Head‐to‐head comparison of the pharmacokinetic profiles of a high‐purity factor IX concentrate (AlphaNine®) and a recombinant factor IX (BeneFIX®) in patients with severe haemophilia B
Abstract:Head-on comparative studies of factor IX (FIX) concentrates performed under standardized conditions are rarely conducted regardless of being a valuable instrument guiding health care providers towards better informed and cost-effective decisions. This study is an extension of a multicentre study that assessed the efficacy, safety and pharmacokinetics (PK) of AlphaNine(®) in 25 previously treated patients with severe haemophilia B (FIX:C ≤ 2%). After a washout period ≥ 7 days following the last PK performed wit… Show more
“…In the present comparative evaluation, incremental recovery was lower for Bax326 than for Immunine â infusions in both age categories, confirming the results of previous studies in which the recovery was approximately 68-86% of that expected for pdFIX concentrates [7,10,11]. Although the paediatric (<12 years) sample size in this study is not substantial, as direct comparison of pdFIX vs. rFIX has primarily been displayed in terms of PK profiles in only three cross-over studies [7,8] and one recent head-to-head comparison [26], we believe that considering the importance of IR for dose adjustment following a switch from pdFIX to Bax326, the within subjects prospective comparative analysis in patients aged >12 years will provide not only new insight but also overcome common weaknesses of between-study variability when comparing pdFIX vs. rFIX data obtained from studies with different designs and clinical settings. The same multiplication factor of 1.25 could be used for children <12 years, but the available data are limited due to the small sample size and therefore the use of the patient's individual incremental recovery is suggested.…”
The ability to switch between coagulation factors safely is of common interest to haemophilia patients and treating physicians. This is the first formal prospective comparative evaluation of safety, efficacy and incremental recovery of a plasma-derived FIX (pdFIX) and a recombinant FIX (rFIX) in the same haemophilia B patients following a switch from pdFIX Immunine® to a recently developed rFIX Bax326 product. Patients (aged <65 years) who completed a pretreatment study which prospectively documented the exposure to Immunine® and monitored FIX inhibitors while receiving prophylactic treatment were transitioned into pivotal (patients aged 12-65 years) and paediatric (patients aged <12 years) clinical studies investigating prophylaxis and treatment of bleeding episodes with Bax326. None of the 44 patients developed inhibitory or specific binding anti-FIX antibodies during the course of the studies. A total of 38 unrelated adverse events (AEs) were occurred in 20/44 (45.5%) subjects during the Immunine® study. Following a switch to Bax326, 51 AEs were reported in 25/44 (56.8%) subjects. The incidence of AEs related to Bax326 treatment (two episodes of dysgeusia in one patient) was low (2.3%); there were no serious adverse reactions. The comparison between Immunine® and Bax326 demonstrated analogous haemostatic characteristics and annualized bleeding rates. Overall, there is direct evidence indicating a safe and clinically effective transition from a pdFIX (Immunine®) to a newly developed rFIX (Bax326(1) ) for prophylaxis and treatment of bleeding in previously treated patients of all age cohorts with severe or moderately severe haemophilia B.
“…In the present comparative evaluation, incremental recovery was lower for Bax326 than for Immunine â infusions in both age categories, confirming the results of previous studies in which the recovery was approximately 68-86% of that expected for pdFIX concentrates [7,10,11]. Although the paediatric (<12 years) sample size in this study is not substantial, as direct comparison of pdFIX vs. rFIX has primarily been displayed in terms of PK profiles in only three cross-over studies [7,8] and one recent head-to-head comparison [26], we believe that considering the importance of IR for dose adjustment following a switch from pdFIX to Bax326, the within subjects prospective comparative analysis in patients aged >12 years will provide not only new insight but also overcome common weaknesses of between-study variability when comparing pdFIX vs. rFIX data obtained from studies with different designs and clinical settings. The same multiplication factor of 1.25 could be used for children <12 years, but the available data are limited due to the small sample size and therefore the use of the patient's individual incremental recovery is suggested.…”
The ability to switch between coagulation factors safely is of common interest to haemophilia patients and treating physicians. This is the first formal prospective comparative evaluation of safety, efficacy and incremental recovery of a plasma-derived FIX (pdFIX) and a recombinant FIX (rFIX) in the same haemophilia B patients following a switch from pdFIX Immunine® to a recently developed rFIX Bax326 product. Patients (aged <65 years) who completed a pretreatment study which prospectively documented the exposure to Immunine® and monitored FIX inhibitors while receiving prophylactic treatment were transitioned into pivotal (patients aged 12-65 years) and paediatric (patients aged <12 years) clinical studies investigating prophylaxis and treatment of bleeding episodes with Bax326. None of the 44 patients developed inhibitory or specific binding anti-FIX antibodies during the course of the studies. A total of 38 unrelated adverse events (AEs) were occurred in 20/44 (45.5%) subjects during the Immunine® study. Following a switch to Bax326, 51 AEs were reported in 25/44 (56.8%) subjects. The incidence of AEs related to Bax326 treatment (two episodes of dysgeusia in one patient) was low (2.3%); there were no serious adverse reactions. The comparison between Immunine® and Bax326 demonstrated analogous haemostatic characteristics and annualized bleeding rates. Overall, there is direct evidence indicating a safe and clinically effective transition from a pdFIX (Immunine®) to a newly developed rFIX (Bax326(1) ) for prophylaxis and treatment of bleeding in previously treated patients of all age cohorts with severe or moderately severe haemophilia B.
“…This is the reason why lower values of AUC, higher clearance and shorter half‐life have been reported with respect to the outcomes of our study. On the contrary, when the sampling time was prolonged up to 72 h , the PK outcomes resulted very similar to ours. The average values of all clearances observed in our study resulted 50% less than those reported in previous comparative studies of N9‐GP or rFIX‐FP because of different AUC.…”
Section: Discussionmentioning
confidence: 99%
“…The average values of all clearances observed in our study resulted 50% less than those reported in previous comparative studies of N9‐GP or rFIX‐FP because of different AUC. The clearance observed in this study is similar to that of rFIX‐Fc . In addition, the Vss was quite small compared with the large Vss of rFIX‐Fc, whose mean value was 250 mL kg −1 .…”
Introduction: Pharmacokinetic (PK) studies on recombinant FIX concentrate, Nonacog alpha, were conducted with different sampling time designs which gave rise to not complete and homogenous outcomes. In addition, patient's FIX genotype/PK relationship has never been investigated. Aim: Investigate how different sampling times may affect PK parameters and try to find a FIX genotype/PK relationship. Patients and Methods: A cohort pharmacokinetic, Nonacog Alpha single-dose, open-label, non-comparative study was conducted in eight Comprehensive Care Haemophilia Centres in Italy. Seventeen previously treated moderate or severe haemophilia B patients were enrolled. Factors IX:C one-stage clotting assay, FIX genotype and PK analysis were centralized. Results: The evaluation of PK outcomes showed a quite long half-life, smaller clearance and volume of distribution of Nonacog Alpha in comparison with the results from previously reported studies, where blood sampling was stopped too early. The relationship between PK outcomes and FIX genotype showed that small deletions displayed the higher clearance and shorter half-life, the nonsense mutations (the lower and the longer respectively), and missense mutations were in between. Conclusions: It is evident that area under the curve (AUC) and other PK parameters depend from the sampling time design. In order to have a complete evaluation of clotting factors in vivo decay, blood samples must be collected until the baseline factor concentration has been achieved again. Due to the relationship between FIX genotype and clearance, tailored prophylaxis of HB patients could be partially predicted by genotyping.
“…From March 2013 to July 2014, eight (19.0%) of the 42 so far unpublished RT were published in 10 JA. Published trials on new factor IX products comprised NCT01027364 , NCT01361126 , NCT00093210 , NCT01128881, NCT01174446 and NCT01488994 with several publications , of which one relates to HRQoL , and NCT01507896 on surgery with a new factor IX product . A first randomized study comparing on‐demand treatment with two prophylaxis regimens in haemophilia B patients trial NCT00364182 was published as well .…”
Payers in European countries request studies with high levels of evidence for decision making also for rare diseases like haemophilia B (HB). The objective of the study was to determine the status quo of current studies in HB regarding the overall level of evidence generated. The methods used for performing the study were systematic literature research in EMBASE and MEDLINE, search terms 'HB' and 'factor IX' (FIX). The inclusion criteria were journal articles (JA), conference abstracts (CA), English language, published between January 2009 and March 2013, studies only; screening of titles, abstracts, full texts subsequently. ClinicalTrials.gov search: unpublished registered trials (RT) concerning HB or FIX. The analysis was performed on research topic, sponsor, recruitment status and study design. Screening of 1639 hits yielded 31 JA describing 35 studies, and 62 CA. FIX was subject of 21 studies (60.0%) and 29 CA (46.8%). Seven studies focused on various aspects of HB, six on haemophilia studies with separate HB data. Screening of 173 hits from ClinicalTrials.gov yielded 42 RT. Overall, 32 RT (76.2%) related to FIX. Measurement of health-related quality of life (HRQoL) was identified in none of these studies, four CA (6.5%), four RT (9.5%). Randomized study design was found in one study (2.9%), four RT (9.5%). Three studies (8.6%) and seven RT (16.7%) were prospective, observational and comparative. The majority of published clinical studies do not meet payers' expectations for evidence. Therefore, clinical investigation concepts addressing randomization, outcomes research including HRQoL and comparison of therapy options should be discussed. Refined statistical methods and exploitation of complementary real-life data sources may fill current evidence gaps concerning rare diseases.
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