use clinical practice, including when to start treatment, how to monitor therapy, and optimum dosage for surgical procedures and immune tolerance induction.

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