Rurioctocog Alfa Research Articles

Convenience Comparison Study of Reconstitution Devices for the Blood Coagulation Factor VIII Products Rurioctocog Alfa Pegol and Antihemophilic Factor (Recombinant).

IntroductionThe Baxject® II Hi-Flow device has previously been used to reconstitute the factor VIII products antihemophilic factor (recombinant) (ADVATE®) and rurioctocog alfa pegol (ADYNOVATE®).MethodsIn this crossover study in healthy men, the convenience of an advanced device, Baxject III® with and without a nonslip sleeve, was compared with that of Baxject II Hi-Flow. The primary endpoint was the operational time for reconstitution; secondary endpoints included participants’ assessment of the usability of the devices for reconstitution and their preference for using each of the devices.ResultsTwelve healthy adult men (mean ± standard deviation [SD] age: 36.7 ± 7.0 years) and 12 healthy elderly men (mean ± SD age: 70.3 ± 4.8 years) participated in the study. In the adult group, the mean operational time for reconstitution was shorter using Baxject III (mean ± SD: 19.7 ± 2.7 and 19.9 ± 5.2 seconds with and without a nonslip sleeve, respectively) than when using Baxject II Hi-Flow (49.6 ± 7.2 seconds, P < 0.0001 for both comparisons). Adult participants rated preference (P < 0.0001) and ease of reconstitution (P < 0.0001) as higher for Baxject III with a nonslip sleeve than for Baxject II Hi-Flow. Results were consistent regardless of age group or the use of the nonslip sleeve.ConclusionOwing to the convenience of Baxject III, this device will improve the reconstitution process for patients with hemophilia treated with rurioctocog alfa pegol or antihemophilic factor (recombinant) at home.

Dosing, Patient Satisfaction and Other Patient-Reported Outcomes after Switching to Rurioctocog Alfa Pegol in Athn 2: A Longitudinal, Observational Study of Previously Treated Hemophilia Patients Switching Coagulation Replacement Factor Products

Dosing, Patient Satisfaction and Other Patient-Reported Outcomes after Switching to Rurioctocog Alfa Pegol in Athn 2: A Longitudinal, Observational Study of Previously Treated Hemophilia Patients Switching Coagulation Replacement Factor Products

Excellent Clinical and Pharmacokinetic Real-World Experience after Switching to Rurioctocog ALFA Pegol

Background:Prophylactic treatment with standard half-life coagulation factors (SHL) requires 3-4 weekly periodic infusions. Extended half-life (EHL) factor VIII (FVIII) provides improvements in half-life (t1/2) and area under the curve (AUC) of 1.3 and 1.25 times compared to standard half-life (SHL) products. Rurioctocog alfa pegol is an extended half-life (EHL) rFVIII (rFVIII-EHL) treatment that could be a more convenient and cost-effective therapeutic alternative than SHL, since it would reduce the number of weekly infusions (NWI). Aims:The aim of this study is to analyze pharmacokinetic (PK) parameters and compare NWI and bleeding rates after switching from SHL to this EHL in hemophilia A (HA) patients. Methods:In a prospective study, the number of weekly infusions (NWI), annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and PK parameters were compared between previous treatment with FVIII-SHL vs rFVIII-EHL (Rurioctocog alfa pegol). The assessment of the PK parameters: volume of distribution (Vd (dL/kg)), clearance (Cl (dL/h/kg)) and half-life time (t½ (h)) was performed by using the pharmacokinetic poblacional software online myPKFiT®. Results:Nineteen patients from 2 Spanish hospitals (n=12 Vall d'Hebron Hospital, n=7 Hospital Regional Universitario de Málaga) were recruited. Median age was 30 years (range, 12-54), with five pediatric patients, and 18 had severe HA (one moderate HA). Sixteen patients were under prophylactic treatment with Advate® and 1 with Kovaltry®. Two patients were switched from on-demand treatment to prophylaxis. The median use of rFVIII-EHL was 15.63 month. The PK parameters after the switch to the rFVIII-EHL in entire cohort and pediatric cohort are shown in Table 1. The t ½ of rFVIII-EHL was positively correlated to preinfusion plasma levels of von Willebrand factor antigen (vWF:Ag) (Figure 1). ABR and AJBR were reduced, as well as weekly infusion frequency (33.3%, IQR:0-50%) (Table 2). Of note, 57.9% of patients presented zero joint bleeding events after switchingtorFVIII-EHL. Conclusions:In this prospective analysis rFVIII- EHL presents as a therapeutic alternative that allows reducing ABR and AJBR as well as weekly infusion frequency according to PK patient parameters. Disclosures Bosch: Roche:Honoraria;Celgene:Honoraria;Jansen:Honoraria;Abbvie:Honoraria;Novartis:Honoraria;Astra Zeneca:Honoraria;Takeda:Honoraria.Gironella Mesa:Bristol Myers Squibb:Honoraria, Speakers Bureau;Janssen:Consultancy, Honoraria.

Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0–tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 (ClinicalTrials.gov identifier). Date of registration: July 9, 2019

A Retrospective Observational Study of Rurioctocog Alfa Pegol in Clinical Practice in the United States.

Research describing patient experience and outcomes with extended half-life recombinant factor VIII (EHL rFVIII) outside of clinical trials is limited. Real-world rFVIII consumption studies, when people with hemophilia A (PWHA) switch from standard half-life (SHL) to EHL rFVIII, may help payers and clinicians make more informed treatment choices. To conduct a retrospective, observational, U.S.-based analysis to describe clinical and demographic profiles of PWHA who switched to prophylactic rurioctocog alfa pegol. Data were obtained from PWHA treated by 38 prescribers across 21 states using specialty pharmacy database case report forms, electronic medical records, and direct communication with providers, PWHA, or their guardians. Assessments included disease severity, pain severity, number and location of target joints, prior HA therapy, reasons for switching, treatment duration, dosing frequency, adherence, and annualized bleeding rates (ABRs) before and after switching to rurioctocog alfa pegol from SHL or another EHL rFVIII. Data were collected from 56 PWHA. The mean age was 26 years (range = 5-88); median age was 24 years (interquartile range = 14-34); 20% were aged < 12 years; and 89% (50/56) had severe HA. All PWHA had ≥ 12 months of rFVIII treatment before switching to rurioctocog alfa pegol. The population had a mean 1.8 target joints. Baseline subjective pain assessment was mild to moderate for 68% (38/56) of respondents. Before receiving rurioctocog alfa pegol, most PWHA received antihemophilic factor (recombinant) for prophylaxis (73%, 41/56) or breakthrough bleeding (59%, 33/56). Mean dosing frequency for prior prophylaxis was 2.8 per week for SHL rFVIII and 1.8 per week for EHL rFVIII, and 2.2 per week for all PWHA after switching to rurioctocog alfa pegol prophylaxis. The median time on rurioctocog alfa pegol prophylaxis was 12.0 months versus 80.8 months on previous SHL rFVIII and 13.5 months on previous EHL rFVIII. Mean ABRs on prior prophylaxis were 5.9 for SHL rFVIII (n = 35) and 4.7 for EHL rFVIII (n = 3). After switching to rurioctocog alfa pegol, the overall mean ABR reduced by 71% (5.8 to 1.7, P < 0.001) and 20/56 PWHA had no bleeding events. There was also a 20.9% reduction in the mean days per week of factor administration (P < 0.001) after switching to prophylactic rurioctocog alfa pegol. For 47 PWHA who switched from SHL rFVIII, their weekly dose decreased from 109.8 to 100.6 IU per kg with rurioctocog alfa pegol (P = 0.094). The proportion of PWHA with good/complete treatment adherence increased from 68% (38/56) on any prior rFVIII to 80% (45/56) on rurioctocog alfa pegol. The most common reason PWHA switched to rurioctocog alfa pegol was to reduce treatment infusions. Switching from either an SHL or EHL rFVIII to rurioctocog alfa pegol is associated with fewer bleeding episodes owing to more effective prophylaxis and improved adherence. Those who switched from an SHL rFVIII reported reduced factor consumption with rurioctocog alfa pegol. This long-acting factor is an important additional option for the care of PWHA. This study was funded by Shire Development LLC, a Takeda company, Lexington, MA. Trio Health was involved in study design and acquisition, analysis, and interpretation of data and was funded by Shire Development LLC, a Takeda company. Aledort serves on the data and safety monitoring boards of Baxalta U.S. Inc., a Takeda company, and Octapharma; is chair of the scientific advisory board of Kedrion; and receives consultancy fees and honoraria from Baxalta U.S. Inc., a Takeda company. Milligan is an employee of Trio Health and reports research support from AbbVie, Gilead, Merck, Sanofi, and ViiV, unrelated to this study. Watt is an employee of Shire International GmbH, a Takeda company, and owns stock in the company. Booth was an employee of Baxalta U.S. Inc., a Takeda company, at the time of this study and owns stock in the company. Data from this study were presented at the AMCP Managed Care and Specialty Pharmacy Annual Meeting; April 23-28, 2018; Boston, MA; SETH (2018) Sociedad Espanola de Trombosis y Hemostasia-XXXIV Congreso Nacional; October 11-13, 2018; Grenada, Espana; and Blood 2018 Annual Scientific Meeting; October 21-24, 2018; Brisbane, Australia.

Real-World Age-Stratified FVIII Consumption and Bleed Outcomes Before and After Switching to Rurioctocog Alfa Pegol in a Retrospective, Observational Study Using US Specialty Pharmacy Data

Introduction: The safety and efficacy of rurioctocog alfa pegol (BAX 855, SHP-660, TAK-660; Adynovate®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in patients with severe hemophilia A has been reported previously (Konkle BA et al., Blood 2015, 126:1078-85; Brand B et al., Haemophilia 2016, 22:e251-8; Mullins ES et al., Haemophilia 2017, 23:238-46); however, research describing patient experience with extended half-life (EHL) recombinant factor VIII (FVIII) products outside clinical trials is limited. The objective of this study was to assess real-world utilization of TAK-660 in patients with hemophilia A and describe their clinical profiles before and after switching to TAK-660. Factor consumption and bleed outcomes stratified by age (&lt;18 and ≥18 years) are reported herein. Methods: This was a retrospective, observational database study of patient data from US specialty pharmacies. Pharmacy data sources included patient records, prescriptions, and patient-reported bleed logs. Informed consent was obtained for all analyzed patient data. Eligible patients with hemophilia A were treated with prophylactic TAK-660 with on-label dosing from November 2015 to September 2018, and had received ≥90 days of FVIII (standard half-life [SHL] or EHL) therapy before switching to TAK-660. Main exclusion criteria were participation in a TAK-660 clinical trial before/during this study, only on-demand treatment before switching to TAK-660, or presence of active FVIII inhibitor requiring treatment and/or use of immune tolerance induction during the study period. Assessments included prior hemophilia therapy, FVIII administration frequency and consumption, and annualized bleeding rate (ABR) before and after switching to TAK-660. Results: Data was collected from 82 patients (of 61 providers in 44 practices across 25 states in the United States): 44% of the patients (36/82) were &lt;18 years old; 56% (46/82) were ≥18 years old (none were ≥60 years old); 83% (68/82) had severe hemophilia A; and 88% (72/82) had received prior SHL-FVIII treatment. The SHL antihemophilic factor (recombinant) (Advate®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) was used by 67% (55/82) of patients overall, of whom 47% (26/55) were &lt;18 years old and 53% (29/55) were ≥18 years old. Compared with any prior FVIII therapy, switching to TAK-660 increased FVIII dose per administration in patients &lt;18 and ≥18 years old (+39.5% and +22.9%, respectively), while their weekly administration frequency decreased (-21.4% and -28.1%, respectively; Table 1). Weekly FVIII consumption increased in patients aged &lt;18 years (+11.2%) and decreased in those aged ≥18 years (-12.8%). FVIII administration frequency and consumption by prior SHL- or EHL-FVIII are reported in Table 1. ABR data before and after switching were available in 47 of 82 patients. Compared with any prior FVIII therapy, mean ABR decreased in patients aged &lt;18 years (-39.5%; 2.8 to 1.7) and ≥18 years (-50.3%; 3.4 to 1.7) with TAK-660 treatment (Table 2). Changes in mean ABR by prior FVIII therapy and disease severity are reported in Table 2. The small number of patients who received prior EHL FVIII was a limiting factor in the comparison of patients who received prior SHL- and EHL-FVIII therapy. Conclusions: In patients with hemophilia A previously treated with SHL- or EHL-FVIII products, switching to TAK-660 prophylaxis resulted in a significant decrease in ABR of 40-50% in both age groups analyzed. The adult population (ie, ≥18 years old) showed a tendency for reduced weekly FVIII consumption. These findings from real-world data are in agreement with TAK-660 clinical trial results. The observed differences in FVIII consumption between patients &lt;18 and ≥18 years old may have been in part a result of age-related changes in bleeding patters, growth, and other factors. Disclosures Watt: Shire International GmbH, a Takeda company: Employment, Other: a Takeda stock owner. Milligan:Sanofi: Research Funding; Merck: Research Funding; Gilead: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Trio Health: Employment; Viiv: Research Funding.

Cross-Sectional Comparative Study of PK-Guided Switch between Standard Half-Life and Extended Half-Life Factor VIII Products

Background The high inter-individual variability in pharmacokinetics (PK) of factor VIII (FVIII) justifies the use of PK-guided prophylaxis, especially in switching between different products. A proposed definition of extended half-life (EHL) FVIII requires improvements of at least 1.3 times in half-life (t1/2) and 1.25 times the area under the curve (AUC) compared to standard half-life (SHL) products (Mahlangu et al. Haemophilia. 2018;24(3):348-358). The objective of this multicenter study was to analyze the results of a PK-guided switch from SHL to EHL in patients with hemophilia A (HA). Methods Multicenter comparative, cross-sectional, prospective study in HA severe/moderate patients in prophylaxis analyzing PK differences after switch from SHL to EHL (efmoroctocog alfa [rFVIII-Fc] and rurioctocog alfa pegol [PEG-rFVIII]). WAPPS-Hemo® was used to analyze PK parameters with 2-3 samples: t1/2; AUC, peak level (PL); trough level at 24, 48 and 72 h (TL24, TL48, TL72); and time to reach FVIII levels of 1, 2, 5% (T1%, T2%, T5%). We have also compared the ratio of t1/2 and AUC, the number of weekly doses and the dose/kg/week before and after the switch. Wilcoxon and Kruskal-Wallis tests (SPSS®) were used to compare the PK parameters. Results are expressed with the median and interquartile range (IQR) or range, and mean and standard deviation (SD). Results Eighty-one patients from 8 Spanish hospitals were analyzed (61 rFVIII-Fc; 20 PEG-rFVIII), 78 had severe HA and 3 moderate HA. Mean age was 30 years (range=3-64) and no differences in weight were observed between both periods [70 (range=12-116) vs 70 (13.7-116) kg; p=0,141]. Dose/kg/week and weekly infusion frequency were reduced after the switch to EHL, and significant improvements were observed in all PK parameters after the change from SHL to EHL (Table 1). These results were similar in adult and pediatric patients switching to rFVIII-Fc. The median ratios of t1/2 and AUC were 1.3 (IQR:1.2-1.6) and 1.5 (IQR:1.3-2.3) in the entire cohort. These results were reproduced in the subset of patients with ≥12 years treated with rFVIII-Fc and PEG-rFVIII (ratio t1/2: 1.4 [IQR:1.3-1.6]; ratio AUC: 1.6 [IQR:1.3-2.3]), and were slightly in the cohort of 15 patients &lt;12 years treated with rFVIII-Fc (ratio t1/2: 1.3 [IQR:0.9-1.3]; ratio AUC: 1.3 [IQR:1.1-1.9]), the only EHL approved in Europe for children. After the switch to EHL, weekly dose frequency (median 23.3%, IQR:0-33.3%) and dose/kg/week (median 16%, IQR:5.3-30%) were reduced. In a small subset of 17 patients the dose/kg/week increased a median of 31.4%, and this subset was younger than the patients with dose/kg/week reduction or no changes (median age 18 [IQR:8-22] vs. 33 [IQR:16.5-42.5]). No differences were observed in any of the PK parameters and median ratios of t1/2 and AUC in patients aged ≥12 years treated with rFVIII-Fc vs. PEG-rFVIII (46 rFVIII-Fc; 20 PEG-rFVIII; Table 2). Conclusions EHL FVIII have shown significant PK improvements in clinical real practice, allowing to reduce weekly infusion number and dose/kg/week, especially in adult patients. Outside the clinical trial setting, we have observed an increase in t1/2 and AUC ratios accordingly to EHL definition. Comparisons regarding clinical outcomes (bleeding rate after switch) will be performed after a follow-up of 1 year with EHL for the full cohort. WAPPS-Hemo PK-guided switch easily facilitates individualization of prophylaxis with a potential reduction in the cost of treatment and patient perceived outcomes. Disclosures Megias: Baxalta US INC.: Research Funding; Grifols: Research Funding. Bonanad Boix:Baxalta US INC.: Research Funding. Berrueco:NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL-Bering: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mingot-Castellano:Sobi: Consultancy; Bayer: Consultancy; Amgen: Consultancy; Roche: Consultancy; Novartis: Consultancy; Novonordisk: Consultancy; Takeda: Consultancy; CSL Behring: Consultancy. Cid:Shire, a Takeda company: Honoraria; Novo Nordisk: Honoraria. Sanz:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Benefits of Ehl Factor VIII Replacement Therapy in Hemophilia: Observations on Coverage, Physical Activity and Phisiotherapy

Introduction: Prevention of haemophilic arthropathy and quality of life´s (QoL) improvement are still the main goals in the haemophilia community. Haemophilic arthropathy is the result of clinical and subclinical bleeding during everyday activities and/or traumatic situations. Prophylaxis with extended half-life (EHL) factor replacement therapy is understood as an improvement solution for factor VIII (FVIII) PK properties, as half-life (T1/2) and area under the curve (AUC), however few real world data are yet available. EHL improved pharmacokinetic (PK) properties might directly drive into a reduction of the bleeding risk during physical activity (both therapeutical or leisure) for a longer period of time, allowing an increase in QoL. World Health Organization (WHO) has set recommendations focused on the benefits of moderate and intense physical activity to improve joint health as well as to prevent common pathologies (obesity, diabetes, hypertension, cancer, depression, anxiety) and even the risk of death (since the absence of physical activity is the 4th factor risk worldwide). The aim of this study was to define a safe program of physical activity, sport and physiotherapy along the time according the PK profile of patients treated with the EHL rurioctocog alfa pegol. Materials and methods: PK parameters (infusion frequency, dosage, T½, peak level, trough level at 24, 48 and 72 hours (NV24/NV48 and NV72), and time to reach 5%, 2% and 1% FVIII levels (T5,T2 and T1) were analyzed in patients with hemophilia A after switching from an standard half-life (SHL) FVIII to the EHL (rurioctocg alfa pegol) FVIII replacement therapy. Tailored physical activity and physiotherapy programmes in place during SHL treatment were re-evaluated after switching to the EHL according the new individual PK profile. The Functional Independence Score in Hemophilia (FISH) form was used to measure ambulation. Results: Ten patients with hemophilia A (9 severe and 1 moderate) with a mean age of 34.49 (9.46) were analyzed. All the PK parameters evaluated showed a significant statistical improvement after the switch from an SHL to this FVIII EHL (Figure 1, A.). Specifically, higher T½, peak levels and trough levels were achieved using a lower dosage and infusion frequency (Figure 1, B). After switching to the EHL, FVIII trough levels were higher than 5% until 3.4 days (81.5 hours) (Figure 1, C) post-infusion. This allowed us to establish a physiotherapy program as well as an intense-moderate physical activity program in patients without clinical evidence of bleeding events (Figure 1, D). The potentiation physical program to develop muscle tone for elbows, knees and ankles was authorized until the third day of EHL FVIII post-infusion. However, during SHL treatment, vigorous physical activity was never performed after 24 hours of FVIII post-infusion. No joint bleeding events appeared during everyday physical activities nor during physiotherapy programs aimed to maintain joint trajectory and muscle power. Regarding ambulation (FISH), all patients had hemophilic arthropathy in one joint. The results in the item "Run" were: 3 points for 3 patients (activity non comparable to normal activity), 2 points for 3 patients (requires an orthesis) and 1 point for 4 patients (activity not feasible). Conclusions: EHL FVIII replacement with rurioctocog alfa pegol improved significantly all PK parameters compared to SHL factors. The administration of this EHL allows moderate and vigorous physical activity after more than 72 hours post-infusion, due to higher FVIII coverage along the time. Disclosures Querol: Baxalta US INC.: Research Funding. Pérez-Alenda:Baxalta US INC.: Research Funding. Megias:Baxalta US INC.: Research Funding; Grifols: Research Funding. Carrasco:Baxalta US INC.: Research Funding. Cid:Novo Nordisk: Honoraria; Shire, a Takeda company: Honoraria. Bonanad Boix:Baxalta US INC.: Research Funding.

Subgroup analysis of a phase 2/3 study of rurioctocog alfa pegol in patients with severe hemophilia A: efficacy and safety in previously treated Korean patients.

BackgroundThe efficacy and safety of extended half-life, full-length, pegylated recombinant factor VIII rurioctocog alfa pegol [BAX 855, ADYNOVATE (USA)/ADYNOVI (Europe); Baxalta US Inc., a Takeda company, Lexington, MA, USA] was investigated in previously treated Korean patients with severe hemophilia A (HA).MethodsA post hoc data analysis from the international, multicenter, phase 2/3 PROLONG-ATE study of rurioctocog alfa pegol in patients with severe HA (NCT01736475) determined annualized bleeding rates (ABRs) and rates of adverse events (AEs) in Korean patients treated in this study.ResultsAll 10 enrolled Korean patients receiving rurioctocog alfa pegol (9 prophylaxis, 1 on-demand) completed the study [median (range) age, 28.0 (12–50) yr; weight, 64.8 (45–90) kg; 8 patients had ≥1 target joint at screening]. Median (range) ABR was 1.9 (0.0–14.5) for patients on prophylaxis and 62.2 for the patient receiving on-demand treatment. The hemostatic efficacy of rurioctocog alfa pegol was rated “excellent” or “good” and only single infusions were required per bleeding episode. ABRs improved in most patients compared with prestudy values. No dose adjustments were required for prophylaxis, and the dosing frequency was reduced in 8 patients, compared with their previous prophylaxis regimen. No serious AEs were reported; all 9 nonserious AEs (in 3 patients) were mild in severity and unrelated to the study treatment.ConclusionThis post hoc analysis of a small group of Korean patients with severe HA indicated that rurioctocog alfa pegol was effective, and no serious AEs were observed. For most patients, the dosing frequency was also reduced compared with their previous regimen.

Efficacy and Safety Results from a Phase 3b, Open-Label, Multicenter, Continuation Study of Rurioctocog Alfa Pegol for Prophylaxis in Previously Treated Patients with Severe Hemophilia A

Background: Patients with severe hemophilia A experience substantial morbidity and mortality due to frequent spontaneous and traumatic bleeding episodes, especially in joints. Prophylaxis with standard half-life factor VIII (FVIII) is the standard of care to prevent bleeds. Extended half-life products benefit patients by reducing the number of infusions without impacting the treatment efficacy.Methods: This phase 3b, prospective, open-label, multicenter, continuation study (NCT# 01945593) investigated the safety and efficacy of a PEGylated recombinant FVIII with an extended half-life, rurioctocog alfa pegol (SHP660, BAX 855, ADYNOVATE®, Shire, Lexington, MA, USA), for prophylaxis and treatment of bleeding in patients with severe hemophilia A (FVIII <1%). Eligible children and adults were ≤75 years of age and had either completed a previous rurioctocog alfa pegol study (NCT# 01599819, 01736475, 02210091, 02615691, 01913405, or 02585960) and were willing to immediately transition to the continuation study, or were naïve to rurioctocog alfa pegol but had received treatment with plasma-derived or recombinant FVIII for ≥150 (in patients ≥6 years of age) or ≥50 (in patients <6 years of age) exposure days. Patients received prophylactic rurioctocog alfa pegol at least twice weekly, either at a fixed dose (FD; 45 ± 5 IU/kg in patients ≥12 years of age; 50 ± 10 IU/kg in those <12 years of age; dose adjustment ≤80 ± 5 IU/kg allowed) or with pharmacokinetically (PK)-tailored dosing (≤80 ± 5 IU/kg) to maintain FVIII trough levels ≥3%. The co-primary endpoints assessed were the incidence of FVIII inhibitory antibody development (as measured by ≥0.6 BU in the Nijmegen modification of the Bethesda assay) and the spontaneous annualized bleed rate (ABR). Secondary endpoints included overall hemostatic efficacy ratings and occurrence of adverse events (AEs).Results: The study began in October 2013 and completed in March 2018. Overall, 216 patients receiving prophylaxis were eligible and included in the safety/full analysis dataset (≥1 dose received). Of these, 215 were male, the mean (SD) age at enrollment was 22.8 (15.7) years, the mean (SD) number of documented previous rurioctocog alfa pegol exposure days was 57.0 (39.6), the total ABR over 3-6 months prior to enrollment in the continuation study (including patients naïve to rurioctocog alfa pegol or receiving on-demand or prophylactic treatment with rurioctocog alfa pegol) was mean (SD) 4.7 (12.6), median (range) 0.0 (0-69). Most patients (206; 95.4%) had participated in a previous rurioctocog alfa pegol study. Overall, 215 patients received ≥1 dose in the FD regimen and 25 received ≥1 dose in the PK regimen. These patients received a mean (SD) of 1.72 (0.29) and 2.11 (0.61) prophylactic infusions per week, respectively, with a mean (SD) dose per infusion of 51.15 (8.11) IU/kg and 52.14 (17.03) IU/kg, respectively.None of the patients developed a confirmed FVIII inhibitor in this study and only 1 treatment-related allergic or hypersensitivity reaction (a nonserious mild AE) was reported. Nonserious AEs assessed by the investigators to be related to treatment occurred in 11/216 (5.1%) patients. Serious AEs (SAEs) occurred in 33 (15.3%) patients; there were no SAEs assessed by the investigators to be related to treatment. Descriptive statistics on spontaneous, joint, and total ABR by prophylactic regimen are shown in the Table. The overall total ABR in all patients was mean (SD) 2.5 (3.1), median (range) 1.6 (0.0-19.5). Overall hemostatic efficacy was rated as good or excellent in 88.5% of all bleeds and 89.4% of all bleeds were treated with 1 or 2 infusions.Conclusions: These results show that in previously treated patients with severe hemophilia A, rurioctocog alfa pegol prophylaxis in FD- and PK-tailored regimens was well tolerated and effective. None of the patients developed FVIII inhibitory antibodies, and a decrease in mean total ABR was reported in these patients compared with baseline. [Display omitted] DisclosuresMullins:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konkle:Genentech: Consultancy; CSL Behring: Consultancy; Gilead: Consultancy; Pfizer: Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy; Bioverativ: Research Funding; Shire: Research Funding; Sangamo: Research Funding. McGuinn:CSL Behring: Consultancy; BioMarin: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark: Consultancy, Research Funding; Genentech: Consultancy; Shire: Research Funding; Pfizer: Research Funding. Engl:Shire: Employment, Equity Ownership. Tangada:Shire: Employment, Equity Ownership.

Personalization of Treatment Regimens for Active Patients: A Comparison of Hemophilia Prophylaxis Treatment Regimens

Background: Personalizing treatment of hemophilia A includes tailoring the product and regimen to patient characteristics and lifestyle. Factor VIII (FVIII) pharmacokinetic (PK) parameters such as peaks and troughs, area under the curve, and time spent below a certain FVIII level may be important factors in determining risk for hemarthroses or other bleeds, particularly during periods of high activity when patients are at risk of traumatic bleeding. It is important to identify which patients may be most appropriately treated with different products/regimens. Given a lack of real-world outcomes data, modeling offers a way to estimate bleeding risk with various regimens for different physical activity profiles.Aim: This outcomes research model estimated the relative bleeding risk for different patient physical activity profiles associated with various prophylaxis regimens using standard half-life recombinant FVIII (SHL-rFVIII) and extended half-life rFVIII (EHL-rFVIII), as well as with scenarios based on a theoretical baseline FVIII activity level with minimal variance.Methods: A 1-compartment PK model (Collins, et al. Haemophilia 2011) was used to predict FVIII activity associated with different treatment regimens. For SHL-rFVIII and EHL-rFVIII, half-life (10.4 and 14.3 hours, respectively) and incremental recovery (2.37 and 2.49 [IU/dL]/[IU/kg], respectively) values were used from the PK crossover study (Konkle, et al. Blood 2015) of antihemophilic factor (recombinant) (ADVATE®, Shire, Lexington, MA, USA) and rurioctocog alfa pegol (SHP660, BAX 855, ADYNOVATE®, Shire). The model included 3 prophylaxis regimens: SHL-rFVIII 30 IU/kg every other day (EOD), SHL-rFVIII 35 IU/kg 3x/week, and EHL-rFVIII 45 IU/kg 2x/week, as well as a range of theoretical baseline FVIII activity levels with minimal variance (5%, 10%, 15%, and 20%). Hypothetical activity profiles were created using the activity categories from the National Hemophilia Foundation “Playing It Safe - Bleeding Disorders, Sports and Exercise” report (Anderson & Forsyth, 2017), where Type 1, 2, and 3 activities represent low risk of collisions, collisions might occur, and collisions will occur, respectively. The 6 profiles modeled were: Profile 1, Mon through Fri (M-F) Type 1 activity, Sat through Sun (Sat-Sun) Type 3; Profile 2, M-F Type 2, Sat-Sun Type 1; Profile 3, Mon through Sun (M-Sun) Type 2; Profile 4, M-F Type 3, Sat-Sun Type 1; Profile 5, M-F Type 1, Sat-Sun Type 2; and Profile 6, M-F no activity, Sat-Sun Type 1. Bleeding risk by activity category and FVIII level at the time of activity was estimated using odds ratios from Broderick et al. (JAMA 2012). For each regimen, the infusion schedule with the lowest bleeding risk for the activity profile was used. The model assumed each activity occurred 30 min after infusion time for SHL-rFVIII or EHL-rFVIII, but not for baseline FVIII scenarios. Relative bleeding risks were compared between regimens.Results: Patients with activity Profile 1, 5, and 6 would be best protected with EHL-rFVIII 2x/week, those with activity Profile 2 and 4 would be best protected with SHL-rFVIII 3x/week, and those with activity Profile 3 would be best protected with SHL-rFVIII EOD (Table). Although some regimens were associated with an only slightly higher risk (2-9%) of bleeding, others imposed a moderately increased risk (12-66%), and baseline FVIII activity levels conferred a higher bleed risk (48-210%) in each of the 6 activity profile types, compared with the most protective regimen.Conclusion: Considering estimated bleeding risks and predicted FVIII levels for different patient physical activity profiles, this model suggests that tailored dosing regimens with SHL-rFVIII or EHL-rFVIIII can offer a reduced relative bleeding risk during activities versus a baseline FVIII activity level with minimal variance. This highlights the importance of FVIII peaks to ensure optimal protection levels during activity. Personalized treatment using different products and regimens that take into account the patient's level of physical activity may help to optimize protection from bleeding. Further study of bleed-event rates during different physical activities would be of value for the hemophilia community. [Display omitted] DisclosuresWatt:Shire: Employment, Equity Ownership. Epstein:Stratevi: Employment, Equity Ownership. Xuan:Stratevi: Employment.

Polyethylene Glycol Exposure with Antihemophilic Factor (Recombinant), PEGylated (rurioctocog alfa pegol) and Other Therapies Indicated for the Pediatric Population: History and Safety

Polyethylene glycol (PEG) is an inert, water soluble polymer, used for decades in pharmaceuticals. Although PEG is considered safe, concerns persist about the potential adverse effects of long-term exposure to PEG-containing therapies, specifically in children, following the introduction of PEGylated recombinant factor products used for the treatment of hemophilia. Given the absence of long-term surveillance data, and to evaluate the potential risk, we estimated PEG exposure in the pediatric population receiving PEGylated therapies with pediatric indications administered intravenously or intramuscularly. We used a range of pediatric weights and doses based on prescribing information (PI) or treatment guidelines. PIs and reporting websites were searched for information about adverse events (AEs). For a child weighing 50 kg on the highest prophylactic dose of a FVIII product, the range of total PEG exposure was 40–21,840 mg/year; for factor IX (FIX) products, the range was 13–1342 mg/year; and for other products, the range was 383–26,743 mg/year, primarily as a derivative excipient. No AE patterns attributable to PEG were found for any of these products, including potential renal, neurological, or hepatic AEs. Our analyses suggest the pediatric population has had substantial exposure to PEG for several decades, with no evidence of adverse consequences.

Inhibitor development, safety, and efficacy of Advate® in previously untreated patients with hemophilia A in a postmarketing surveillance in Japan.

Rurioctocog alfa (recombinant Factor VIII: AdvateⓇ) is available for the control of bleeding in patients with hemophilia A in Japan. To evaluate the immunogenicity, safety, and efficacy of prophylactic and on-demand use of rurioctocog alfa, postmarketing surveillance was conducted on 114 previously untreated Japanese patients aged 0-82years with ≤ 3 exposure days under the conditions of routine clinical practice. A post-hoc comparison of mean annualized bleeding rates between patients in the regular prophylaxis group (7.4 bleeds/year) and in the on-demand treatment group (15.7 bleeds/year) using a negative binomial model found a statistically significant difference (P = 0.0164) in the subset of patients with severe hemophilia A. Favorable prophylactic and on-demand hemostatic efficacy ("excellent" or "good") was shown in 71.4-88.5% across all treatment regimens. A total of 31 events of adverse drug reactions were reported. Of 114 patients, 21 (18.4%) developed de novo FVIII inhibitor; of these, 17 occurred within 50 exposures. One death was reported. A family history of positive inhibitors was significantly associated with inhibitor development (Fisher exact P value = 0.0004); no other risk factors were identified. Rurioctocog alfa was found to be well-tolerated and effective in previously untreated Japanese patients with hemophilia A in this postmarketing surveillance of routine clinical practice.

Drugs and their names

Over recent years, drug names have become more complex and difficult to pronounce (e.g. axicabtagene ciloleucel, ▼rurioctocog alfa pegol, ▼riociguat ).1,2 Although some rules underpin drug nomenclature, there are several...

Immunogenicity of BAX 855 in Previously Treated Patients with Congenital Severe Hemophilia Α

Background and objectivesBAX 855 (Antihemophilic Factor [Recombinant] pegylated, rurioctocog alfa pegol) is an extended half-life (EHL) recombinant human coagulation factor VIII (rFVIII) modified with polyethylene glycol (PEG) (Turecek et al., 2012). It was recently approved in the US and Japan for on-demand treatment of bleeding events and for prophylactic treatment for patients with congenital severe hemophilia A.The efficacy and safety of BAX 855 were extensively studied during clinical development of this compound (Konkle et al., 2015). The assessment of BAX855 immunogenicity was of particular interest because the development of neutralizing antibodies (FVIII inhibitors) is the most serious complication following replacement therapies with FVIII products. FVIII inhibitors develop in about 20-32% of previously untreated patients (Gouw SC et al., 2013) and with a rate of 1.55- 3.8 per 1000 patients per year in previously treated patients (Kempton CL, 2010) with severe hemophilia A. To fully understand the potential of BAX855 to induce antibody responses, both FVIII inhibitors and total FVIII-binding antibodies were assessed. Furthermore, potential antibody development against PEG-FVIII, PEG and CHO proteins was investigated.MethodsThe clinical protocols (ClinicalTrials.gov identifier: NCT02585960, NCT02210091, NCT01736475, NCT01913405, NCT01945593, NCT01599819, NCT02615691) and the methods used for antibody analytics (Whelan et al 2013; Lubich et al 2016) were previously described. ELISA technologies were used for the analysis of total binding antibodies, the Nijmegen modification of the Bethesda assay was used for the detection of FVIII inhibitors. Correlation analyses were done to assess any potential correlation between the development of antibodies and potential adverse events.ResultsNone of the 243 subjects (6 PUPs and 237 PTPs) included in the analysis developed FVIII inhibitors (≥ 0.6 BU/mL) A total of 44 subjects tested positive for binding antibodies against FVIII, PEG-FVIII or PEG at single time points. 28 of these 44 subjects showed pre-existing antibodies against FVIII, PEG-FVIII, or PEG prior to first exposure to BAX 855, which disappeared during the study. 13 subjects who tested negative at screening developed transient antibodies against FVIII, PEG-FVIII, or PEG at one or two consecutive study visits after exposure to BAX 855. Antibodies were transient and not detectable at subsequent visits or at completion of the study. Five subjects showed positive results for binding antibodies at study completion or at the time of the data cutoff. No conclusion can be drawn whether these antibodies are of transient or persistent nature. There was no confirmed causal relationship between the appearance of binding antibodies against FVIII, PEG or PEG-FVIII and adverse events, nor was there an impact on hemostatic efficacy in any of the 44subjects. No subject had pre-existing antibodies or developed de novo antibodies to CHO proteins during the study at any time point.ConclusionOur data indicate that BAX855 did not show an increased risk for PTPs to develop FVIII inhibitors. We did not see any FVIII inhibitor development in PUPs, but the small number of overall exposures does not allow general conclusions for PUPs. Importantly, the data suggest that BAX855 did not induce immune responses associated with impaired treatment efficacy or with altered PK parameters. DisclosuresHorling:Shire: Employment. Allacher:IMC Krems: Research Funding. Koppensteiner:Shire: Employment. Engl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Scheiflinger:Shire: Employment, Research Funding. Abbuehl:Baxalta (now part of Shire): Employment. Reipert:Shire: Employment.

Retrospective analysis of in vivo recovery and clearance during continuous infusion of recombinant factor VIII products: a single-institution study.

Continuous infusion (CI) of recombinant FVIII (rFVIII) concentrates has been reported as an effective and safe method to achieve haemostasis during major surgeries or severe bleeding events. For more effective and safer CI, better understanding of in vivo recovery (IVR) and clearance (CL) issues is imperative. We investigated the following factors affecting IVR and CL using univariate and multivariate regression analyses during 47 CIs in 34 patients: rFVIII concentrate type, haemophilia severity, blood type, the presence of hepatitis C virus (HCV) or human immunodeficiency virus (HIV), age and body mass index (BMI). The mean IVR was 1.64 ± 0.49 IU dL-1 per IU kg-1 , and the mean CL during CI was 3.56 ± 1.57 mL h-1 kg-1 . The univariate and multivariate regression analyses showed that the CL of octocog alfa was significantly lower than that of rurioctocog alfa (P = 0.043 and 0.0034, respectively). There was a significant difference in BMI in the univariate and multivariate regression analyses (P = 0.0403 and 0.0376, respectively). This study indicated that CL during CI was potentially affected by the type of rFVIII concentrate used and BMI.