OUR PRINCIPLES

Abstract

INTRODUCTION:

The availability of different 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 two 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 (C_max) were approximately proportional to
dose and correlated well with peak thrombin generation. Total AUC_0-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.

To access the peer-reviewed article, visit http://onlinelibrary.wiley.com/doi/10.1111/hae.13357/epdf

PERSEPT 1

Abstract

INTRODUCTION:

Haemophilia A or B patients with inhibitors have been treated with Factor VIIa (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 hemostasis.

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, crossover study of two 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 12 hours following initiation of treatment, determined by a composite of objective and patient-reported indicators of clinical response. In the 75 μg/kg IDR, 84.9% (95% confidence interval [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 hemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.

To access the peer-reviewed article, visit http://onlinelibrary.wiley.com/doi/10.1111/hae.13301/epdf

To learn more about this trial visit: clinicaltrials.gov

OBJECTIVE:

Collect information about WILLFACT or WILFACTIN in their real-life clinical use and identify the therapeutic practices in an international environment.

PRIMARY OUTCOME MEASURES:

• Documentation of product consumption data [Time Frame: at each follow-up visit, up to 24 months]
• Product consumption (vWF International Units) by analysis of posology, frequency in relation to the severity of bleeding, type of surgery, and other clinical situations.

SECONDARY OUTCOME MEASURES:

• Collection and analysis of adverse events and vWF immunological safety [Time Frame: at each follow-up visit, up to 24 months]
• Adverse event (type, seriousness, severity, frequency, outcome), anti vWF-antibody and anti FVIII-antibody.

Learn more about this trial at clinicaltrials.gov

Abstract

OBJECTIVE:

In order to correct the primary von Willebrand factor (vWF) defect and avoid supra-physiologic plasma levels of factor VIII, a pure VWF concentrate almost devoid of FVIII was developed and used in France since 1989.

METHODS:

The pharmacokinetic (PK) profile of the most recent version of this concentrate (Wilfactin®; LFB, Les Ulis, France), treated with three virus-inactivation/removal methods (solvent/detergent, 35 nm filtration, dry heat treatment), was investigated in 25 patients. Seventeen patients with various types of clinically severe von Willebrand disease (VWD) were included in a crossover, randomized trial carried out in five European centers and comparing Wilfactin® with concentrates containing both FVIII and VWF (FVIII/VWF). Eight type 3 VWD patients were included in another trial carried out in six French centers comparing Wilfactin® with its previous version (Facteur Willebrand-LFB®; LFB) that adopted one virus-inactivation method only.

RESULTS:

For both the measurements evaluated in this study (VWF antigen, VWF:Ag; and VWF ristocetin co-factor activity, VWF:RCo), Wilfactin® had a PK profile similar to that of the FVIII/VWF concentrates and of Facteur Willebrand-LFB®. VWF:RCo and VWF:Ag recoveries were 2.1 ± 0.3 and 1.8 ± 0.3 per IU/kg, respectively, and the half-lives were 12.4 ± 1.8 and 15.9 ± 1.5 h. The FVIII synthesis rate was 5.8 ± 1.0 IU/dL/h, with a half-life of 15.8 ± 2.4 h.

CONCLUSION:

The PK of vWF and FVIII have not been altered by the three virus-inactivation/removal steps during the manufacturing of Wilfactin®.

To access the peer-reviewed article, visit onlinelibrary.wiley.com

Abstract

BACKGROUND AND OBJECTIVES:

A plasma-derived von Willebrand factor (vWF) concentrate with low factor VIII (FVIII) content was specifically developed to treat von Willebrand disease (VWD). Efficacy and safety were investigated by merging the results of two comparable protocols conducted prospectively in 5 European and 12 French centers.

METHODS AND RESULTS:

Fifty patients with clinically severe VWD (72% had VWF ristocetin cofactor activity less than 10 IU/dL and 46% had FVIII < 20 IU/dL) were treated with the concentrate as the only therapy, except for clinical situations requiring a priming dose of FVIII to rapidly correct an intrinsic coagulation defect. A total of 139 spontaneous bleeding episodes were treated; only 53 (38%) needed a concomitant FVIII dose. Outcome was “excellent” or “good” in 89% of the episodes. Forty-four patients underwent 108 surgical or invasive procedures. Outcome was “excellent” or “good” in 95 scheduled procedures (only VWF was infused) and 13 emergency procedures (a priming FVIII dose was co-administered with the first VWF infusion). There were no thrombotic complications, and none of the 18 patients with type 3 VWD developed anti-VWF or anti-FVIII antibodies.

CONCLUSIONS:

This concentrate safely and effectively provides hemostasis in patients with clinically severe VWD.

To access the peer-reviewed article, visit onlinelibrary.wiley.com

PERSEPT 3

OBJECTIVE:

• To evaluate LR769 for the prevention of excessive bleeding and achievement of hemostasis in congenital hemophilia A or B patients who have inhibitors to Factor VIII or Factor IX , are aged 6 months to 75 years, inclusive; and who are undergoing elective surgical or other invasive procedures. Administration of LR769 will be performed just prior to surgery/procedure and will be repeated during and after the surgery/procedure to achieve and maintain adequate hemostasis as determined by the investigator’s judgment.

PRIMARY OUTCOME MEASURES:

• Percentage of surgical or other invasive procedures with a “good” or “excellent” response to LR769 treatment [Time Frame: 48 (±4) hours after the last administration of LR769]

SECONDARY OUTCOME MEASURES:

• Percentages of success as defined as the combination of “good” and “excellent” responses by the investigator or designee [Time Frame: Immediately postoperative to 48 (±4) hours after the last administration of LR769]
• Percentages of “poor,” “moderate,” “good,” and “excellent” response by the investigator or designee [Time Frame: Immediately post operative to 48 (±4) hours after the last administration of LR769]
• Percentages of success as defined as the combination of “good” and “excellent” responses by the surgeon /practitioner [Time Frame: Intraoperative period]
• Percentages of “poor,” “moderate,” “good,” and “excellent” response by the surgeon/practitioner [Time Frame: Intraoperative period]
• Intraoperative blood loss [Time Frame: Intraoperative period]
• The maximum expected volume of blood loss and the estimated volume of blood loss during the procedure will be recorded.
• Number of events requiring transfusion [Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769]
• Changes in hemoglobin [Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769]
• Amount of LR769 used [Time Frame: Intraoperative period to last dose of LR769]
• Number and type of bleeding episodes at the surgical site [Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769]
• Number of surgical interventions/re-explorations for bleeding episodes [Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769]

Learn more about this trial at clinicaltrials.gov

PERSEPT 2

OBJECTIVE:

To assess the safety, efficacy, and pharmacokinetics of two separate dose regimens (75 µg/kg and 225 µg/kg) of Coagulation Factor VIIa (Recombinant) for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or IX in 12 patients (birth to <6 years old), and 12 patients (≥6 years old to <12 years)

PRIMARY OUTCOME MEASURES:

• Bleeding episode treatment success [Time Frame: 12 hours after first administration of study drug]
• No additional hemostatic product required after 12 hours of first dose

SECONDARY OUTCOME MEASURES:

• Time to bleeding success [Time Frame: 12 hours]
• Patients shall rate the treatment of each bleeding episode. If treatment occurs under direct supervision of treating physician, the physician shall rate the response. Ratings based on a four-point scale; Excellent, Good, Moderate, None

Learn more about this trial at clinicaltrials.gov