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

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 https://onlinelibrary.wiley.com/doi/10.1111/hae.13301/epdf

To learn more about this trial visit: clinicaltrials.gov

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 https://onlinelibrary.wiley.com/doi/10.1111/hae.13357/epdf