Kinetic analysis and binding studies of a new recombinant human factor <scp>VII</scp>a for treatment of haemophilia

Grandoni, J A; Perret, Gérald; Forier, Cynthia

doi:10.1111/hae.13110

Cited by 16 publications

(31 citation statements)

References 36 publications

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“…Variations in acute bleeding aetiologies, sites of bleeding, intermittent telephonic guidance and an accumulating disease burden, combine to make at‐home treatment difficult in patients with inhibitors. We examined the hypothesis that a new recombinant FVIIa molecule with differing posttranslational modifications and binding affinities, would demonstrate dose‐proportional and acceptable efficacy in a prospective, randomized, cross‐over study of BE response to different IDRs . Results show that both the 75 μg/kg and 225 μg/kg IDRs provided a high likelihood of efficacy at 12 hours without requiring redosing once symptom relief was obtained.…”

Section: Discussionmentioning

confidence: 99%

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PERSEPT 1: a phase 3 trial of activated eptacog beta for on‐demand treatment of haemophilia inhibitor‐related bleeding

Wang¹,

Lawrence

Quon

et al. 2017

Haemophilia

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Introduction Haemophilia A or B patients with inhibitors have been treated with FVIIa‐containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. Aim Evaluate the dose‐dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). Methods A Phase 3, randomized, cross‐over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on‐demand treatment of mild/moderate BEs. Intravenous 75 μg/kg or 225 μg/kg initial doses with 75 μg/kg subsequent doses by schedule were administered until clinical response. Results The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 μg/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 μg/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins. Conclusion The dose‐dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.

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Section: Discussionmentioning

confidence: 99%

“…A new bypassing agent, activated eptacog beta (rhFVIIa, LFB SA), has been developed to address this advancing strategy . rhFVIIa is a recombinant human FVIIa manufactured using rPro ® Technology, developed for the treatment of inhibitor‐associated BEs.…”

Section: Introductionmentioning

confidence: 99%

PERSEPT 1: a phase 3 trial of activated eptacog beta for on‐demand treatment of haemophilia inhibitor‐related bleeding

Wang¹,

Lawrence

Quon

et al. 2017

Haemophilia

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“…Bleeding episodes (BEs) in these patients are treated with factor replacement therapy; however, during their lifetime, 20%‐30% of patients with haemophilia A, and 5% with haemophilia B, will develop inhibitory antibodies (inhibitors) to FVIII or FIX . In such patients, haemostasis may not be achievable with replacement of the deficient factor (depending upon the inhibitor titre) and thus may require administration of bypassing agents, such as plasma‐derived activated prothrombin complex concentrates (aPCC) or activated recombinant factor VII (rFVIIa) …”

Section: Introductionmentioning

confidence: 99%

Safety and dose‐dependency of eptacog beta (activated) in a dose escalation study of non‐bleeding congenital haemophilia A or B patients, with or without inhibitors

et al. 2017

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Introduction Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients. Aim To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non‐bleeding patients with congenital haemophilia A or B with or without inhibitors. Methods Adult male patients (18‐75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 μg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data. Results Administration of rhFVIIa at all doses was well tolerated. Pharmacokinetic analyses showed that peak FVIIa plasma levels (Cmax) were approximately proportional to dose and correlated well with peak thrombin generation. Total AUC0‐inf also was approximately dose proportional. Clot formation and duration correlated with FVIIa activity. Repeat doses did not produce an immunological response. Conclusion In the first dose‐escalation study of rhFVIIa to support product registration, eptacog beta at doses of 25, 75, and 225 μg/kg was pharmacodynamically active and well tolerated in non‐bleeding patients with congenital haemophilia A or B.

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“…Two early investigational variants, vatreptacog alfa and BAY 86-6150, had increased biological activity from specific amino acid mutations; however, both failed in clinical trials due to the observation of antidrug antibodies. 49,50 Eptacog beta also showed increased efficacy and a reduction in time to haemostasis with a higher initial dose compared with multiple smaller doses. 48 Two investigational variants continue to show promising clinical data: eptacog beta (on-demand) and marzeptacog alfa (prophylaxis); neither product is currently indicated for use.…”

Section: New Rfviia Variantsmentioning

confidence: 99%

The evolution of factor VIIa in the treatment of bleeding in haemophilia with inhibitors

Meeks

Leissinger

2019

Haemophilia

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The use of activated factor VII (FVIIa) for the treatment of bleeding events in haemophilia patients with inhibitors was first reported over 30 years ago. Since then clinical trials, registries, case series, real‐world experience and an understanding of its mechanism of action have transformed what was originally a scientific curiosity into one of the major treatments for inhibitor patients, with innovative therapeutic regimens, dose optimization and individualized care now widely practiced. Given current understanding and use, it might be easy to forget the years of clinical research that led up to this point; in this review, we lay out changes based on broad eras of rFVIIa use. These eras cover the original uncertainty associated with dosing, efficacy and safety; the transformation of care ushered in with its widespread use; and the optimization and individualization of patient care and the importance of specialized support provided by haemophilia treatment centres. Today with the introduction of novel prophylactic agents such as emicizumab, we once again find ourselves dealing with the uncertainties of how best to utilize rFVIIa and newer investigational variants such as marzeptacog alfa and eptacog beta; we hope that the experiences of the past three decades will serve as a guide for this new era of care.

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Kinetic analysis and binding studies of a new recombinant human factor VIIa for treatment of haemophilia

Cited by 16 publications

References 36 publications

PERSEPT 1: a phase 3 trial of activated eptacog beta for on‐demand treatment of haemophilia inhibitor‐related bleeding

PERSEPT 1: a phase 3 trial of activated eptacog beta for on‐demand treatment of haemophilia inhibitor‐related bleeding

Safety and dose‐dependency of eptacog beta (activated) in a dose escalation study of non‐bleeding congenital haemophilia A or B patients, with or without inhibitors

The evolution of factor VIIa in the treatment of bleeding in haemophilia with inhibitors

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