Real-world data demonstrate improved bleed control and extended dosing intervals for patients with haemophilia B after switching to recombinant factor IX Fc fusion protein (rFIXFc) for up to 5 years.

INTRODUCTION: In clinical trials, recombinant factor IX fusion protein (rFIXFc) has demonstrated safety, efficacy and prolonged activity with extended dosing intervals for treatment of haemophilia B. AIM: To assess the real-world clinical utility of rFIXFc in a variable patient population and routine clinical practice. METHODS: A multicentre, retrospective chart review was conducted of patients with haemophilia B who had received rFIXFc prophylaxis or on-demand treatment for ≥6 months across six sites in the United States. RESULTS: Sixty-four eligible patients were identified who had a median (range) duration on rFIXFc of 2.7 (0.5-5.0) years. Of 32 patients on rFIXFc prophylaxis who switched from prophylaxis with another factor treatment (ie pre-rFIXFc) and had a known pre-rFIXFc dosing interval, the initial dosing interval was lengthened for 26 (81%) patients and maintained for the remaining 6 (19%) patients. Most (n = 48 [91%]) patients who received rFIXFc prophylaxis from the beginning to the end of the chart review period (n = 53) maintained or lengthened the dosing interval from first through last dose of rFIXFc. For patients receiving rFIXFc prophylaxis, there was an approximate 50% reduction in weekly factor consumption compared with pre-rFIXFc prophylaxis. Overall annualized bleed rates, annualized spontaneous bleed rates and annualized joint bleed rates decreased after switching to rFIXFc prophylaxis (n = 24 with bleed data). Compliance to recommended treatment improved or remained stable in most patients with available data (30/31). CONCLUSION: Recombinant factor IX fusion protein prophylaxis improved bleed control, reduced overall consumption, reduced frequency of infusion and improved compliance for patients with haemophilia B in a real-world setting.

Post hoc longitudinal assessment of the efficacy and safety of recombinant factor IX Fc fusion protein in hemophilia B.

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B.

Physical activity and bleeding outcomes among people with severe hemophilia on extended half-life or conventional recombinant factors.

BACKGROUND: Few have assessed physical activity (PA) and annual bleed rates (ABRs) among people with hemophilia on extended half-life (EHL) factors (recombinant factor VIII Fc [rFVIIIFc]/recombinant factor IX Fc [rFIXFc]) and conventional factors (recombinant factor VIII [rFVIII]/recombinant factor IX [rFIX]). OBJECTIVE: To assess changes in PA and ABR at consecutive annual visits in individuals with severe hemophilia A and B (HA/HB) on prophylactic treatment with rFVIIIFc/rFIXFc versus rFVIII/rFIX. PATIENTS/METHODS: We conducted a retrospective chart review of 344 people with severe HA/HB (ages 6-35) receiving prophylaxis with rFVIIIFc/rFIXFc (EHL factors) or rFVIII/rFIX (conventional factors) for ≥6 months in 2014-2015. Differences in changes in outcomes from 2014 to 2015 were compared across the treatment groups. RESULTS: Baseline characteristics and adherence to the prophylactic regimen were similar across the treatment groups. Greater increase in weekly PA frequency and duration were observed among all EHL groups, except for children treated with rFIXFc. The increase in PA frequency was greater among the children on rFVIIIFc group, adults on rFVIIIFc group, and adults on rFIXFc group by 1.2, 1.2, and 1.4 events/week, respectively, compared to their rFVIII/rFIX counterparts. The increases in PA duration were 44, 60, and 80 min/wk greater among the children on rFVIIIFc, adults on rFVIIIFc, and adults on rFIXFc groups, respectively. Larger reductions in total ABR were observed in children and adults treated with rFVIIIFc compared to rFVIII (0.4 and 0.7 fewer bleeds). Larger reductions were also observed in spontaneous ABR in adult rFVIIIFc and rFIXFc groups (0.8 and 0.3 fewer bleeds, respectively). CONCLUSIONS: This study suggests that rFVIIIFc/FIXFc agents can positively impact PA while maintaining low ABRs.

Real-world assay variability between laboratories in monitoring of recombinant factor IX Fc fusion protein activity in plasma samples.

INTRODUCTION: Monitoring of factor IX (FIX) replacement therapy in haemophilia B relies on accurate coagulation assays. However, considerable interlaboratory variability has been reported for one-stage clotting (OSC) assays. This study aimed to evaluate the real-world, interlaboratory variability of routine FIX activity assays used in clinical haemostasis laboratories for the measurement of recombinant FIX Fc fusion protein (rFIXFc) activity. METHODS: Human FIX-depleted plasma was spiked with rFIXFc at 0.80, 0.20 or 0.05 IU/mL based on label potency. Participating laboratories tested samples using their own routine OSC or chromogenic substrate (CS) assay protocols, reagents and FIX plasma standards. Laboratories could perform more than one measurement and method, and were not fully blinded to nominal activity values. RESULTS: A total of 142 laboratories contributed OSC results from 175 sample kits using 11 different activated partial thromboplastin time (aPTT) reagents. The median recovered FIX activity for the 0.80, 0.20 and 0.05 IU/mL samples was 0.72 IU/mL, 0.21 IU/mL and 0.060 IU/mL, respectively. Across all OSC reagents, interlaboratory variability (% CV) per aPTT reagent ranged from 9.4% to 32.1%, 8.2% to 32.6% and 12.2% to 42.0% at the 0.80, 0.20 and 0.05 IU/mL levels, respectively. CS results showed excellent median recoveries at all nominal levels (87.5% to 115.0%; n = 11) with low interlaboratory variability (CV 3.6% to 15.4%). CONCLUSION: This large, real-world data set indicates that rFIXFc activity in plasma samples can be accurately measured with the majority of routine OSC and CS assay methods. Given the variation in FIX assay procedures between sites, it is important that individual laboratories qualify their in-house methods for monitoring of rFIXFc activity.

Extending recombinant factor IX Fc fusion protein dosing interval to 14 or more days in patients with hemophilia B.

BACKGROUND: In the phase 3 B-LONG study (NCT01027364), prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) every 7 to >14 days was associated with low annualized bleed rates (ABRs) in males aged ≥12 years with severe hemophilia B. The long-term safety and efficacy of rFIXFc prophylaxis was confirmed in the B-YOND study (NCT01425723), an extension of the B-LONG clinical trial. OBJECTIVE: The aim of this post-hoc analysis was to evaluate the efficacy of a ≥14-day rFIXFc dosing interval in patients treated prophylactically during B-LONG or B-YOND. METHODS: The analysis included 22 patients aged ≥12 years who received prophylactic rFIXFc with a ≥14-day dosing interval at any time during B-LONG or B-YOND up until the second interim analysis of B-YOND (September 2015). RESULTS: The median (interquartile range [IQR]) rFIXFc exposure on the ≥14-day dosing interval was 3.4 (1.8-4) years. Patients treated with a ≥14-day dosing interval were well controlled with a median (IQR) overall ABR of 1.6 (0.6-2.7) and a median (IQR) spontaneous ABR of 0.7 (0.3-1.1) in 18 evaluable patients. A rFIXFc dosing interval of ≥14 days was well tolerated, with no new safety concerns identified. CONCLUSION: Most patients on rFIXFc prophylaxis, with a dosing interval of ≥14 days, remained well controlled; ABRs were consistent with those reported in the overall study population. A ≥14-day dosing interval can be utilized in some well controlled individuals and reduces the burden imposed by frequent prophylactic injections while maintaining adequate bleed suppression.

Bleeding patterns with monophasic and triphasic low-dose ethinyl estradiol combined oral contraceptives.

BACKGROUND: This retrospective analysis evaluated the association of age and weight with cycle control in women using either of two formulations of low-estrogen-dose oral contraceptives. STUDY DESIGN: Data for this secondary analysis were derived from a randomized multicenter trial assessing the efficacy and safety of norgestimate (NGM) 180/215/250 mcg/ethinyl estradiol (EE) 25 mcg (n=1506) and norethindrone acetate 1 mg/EE 20 mcg (n=1057). In this retrospective analysis, the incidence of breakthrough bleeding/spotting (BTB/S) was evaluated in women stratified by age (18-24, 25-34 and >34 years) and weight (155 lb). RESULTS: A lower percentage of women experienced BTB/S with NGM/EE during most cycles, regardless of age or weight, compared with norethindrone acetate/EE. At Cycle 6, the incidences of BTB/S for NGM/EE versus norethindrone acetate/EE were as follows: 18-24 years, 10.9% versus 29.7% (p<.0001); 25-34 years, 10.9% versus 18.6% (p<.001); >34 years, 8.1% versus 19.1% (p<.005); 155 lb, 10.0% versus 18.3% (p<.01). CONCLUSION: NGM/EE provided better cycle control as defined by BTB/S compared with norethindrone acetate/EE, regardless of subject age or weight for six cycles.

Treatment satisfaction with a transdermal contraceptive patch or oral contraceptives.

OBJECTIVE: The study was conducted to examine the influence of demographics, health-related quality of life (HRQL) and duration of use on satisfaction with the transdermal contraceptive patch or oral contraceptives (OCs). METHODS: In this cross-sectional analysis of the 2004 National Health and Wellness Survey (NHWS), women were currently using the patch (n=257) or OCs (n=1824). Outcome variable was a five-point satisfaction scale (1=not at all; 5=extremely). Satisfaction rates were computed as the percentage of patients reporting a 4 or 5. Independent variables included demographics, HRQL (SF-8), duration of use, and treatment (patch or OCs). Logistic regression evaluated association of independent variables. RESULTS: Patch use was associated with significantly higher satisfaction than OCs (OR=2.05; 95% CI=1.34-3.15; p=.001) in the logistic regression model. Months using product (p<.001), days used product in past month (p<.001) and mental well-being (p=.02) were other variables associated with satisfaction. CONCLUSION: Patch use, duration of use and mental well-being were associated with satisfaction.

Association between efficacy and body weight or body mass index for two low-dose oral contraceptives.

BACKGROUND: This analysis investigated the association of oral contraceptive efficacy with body weight and body mass index (BMI) for hypothesis-generating purposes. STUDY DESIGN: Data were from a randomized, parallel-group trial of 180/215/250 mcg of norgestimate (NGM)/25 mcg of ethinyl estradiol (EE) (given to 1671 women) and 1 mg of norethindrone acetate (NETA)/20 mcg of EE (given to 1139 women). Pregnancies were evaluated across BMI deciles and by BMI and body weight dichotomies. A Pearl index was calculated for each treatment group. The relative risk (RR) of pregnancy was calculated with a Cox proportional hazards model. RESULTS: The Pearl index for women who received NGM/EE was 2.36 [95% confidence interval (CI)=1.33-3.40]; for those who received NETA/EE, the Pearl index was 3.29 (95% CI=1.81-4.77). Consistent, weak positive associations between weight and pregnancy risk were found. Overall, for women with a BMI >or=25 kg/m(2) (compared with women with a BMI <25 kg/m(2)), the RR of pregnancy was 1.84 (95% CI=0.98-3.45); that for women who received NGM/EE was 1.39 (95% CI=0.57-3.40), whereas that for women who received NETA/EE was 2.49 (95% CI=1.01-6.13). For women with a body weight >or=70 kg (compared with women with a body weight <70 kg), the RR was 1.25 (95% CI=0.63-2.46); that for women who received NGM/EE was 1.41 (95% CI=0.56-3.54), whereas that for women who received NETA/EE was 1.12 (95% CI=0.40-3.12). CONCLUSION: Women in the higher body weight or BMI category showed a small increase in the risk of pregnancy with these oral contraceptives, but this increase was not statistically significant overall or for either formulation studied.