| Literature DB >> 30364483 |
Abstract
Whilst the global prevalence of haemophilia B is less than that of haemophilia A, rapid and remarkable innovations have been made in the development of haemophilia B therapies in the last decade. The most recent developments are the evolution of extended half-life haemophilia B replacement therapies which are designed to reduce the treatment burden associated with prophylactic infusion of factor IX (FIX) to prevent bleeding in haemophilia B participants. Clinical development programmes have culminated in the completion of three phase III studies on extended half-life (EHL) recombinant FIX (rFIX) products and subsequent approval and registration of these in many countries around the world. Current data from the three EHL rFIX clinical studies indicate that these products have acceptable safety profiles with no allergic reactions, thromboembolic phenomena or neutralizing antibodies when given to previously treated adolescent and adults for the prevention of bleeds, for the treatment of bleeds and in the perisurgical haemostasis use. Studies in previously untreated paediatric participants are currently ongoing. The EHL rFIX products have the potential impact to reduce the treatment burden associated with prophylactic infusion of replacement FIX, to treat and prevent bleeds in participants with haemophilia B and to improve the participant's health-related quality of life. The impact of EHL rFIX is likely to be modified by current development of other haemophilia B therapy such as antitissue factor pathway inhibitors and haemophilia B gene therapy. In this review, we aim to provide an update on the safety and efficacy data from the three EHL rFIX clinical studies and to consider their roles in the face of novel haemophilia B therapy currently evolving.Entities:
Keywords: efficacy; extended half-life; haemophilia B; pharmacokinetics; recombinant FIX; safety
Year: 2018 PMID: 30364483 PMCID: PMC6196631 DOI: 10.1177/2040620718802606
Source DB: PubMed Journal: Ther Adv Hematol ISSN: 2040-6207
Summary of pharmacokinetic and pharmacodynamic properties of extended half-life recombinant factor IX products.
| rFIXFc | rFIX-FP | N9-GP | SHL-FIX | |
|---|---|---|---|---|
| Dose used, IU/kg | 50 | 50 | 40 | 50 |
| AUC, IU.h/dl | 3664 | 7176 | 14130 | 548 |
| Clearance, ml/kg | 0.74 | 0.77 | 0.42 | 8.62 |
| Incremental recovery, IU/dl or IU/kg | 0.92 | 1.27 | 2.00 | 0.084 |
| Half-life for EHL product, mean | 82.1 | 102.0 | 96.2 | |
| Half-life extension relative to SHL product | 2.4-fold | 4.2-fold | 4.8-fold |
AUC, area under the curve; EHL rFIX, extended half-life recombinant factor IX; N9-GP, nonacog beta pegol; rFIXFc, fragment crystallizable recombinant factor IX; rFIX-FP, recombinant factor IX albumin fusion protein; SHL, standard half-life.
Summary of safety profile of extended half-life recombinant factor IX products in the published pivotal studies.
| rFIXFc | rFIX-FP | N9-GP | |
|---|---|---|---|
| Number of participants with inhibitors | 0 | 0 | 0 |
| Number of participants with non-inhibitor antibodies | 3 | 0 | 3 |
| Number of deaths or thromboembolisms | 0 | 0 | 0 |
| Number of drug-related serious adverse events | 0 | 0 | 0 |
| Number of drug-unrelated serious adverse events | 11 | 3 | 4 |
N9-GP, nonacog beta pegol; rFIXFc, fragment crystallizable recombinant factor IX; rFIX-FP, recombinant factor IX albumin fusion protein.
Summary of efficacy of extended half-life recombinant factor IX products in the treatment of bleeds.
| rFIXFc | rFIX-FP | N9-GP | |
|---|---|---|---|
| Dose, IU/kg | 50 | 50 | 40 |
| Number of injections, | 1 or 2 | 1 or 2 | 1 or 2 |
| Overall haemostatic efficacy, % | 97.2 | 96.7 | 97.1 |
N9-GP, nonacog beta pegol; rFIXFc, fragment crystallizable recombinant factor IX; rFIX-FP, recombinant factor IX albumin fusion protein.
Summary of efficacy of extended half-life recombinant factor IX products in the prevention of bleeds.
| rFIXFc | rFIX-FP | N9-GP | ||||
|---|---|---|---|---|---|---|
| Number of participants, | 61 | 26 | 40 | 21 | 30 | 29 |
| Dose, IU/kg | 50 | 100 | 40 | 75 | 10 | 40 |
| Dose frequency, q | q7 days | q10 days | q7 days | q4 days | q7 days | q7 days |
| ABR, median (IQR) | 3.0 | 1.4 | 0.0 | 1.08 | 2.93 | 1.0 |
ABR, annualized bleeding rate; IQR, interquartile range; N9-GP, nonacog beta pegol; rFIXFc, fragment crystallizable recombinant factor IX; rFIX-FP, recombinant factor IX albumin fusion protein; qx days, every x number of days.
Summary of efficacy of extended half-life recombinant factor IX products in the perisurgical use.
| rFIXFc | rFIX-FP | N9-GP | |
|---|---|---|---|
| Number of surgeries, | 12 | 8 | 9 |
| Number of intraoperative injections, | 0 | 0 | 0 |
| Overall excellent and good outcomes, % | 100 | 100 | 100 |
N9-GP, nonacog beta pegol; rFIXFc, fragment crystallizable recombinant factor IX; rFIX-FP, recombinant factor IX albumin fusion protein.