Pharmacokinetics,efficacy and safety of BAX326, a novel recombinant factor IX: a prospective,controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B

BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12–65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non‐serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC_0–72 h per dose. Twice‐weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg^?1 per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on‐demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.     

Recombinant factor IX (BAX326) in previously treated paediatric patients with haemophilia B: a prospective clinical trial

A newly developed recombinant factor IX (BAX326¹) was investigated for prophylactic use in paediatric patients aged <12 years with severe (FIX level <1%) or moderately severe (FIX level 1–2%) haemophilia B. The aim of this prospective clinical trial was to assess the safety, haemostatic efficacy and pharmacokinetic profile of BAX326 in previously treated paediatric patients. BAX326 was administered as prophylaxis twice a week for a period of 6 months, and on demand for treatment of bleeds. Safety was assessed by the occurrence of related AEs, thrombotic events and immunologic assessments. Efficacy was evaluated by annualized bleeding rate (ABR), and by treatment response rating (excellent, good, fair, none). PK was assessed over 72 h. None of the 23 treated paediatric subjects had treatment‐related SAEs or AEs. There were no thrombotic events, inhibitory or specific binding antibodies against FIX, rFurin or CHO protein. Twenty‐six bleeds (19 non‐joint vs. 7 joint bleeds) occurred (mean ABR 2.7 ± 3.14, median 2.0), of which 23 were injury‐related. Twenty subjects (87%) did not experience any bleeds of spontaneous aetiology. Haemostatic efficacy of BAX326 was excellent or good for >96% of bleeds (100% of minor, 88.9% of moderate and 100% of major bleeds); the majority (88.5%) resolved after 1–2 infusions. Longer T_1/2 and lower IR were observed in younger children (<6 years) compared to those aged 6 to 12 years. BAX326 administered as prophylactic treatment as well as for controlling bleeds is efficacious and safe in paediatric patients aged <12 years with haemophilia B.     

Safe switching from a pdFIX (Immunine®) to a rFIX (Bax326)

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 (Bax326¹) for prophylaxis and treatment of bleeding in previously treated patients of all age cohorts with severe or moderately severe haemophilia B.     

Efficacy and safety of Nuwiq® (human‐cl rhFVIII) in patients with severe haemophilia A undergoing surgical procedures

Introduction

Haemophilia A patients are at a high risk of excess bleeding during surgeries. The aim of haemostatic therapy during the perioperative period is to normalize FVIII level perioperatively and postoperatively to maintain normal haemostasis until wound healing is complete.

Aims/Methods

To examine the efficacy of Nuwiq^® (simoctocog alfa, human‐cl rhFVIII), a 4^th generation recombinant FVIII produced in a human cell line, for surgical prophylaxis in patients with severe haemophilia A. This analysis assessed the efficacy of Nuwiq^® during surgical procedures and in the postoperative period in seven clinical studies of previously treated patients (PTPs) with severe haemophilia A.

Results

Thirty‐six patients, aged 3‐55 years, received surgical prophylaxis with Nuwiq^® for 60 surgeries (28 major and 32 minor). Efficacy was evaluated for 52 surgeries (25 major and 27 minor). The success rate of Nuwiq^® treatment was 98.1% (51 of 52 evaluated surgeries); haemostatic efficacy was assessed as “excellent” or “good” in all but one major surgery (assessed as “moderate”). The number of infusions ranged from 1 to 19 for minor surgeries and from 3 to 76 for major surgeries. The median (range) daily doses were 42.0 (28.2‐100.9) IU kg^?1 for minor surgeries and 69.3 (43.3‐135.6) IU kg^?1 for major surgeries. There were no serious treatment‐related adverse events, and none of the patients developed FVIII inhibitors.

Conclusions

The results of this pooled analysis show that Nuwiq^® was efficacious in maintaining haemostasis during and after major and minor surgical procedures in PTPs with severe haemophilia A.     

Efficacy and safety of monoclonal antibody purified factor IX concentrate in haemophilia B patients undergoing surgical procedures

The present study summarizes results of the efficacy and safety of monoclonal antibody (MAb) purified factor IX concentrate [Mononine® Coagulation Factor IX (Human), Centeon L.L.C., King of Prussia, PA, USA] for surgical prophylaxis in 74 patients with mild, moderate or severe haemophilia B who underwent a total of 81 different operative interventions. Surgical procedures included joint replacement/arthroplasty ( n = 12), gastrointestinal (GI) or rectal surgery ( n = 6), synovectomy/osteotomy ( n = 8), hernia repair ( n = 4), central catheter insertion ( n = 3), ENT surgery ( n = 4), dental procedures ( n = 14), biopsies ( n = 2), gynaecological procedures ( n = 4), ophthalmological surgery ( n = 4), spinal surgery ( n = 4), urogenital surgery ( n = 2), other orthopaedic surgery ( n = 4) or other miscellaneous procedures ( n = 10). All patients demonstrated haemostasis rated as 'excellent' by the investigators. No patients experienced clinically evident thromboembolic complications during treatment with MAb factor IX. These results, from a large and varied random group of patients, demonstrate that this highly purified factor IX concentrate is safe and effective for surgical prophylaxis in patients with haemophilia B, including those patients who have experienced thromboembolic complications during prior treatment with prothrombin complex concentrates.     

Low incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A treated with octanate®: Final report from a prospective study

Introduction

Octanate^® is a human, plasma‐derived, von Willebrand factor‐stabilized coagulation factor VIII (FVIII) concentrate with demonstrated haemostatic efficacy in previously treated patients with haemophilia A.

Aim

This prospective, open‐label study aimed to assess the immunogenicity of octanate^® in previously untreated patients (PUPs).

Methods

The study monitored development of FVIII inhibitors in 51 PUPs. Tolerability, viral safety, FVIII recovery and efficacy of octanate^® for the prevention and treatment of bleeds and in surgical procedures were also assessed.

Results

Five (9.8%) of the 51 patients developed inhibitors during the study, 4 of which (7.8%) were high titre. Three inhibitor cases (5.9%) were considered clinically relevant; 2 were transient inhibitors that disappeared during regular octanate^® treatment without a change in dose or treatment frequency. Amongst 45 patients with FVIII:C <1% at baseline and who received ≥20 exposure days (EDs) or had <20 EDs but developed an inhibitor, inhibitor incidence was 11.1% (6.7% clinically relevant). All clinically relevant inhibitors developed within 20 EDs of on‐demand treatment. No inhibitors developed in PUPs receiving prophylaxis. All patients who developed inhibitors had either intron 22 inversions or large deletions. Irrespective of the reason for administration, haemostatic efficacy was rated as “excellent” in 99.6% of all infusions (4700 of 4717 infusions), and no complications were reported in 23 surgical procedures. Mean incremental in vivo recovery was 2.0%/IU/kg (±0.7) and 1.9%/IU/kg (±0.5) for the first and second assessments, respectively. Tolerability was rated “very good” in 99.9% of infusions.

Conclusion

In PUPs with severe haemophilia A, octanate^® demonstrated haemostatic efficacy with a low rate of inhibitor development.     

Improvement in health‐related quality of life with recombinant factor IX prophylaxis in severe or moderately severe haemophilia B patients: results from the BAX326 Pivotal Study

Little is known about the health‐related quality of life (HRQoL) burden of haemophilia B. The aim of this study was to assess HRQoL burden of haemophilia B, the benefit of recombinant factor IX (rFIX) prophylaxis and the HRQoL benefit of achieving a zero annual bleed rate. Subjects receiving rFIX (BAX326) prophylaxis or on‐demand completed the SF‐36 survey. Baseline SF‐36 scores were compared to the general US population scores to understand the HRQoL burden. Changes in SF‐36 scores between baseline and follow‐up were tested using t‐tests. Subgroup analysis was conducted to examine SF‐36 change among subjects who switched to BAX326 prophylaxis. SF‐36 scores were also compared between those with zero bleeds and those who bled during the study. Compared to the US norms, subjects reported lower average scores in all physical and several mental HRQoL domains. At follow‐up, prophylaxis subjects reported statistically significant and clinically meaningful improvements in overall physical HRQoL, as measured by the Physical Component Score (PCS) (mean change 2.60, P = 0.019), Bodily Pain (BP) (3.45, P = 0.015) and Role Physical (RP) domains (3.47, P = 0.016). Subjects who switched to prophylaxis from intermittent prophylaxis or on‐demand experienced more pronounced improvements not only in the PCS (3.21, P = 0.014), BP (3.71, P = 0.026), RP (4.43, P = 0.008) but also in Vitality (3.71, P = 0.04), Social Functioning (5.06, P = 0.002) and General Health domains (3.40, P = 0.009). Subjects achieving zero bleeds reported lower BP (P = 0.038). Prophylaxis with BAX326 significantly improved HRQoL in patients with moderately severe or severe haemophilia B by reducing bleeds.     

Efficacy of a high purity, chemically treated and nanofiltered factor IX concentrate for continuous infusion in haemophilia patients undergoing surgery

We have evaluated the haemostatic efficacy of plasma derived, highly purified, solvent-detergent treated factor IX concentrate (Nanotiv®), to which a nanofiltration step has recently been added to improve safety with regard to parvovirus B19, hepatitis A and other nonlipid enveloped viruses. Thirteen surgical procedures, including eight orthopaedic operations, were carried out using continuous infusion of Nanotiv in 10 haemophilia B patients (nine severe and one mild). Tranexamic acid was used for 11 of the 13 procedures. The mean factor IX levels on the day of surgery and postoperative days 1–3 were 0.77, 0.89, 0.80 and 0.73 IU mL^–1, respectively. The haemostatic effect was rated as normal or excellent and no blood transfusions were needed. One patient had thrombophlebitis twice at the infusion site. The remaining cases received heparin, 5 units per 100 IU of Nanotiv, and had neither superficial nor deep venous thromboembolic complications. The requirement for factor IX in the four joint replacement operations was 663 IU kg^–1 during the first 9 days, which compares favourably with previous materials. Thus, continuous infusion with this highly purified factor IX concentrate with improved viral safety is effective for surgery in haemophilia B.     

Clinical efficacy,safety and pharmacokinetic properties of the plasma‐derived factor IX concentrate Haemonine® in previously treated patients with severe haemophilia B

Summary. Plasma‐derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine ^® is a high purity double‐virus inactivated human plasma‐derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open‐label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long‐term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on‐demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3 months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half‐life. Mean terminal elimination half‐life was 27.6 h and 25.0 h, mean incremental recovery (IU dL^?1/IU kg^?1) was 1.55 and 1.60, at baseline and 3 months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as ‘excellent’ or ‘good’. Moreover, ‘excellent’ haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long‐term prophylaxis, TOD and when applied after minor and major surgeries.     

Efficacy and safety of 40 mg or 60 mg duloxetine in Japanese adults with diabetic neuropathic pain: Results from a randomized, 52‐week,open‐label study

Introduction

To examine the long‐term efficacy and safety of duloxetine in the treatment of Japanese patients with diabetic neuropathic pain, we carried out a 52‐week, randomized, open‐label extension of a 12‐week, double‐blind, placebo‐controlled study.

Materials and Methods

Japanese adults with diabetic neuropathic pain who completed the double‐blind study were eligible for this long‐term study, carried out at 71 sites in Japan (March 2008 to March 2010). Participants (n = 258) were re‐randomized (1:1) to 40 mg/day or 60 mg/day duloxetine. Pain (Brief Pain Inventory severity and interference), quality of life (Patient''s Global Impression of Improvement), and safety (primary outcome; adverse events, vital signs, metabolic measures) were measured.

Results

Significant (P < 0.0001) and sustained improvements (change ± standard deviation; n = 257) were observed in Brief Pain Inventory severity (average pain score −2.1 ± 1.7). Improvements were also seen in Brief Pain Inventory interference (mean of subscores −0.96 ± 1.52) and Patient''s Global Impression of Improvement (−0.9 ± 1.1) scores; these scores decreased significantly (P < 0.0001) during the long‐term study. Frequently reported adverse events included somnolence (13.6%), constipation (13.2%) and nausea (10.5%). Increases were observed in plasma glucose, glycosylated hemoglobin and total cholesterol levels, and in bodyweight and heart rate; however, none of these were clinically meaningful. Overall, there were no clinically significant safety concerns.

Conclusions

This is the first publication of a long‐term study carried out in Asia with an entirely Japanese patient population to suggest that long‐term duloxetine therapy for diabetic neuropathic pain is effective and has an acceptable safety profile.