Turoctocog Research Articles

Real-world insights into the management of hemophilia A in Italy: treatment patterns and healthcare resource utilization

PurposeThis real-world analysis described the Hemophilia A (HA) population in Italy, evaluating drug utilization and consumption of factor VIII (FVIII) products of patients under prophylaxis and on-demand therapy.MethodsFrom Jan-2017 to Jun-2022, male patients with HA were identified through prescriptions of FVIII products [extended half-life FVIII, standard half-life recombinant FVIII, and plasma-derived FVIII (EHL FVIII, SHL rFVIII, and pdFVIII, respectively)], or emicizumab or FVIII plus von Willebrand factor or HA-related hospitalization using administrative flows of Italian healthcare entities. Patients on treatment with FVIII products during 2021–2022 were stratified by treatment regimen (prophylaxis/on-demand). The mean annual consumption expressed in International Units (IU) of EHL FVIII and SHL FVIII in patients treated during 2021–2022 having at least 12-month follow-up were assessed.ResultsAmong included HA patients, 145 (39.5%) received EHL FVIII and 222 (60.5%) SHL FVIII. Of 165 patients on prophylaxis, 105 (64%) received an EHL FVIII and 60 (36%) an SHL FVIII. The mean annual consumption of FVIII was 336,700 IU (median 319,000 IU) for EHL FVIII and 440,267 IU (median 360,500 IU) for SHL FVIII. Specifically, for patients on EHL FVIII, the most common drugs were efmoroctocog alfa (N = 51) and damoctocog alfa pegol (N = 50), followed by turoctocog alfa pegol (N = 25) and rurioctocog alfa pegol (N = 19). Of 702 HA patients initially treated with FVIII products, 74 (10.5%) switched to emicizumab during follow-up.ConclusionThese findings revealed an extensive use of EHL FVIII products, suggesting growing efforts from clinicians to optimize prophylactic strategies and achieve better bleeding protection.

Tailored therapy with turoctocog alfa pegol according to patient’s lifestyle and hemorrhagic phenotype: from clinical trial to real-life

Although the use of prophylaxis regimens with prolonged half-life factors is now widespread in the world of hemophilia A, there is a lack of real-life evidence on the impact of these products on joint health, adherence, and quality of life of patients. Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half-life (EHL), developed for prophylaxis, treatment of bleeds, and perioperative management in patients with hemophilia A. We report here on three cases of three patients affected by severe hemophilia A, with variable bleeding phenotype and lifestyle, to describe our clinical practice on prophylaxis with turoctocog alfa pegol. As confirmed in our cases, FVIII trough levels remained coherent with those experienced in the registration trial after the switch to the commercial EHL drug. Moreover, the cases highlight how the current clinical management of hemophilia can personalize treatment in several specific conditions.

Real-world long-term safety and effectiveness of turoctocog alfa in the treatment of haemophilia A in Japan: results from a multicentre, non-interventional, post-marketing study

ABSTRACT Objectives To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan. Methods This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period. Results The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69–10.38). The mean (SD) total consumption of turoctocog alfa (n = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis. Discussion The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens. Conclusion Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan.

Real-World Experience of People with Hemophilia A Receiving Turoctocog Alfa Pegol (N8-GP): Results from a Patient Experience Survey.

Turoctocog alfa pegol (N8-GP) is an extended half-life recombinant factor VIII molecule used for the treatment of hemophilia A (HA). The purpose of this study was to investigate real-world experiences of patients with HA treated with N8-GP. A 25-minute online survey was completed by adults (≥18 years) and caregivers of adolescents (12-16 years) with HA receiving N8-GP across six countries (Germany, Italy, Portugal, Spain, UK and US). Patients were recruited using a multichannel approach through recruitment panels, referrals from healthcare professionals and patient associations. The survey comprised a questionnaire with metrics including satisfaction and preferences for N8-GP, quality of life (QoL) and long-term impact. A total of 62 participants (98% male [n=61], mean age 29 years) comprising 46 patients and 16 caregivers completed the survey. Patients (60% non-severe [n=37] and 40% severe [25]) were on N8-GP for a mean period of 1.4 years. Patients expressed satisfaction (95%vs 42%, p<0.001) and preference (91% vs 9%, p<0.001) for N8-GP vs their previous treatments. Most patients with severe HA (87%, p=0.038) and patients on prophylaxis (84%, p<0.001) stated lower frequency of injections as their main reason for satisfaction, while improved QoL drove satisfaction for non-severe patients (81%, p=0.053). Overall, patients perceived that QoL score improved (74.8 vs 65.9, p=0.01) with N8-GP treatment compared with previous treatments. Flexibility to store at room temperature was one of the key convenience factors driving satisfaction. Patients believed that N8-GP can offer a long-term impact in areas such as ability to perform day-to-day activities (68%), independence to live like a person without hemophilia (63%), ability to travel (60%) with a feeling of optimism and hopefulness (82%). Lower frequency of injections, storage flexibility and improved QoL drove satisfaction and preference for N8-GP over previous treatments among patients with HA.

PB1261 Matching Adjusted Indirect Comparisons Between Personalized Prophylaxis with Simoctocog Alfa versus Standard Prophylaxis with Turoctocog Alfa in Adults with Severe Hemophilia A

PB1261 Matching Adjusted Indirect Comparisons Between Personalized Prophylaxis with Simoctocog Alfa versus Standard Prophylaxis with Turoctocog Alfa in Adults with Severe Hemophilia A

Cases of less-than-expected FVIII activity in previously treated patients during post-marketing surveillance of N8-GP.

Turoctocog alfa pegol (N8-GP) is a glycoPEGylated, extended half-life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019,>800 patients have been treated worldwide. To present data from identified post-marketing cases of less-than-expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8-GP. The post-marketing safety database was searched using keywords such as 'coagulation FVIII level decreased'. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded. Here we report 14 cases of less-than-expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post-dose) to 51% (2 days post-dose). Seven patients experienced bleeding episodes after switching to N8-GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti-PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product. In conclusion, the 14 reported cases of less-than-expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti-PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8-GP continues.

The immunogenicity, safety, and efficacy of N8-GP in previously untreated patients with severe hemophilia A: pathfinder6 end-of-trial results

BackgroundThe pathfinder6 (NCT02137850) international phase 3 trial examined immunogenicity, safety, and efficacy of the extended half-life factor VIII (FVIII) replacement product N8-GP (turoctocog alfa pegol; Esperoct) in previously untreated patients (PUPs) with hemophilia A. ObjectivesWe present end-of trial results for extended PUP N8-GP treatment for up to a median (range) 2.5 (0.0; 7.4) years. Patients/MethodsLonger-term N8-GP treatment in PUPs with hemophilia A was examined. The prophylaxis regimen was ∼60 IU/kg N8-GP i.v. twice weekly, or every 3 or 7 days. The primary endpoint was the incidence of FVIII inhibitors. ResultsOverall, 81 patients received N8-GP and were included in this analysis. The inhibitor incidence was 30.0% (15.7% high-titer [>5 BU]) for the extension phase. Patients had a median (range) 2.9 (0.1; 7.2) years of prophylaxis following the pre-prophylaxis period. During prophylaxis, the median annualized bleeding rate (ABR) (interquartile range) was 1.4 (0.6; 3.5), 13% of patients experienced no bleeding episodes, and 55.1% of patients experienced no spontaneous bleeds. The proportion of patients without any spontaneous bleeding episodes increased after the first year of prophylaxis. The hemostatic success rate in the treatment of bleeding episodes was 87.6%. No additional safety concerns were observed in patients with previously reported observation of temporarily decreased incremental recovery (IR). ConclusionLong-term end-of-trial PUP N8-GP prophylaxis data indicate that PUPs respond well to long-term N8-GP treatment. The inhibitor incidence was consistent with previous results. Median ABR during prophylaxis was 1.4. There were no lasting clinical impacts or safety concerns for patients with an observation of temporarily decreased IR.

Measurement of extended half-life recombinant FVIII molecules: In vitro and ex vivo evidence of relevant assay discrepancies

BackgroundExtended half-life recombinant FVIII products (EHL-rFVIIIs) have been engineered to improve the pharmacokinetic profile of FVIII, enabling better hemostatic protection with a reduced number of injections in persons with hemophilia. Previous studies showed several discrepancies in FVIII activity (FVIII:C) measurements for EHL-rFVIIIs comparing one-stage clotting assay (OSA) and chromogenic assay (CSA), although a systematic investigation of this phenomenon is still lacking. ObjectiveEvaluation of the accuracy and precision of measurement of all available EHL-rFVIIIs with 5 different assays both in vitro and ex vivo. MethodsDamoctocog alfa pegol, rurioctocog alfa pegol, turoctocog alfa pegol, and efmoroctocog alfa were tested with 3 OSA types: (1) aPTT-based commercial reagents with colloidal silica (Synthasil, Werfen-IL); (2) ellagic acid, Synthafax (Werfen-IL); and (3) OSA calibrated with each EHL-rFVIII product and colloidal silica. Measurements were also carried out with 2 different commercially available CSA reagents (Coamatic Factor VIII, Chromogenix-Werfen) and Trinichrom FVIII (Tcoag-Stago). A Bland–Altman analysis was performed to compare all assays. ResultsThe simple OSA showed significant discrepancies between the expected and measured EHL-rFVIII concentrations as CSA methods, whereas the calibrated OSA assay was accurate and precise in determining the activity of all EHL-rFVIIIs in the in vitro setting. Comparable results were found using ex vivo plasma samples. ConclusionIn this study, only OSA with a calibration curve constructed with each EHL-rFVIII product showed acceptable accuracy and precision in EHL-rFVIIIs measurements.

PCR242 Understanding the Real-World Experience of People With Haemophilia A Receiving Turoctocog Alfa Pegol (N8-GP): Results From a Patient Experience Survey

Turoctocog alfa pegol (N8-GP) is an extended half-life factor VIII molecule for use in adults and children with haemophilia A (HA) for routine prophylaxis, on-demand treatment including control of bleeding episodes, and perioperative management. This study aims to understand the real-world experience of patients with HA receiving N8-GP.

EE38 Cost-Minimization Analysis of Damoctocog Alfa Pegol With the Treatment of Hemophilia A in Turkey

To compare the lifetime consumption and cost of an extended-half liferecombinant factor VIII (rFVIII), the damoctocog alfa pegol, with reimbursed standard half life (SHL) factors (octocog alfa, moroctocog alfa, turoctocog alfa) for the treatment of haemophilia A (HemA) in patients with age ≥ 12 years in Turkey, from the public payer perspective.

Markedly Reduced FVIII Recovery Associated with Anti-FVIII Peg Antibodies after BNT162b2 Sars-Cov-2 Vaccination

Background The covalent link of polyethylene glycol (PEG) chains to recombinant factor VIII (FVIII) molecule is one of the most established approaches to produce novel therapeutic FVIII products with extended half-life (EHL). To date, three PEGyated-FVIII molecules, rurioctocog alfa pegol, turoctocog alfa pegol, and damoctocog alfa pegol are available for treatment of hemophilia A patients. From the pivotal clinical studies data, they showed comparable safety profile and pharmacokinetic with a mean half-live 1.3-1.7 times longer than the standard non-PEGylated FVIII. Although the PEG polymer is considered non immunogenic, antibodies against PEG, called pre-existing anti-PEG antibodies (APAs), have been reported in persons never treated with PEGylated drugs owing to PEG exposure during the activities of daily living. These antibodies can impact the clinical efficacy of PEGylated drug therapies by accelerating the blood clearance and changing pharmacokinetic. Recently, small amounts of PEG are also included in the lipid nanoparticles of the mRNA SARS-Cov-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). Aim To describe a poor plasma FVIII recovery after the first infusion of a PEGylated FVIII product in two male patients with severe hemophilia A without inhibitor at about one month from the second dose of the BNT162b2 SARS-Cov-2 vaccination. Method About two months after the first dose of the SARS-Cov-2 vaccine and one month after the second, before switching from a standard half-life to a PEGylated FVIII product, patients underwent a PK study by infusion of 50 IU/kg of turoctocog alfa pegol (patient 1) or damoctocog alfa pegol (patient 2). FVIII activity was measured by Chromogenix Coamatic FVIII (Werfen) in plasma samples collected before and after the PEGylated FVIII infusion. Anti-PEGylated FVIII antibodies were searched by means of a home-made ELISA in plasma samples collected before administration of SARS-Cov-2 vaccine and at PK study. The assay was performed by using as capturing substrates each of the licensed PEGylated FVIII product (rurioctocog alfa pegol, turoctocog alfa pegol, and damoctocog alfa). Moreover, a non-PEGylated standard FVIII (Advate®) was employed as control substrate. Results FVIII coagulant activity measured after the infusion of 50 IU/kg of the PEGylated FVIII product showed a very low plasma recovery, 5% for patient 1 and 4% for patient 2. Anti-PEGylated FVIII antibodies reacting with each PEGylated FVIII products were found in plasma samples collected at PK baseline and after FVIII infusion but not in a sample obtained before the SARS-Cov-2 vaccination. No reactivity was found in vitro against the non-PEGylated standard FVIII product (figure). Conclusions Our finding of antibodies reacting with the PEGylated part of the FVIII molecule induced or boosted by BNT162b2 SARS-Cov-2 vaccination supports the view that the administration of the mRNA vaccine could impair plasma FVIII recovery after infusion of a PEGylated product. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hemorrhagic and Thrombotic Adverse Events Associated with Emicizumab and Extended Half-Life FVIII Replacement Drugs in Patients with Hemophilia a: Data from the Eudravigilance Database

Introduction Safety evaluation of novel drugs for treatment of hemophilia A is challenging due to the small number of patients involved in clinical trials. Concerns of increased risk of thrombotic complications against bleeding in patients with hemophilia A have been discussed, particularly with non-replacement treatment and concomitant bypassing agents. Surveillance with Roche Global Database reporting adverse events in emicizumab has been discontinued on May 2021 and reporting was transferred directly to regulators. Aim To evaluate the reporting rate for hemorrhagic and thrombotic adverse drug reactions (ADR) with non-replacement (emicizumab) and replacement extended half-life (EHL) FVIII products as retrieved from the EudraVigilance database during the post-marketing surveillance phase. Methods Total ADR reported during treatment with emicizumab or with EHL FVIII products (rurioctocog alfa pegol, efmoroctocog alfaturoctocog alfa pegol and danoctocog alfa pegol) retrieved from January 1st to December 31st, 2021 from EudraVigilance database were collected. The proportional reporting ratios (PRR), i.e., the ratio of the proportion of all reported cases of event of interest among people exposed to a particular drug compared with the corresponding proportion among people exposed to other drugs was calculated. Moreover, the reporting odds ratio (ROR), i.e,. a derived as a case-control measure where cases of interest such as hemorrhagic or thrombotic ADR represent the case series and the remaining ADR represent the control series, with their relative 95% confidence intervals (CI) was also calculated to express the hemorrhagic and thrombotic ADR reporting frequency ratio between emicizumab and EHL-FVIII products. Results We retrieved from the EudraVigilance surveillance database 406 ADR for emicizumab and 376 for EHL FVIII products. Overall, 232 and 275 hemorrhagic ADR were reported for emicizumab and for EHL FVIII products, respectively. Thrombotic ADR were 24 for emicizumab (i.e. 1 disseminated intravascular coagulation, 1 microangiopathy, 8 venous and 14 arterial thrombosis) and 9 for EHL FVIII products (i.e. 1 disseminated intravascular coagulation for danoctocog alfa pegol, 3 venous and 4 arterial thrombosis for efmoroctocog alfa and 1 arterial thrombosis for turoctocog alfa pegol).On the whole, about 25% of thrombotic ADR were reported in concomitance with eptacog alfa (activated). The reporting rates of hemorrhagic and thrombotic ADR are shown in the Table. The reporting odds of hemorrhagic ADR was smaller for emicizumab than for EHL FVIII products, with a ROR of 0.49 (95% CI 0.36-0.66). On the other hand, excluding 1 thrombotic microangiopathy and 2 disseminated intravascular coagulation events and including only thrombosis in large vessels, the reporting odds of thrombotic ADR was higher in emicizumab than in EHL products, with a ROR of 2,56 (95%CI 1,18-5,59). Conclusion In conclusion, the analysis of pharmacovigilance reports of 2021 detects a signal of increased reporting rate of thrombotic ADR in emicizumab (25% in association with eptacog alfa (activated) and 8% with FVIII) despite a lower reporting rate of hemorrhagic ADR when compared to what observed in EHL FVIII products. We maintain pharmacovigilance is pivotal in monitoring novel drugs in hemophilia. However, this signal requires further validation by mean of cohort studies to estimate the magnitude of the adverse effect minimizing possible. Moreover, the treatment benefit-risk balance should be personalized according to the different hemostatic power of replacement and non-replacement drugs alongside with the individual bleeding and thrombotic risk factors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

EE151 Cost Minimization Analysis Evaluating Turoctocog ALFA (NOVOEIGHT®) and Product X As Prophylaxis Treatment for Paediatric and Adult Patients with Severe Haemophilia a in China

Turoctocog Alfa (Novoeight®), a recombinant factor Ⅷ(rFⅧ), was approved in China in 2021. Product X is the most commonly used rFⅧ product among Chinese patients with haemophilia A. This study was to compare the annual cost between these two products as prophylaxis treatment for paediatric and adult patients with severe haemophilia A from the Chinese healthcare perspective.

Cost analysis comparison of rurioctocog alfa pegol compared to turoctocog alfa pegol in the prophylaxis of Haemophilia A in Italy

Background: Hemophilia-A is an X-linked genetic disorder arising from a mutation to the X chromosome and causing either a quantitative or qualitative deficiency in blood clotting factor-VIII (FVIII). Several recombinant extended half-life FVIII products (rFVIII-EHL) are in use in Italy for the treatment of hemophilia-A. Objective: To estimate the annual average cost of the prophylactic treatment of a patient with hemophilia-A in Italy with rurioctocog alfa pegol or turoctocog alfa pegol, with particular regard to potential dose adjustments as provided in the SPCs. Methods: The comparison between the two rFVIII-EHL, expressed in terms of average annual cost per patient treated, was conducted from the NHS perspective. The average annual consumption (IU/kg) of the two rFVIII-EHL was derived from the clinical trial of reference for in label prophylactic treatment. Adjustments of doses and administration intervals allowed in the SPCs were considered on the basis of the literature. The published ex-factory price considered for both rFVIII-EHL was € 0.72. A scenario analysis focused on possible dosing adjustments was conducted. Results: With regard to the average consumption associated with the posology in label, the average annual treatment cost is almost the same between the two rFVIII-EHL. Whereas taking into account the possible dose adjustments based on once-weekly administration, rurioctocog alfa pegol shows a considerably lower average annual treatment cost compared to turoctocog alfa pegol (– € 42,719). Conclusions: Rurioctocog alfa pegol would be the more sustainable option, based on the annual average cost, for the NHS in the prophylactic treatment of hemophilia-A.

Turoctocog alfa pegol (N8‐GP) in severe hemophilia A: Long‐term safety and efficacy in previously treated patients of all ages in the pathfinder8 study

BackgroundN8‐GP (turoctocog alfa pegol; Esperoct) is a glycoPEGylated human recombinant factor VIII (FVIII). ObjectivesPathfinder8 (NCT01480180) was a phase 3, multinational, open‐label, nonrandomized trial to investigate the long‐term safety and efficacy of N8‐GP in people of all ages with severe hemophilia A previously treated with N8‐GP. Patients/MethodPatients were recruited from the completed phase 3 pathfinder2 and pathfinder5 trials to receive intravenous N8‐GP prophylaxis for up to 104 weeks, administered every 7 days, twice weekly, or three times weekly. Primary and secondary end points were the number of adverse events (AEs) reported and efficacy of treatment, respectively. ResultsOverall, 160 patients were exposed to N8‐GP for a mean of 179 exposure days and 681 calendar days (≈1.9 years) per patient. In total, 119 patients experienced 510 AEs, corresponding to a rate of 1.71 AEs per patient‐year of exposure; 97.5% of AEs were mild or moderate in severity, and no AEs led to withdrawal. No patients developed FVIII inhibitors during the trial. The Poisson estimate of mean annualized bleeding rate for all bleeds (excluding surgery) and across all regimens was 1.10 (median, 0.00), and for spontaneous bleeds was 0.61 (median, 0.00). Most (55.6%) patients experienced no bleeds that required FVIII treatment (excluding perioperative bleeds). The estimated hemostatic success rate for the treatment of 322 bleeding episodes (excluding surgery) was 95.8%, including missing values as failure. ConclusionsLong‐term prophylactic use of N8‐GP appeared safe and efficacious across all age groups in people with severe hemophilia A previously treated with N8‐GP.

Zero incidence of factor VIII inhibitors and successful haemostatic response in previously factor VIII-treated patients with haemophilia A switching to turoctocog alfa in a noninterventional study.

IntroductionTuroctocog alfa (NovoEight®) is a B‐domain‐truncated recombinant factor VIII (FVIII) approved for patients with haemophilia A.AimTo investigate the long‐term safety and efficacy of turoctocog alfa in routine clinical practice.MethodsGuardian 5 was a prospective, multinational, non‐interventional, post‐authorisation safety study. Male previously treated patients (> 150 exposure days [EDs]) of any age with severe/moderately severe haemophilia A (FVIII ≤ 2%) and a negative inhibitor test prior to first dosing (independent of FVIII‐inhibitor history) were included to receive prophylaxis or on‐demand treatment. The primary endpoint was the proportion of patients developing FVIII inhibitors (≥.6 Bethesda Units [BU]) after baseline visit, measured as per routine practice of each study site during clinic visits. Secondary endpoints included haemostatic effect, annualised bleeding rate (ABR), and adverse reactions assessment. The study concluded when 50 patients reached 100 EDs/patient minimum.ResultsSeventy patients were screened and 68 exposed to turoctocog alfa; 63 (92.6%) were on prophylaxis and five received on‐demand treatment. Six (8.8%) patients reported a history of positive inhibitors. During the study, patients were exposed to turoctocog alfa for a mean (standard deviation) of 131.9 (99.0) days/patient. Fifty‐five of 58 patients who completed the study were tested for FVIII inhibitors; no positive tests were reported. Overall success rate of turoctocog alfa for treatment of bleeds was 87.3%. Among patients receiving prophylaxis, median (range) ABR was 1.97 (.0–25.5) bleeds/year; estimated ABR (negative binomial model) was 3.65 (95% confidence interval: 2.53–5.25).ConclusionTuroctocog alfa was safe and efficacious for haemophilia A treatment in routine clinical practice.

Indirect Treatment Comparison of Damoctocog Alfa Pegol versus Turoctocog Alfa Pegol as Prophylactic Treatment in Patients with Hemophilia A.

PurposeTo assess the efficacy and FVIII consumption of BAY 94-9027 versus N8-GP in prophylaxis in adolescent and adult patients with severe hemophilia A (HA).Patients and MethodsA systematic literature review was conducted to identify studies on the efficacy of BAY-94-9027 and N8-GP for prophylaxis in patients with HA aged ≥12 years without a history of inhibitors. Eight studies met systematic literature review inclusion criteria, but only data from PROTECT VIII on BAY 94-9027 and PATHFINDER 2 on N8-GP could be used for an indirect comparison. Matching-adjusted indirect comparison (MAIC) and simulated treatment comparison were performed.ResultsNo significant differences (unadjusted and adjusted) were observed in the mean annualized bleeding rate (ABR) for any bleed and proportion of patients with zero bleeds when comparing BAY 94-9027 to N8-GP. The adjusted treatment difference [incidence rate ratio (IRR)] in terms of ABR was 1.11 (95% CI, 0.85–1.44). The odds ratio (OR) of any bleed, measuring the relative effect of BAY 94-9027 versus N8-GP on the proportion of patients with zero bleeds, was 1.03 (95% CI, 0.60–1.77). FVIII consumption was significantly lower in BAY 94-9027 [mean adjusted difference=−1292.57 IU/kg/year (95% CI, ‒2152.44 to ‒432.70)]; a 26.7% reduction in consumption of BAY-94-9027. The results of the sensitivity analyses were similar to the main analysis for mean ABRs, percentages of patients with zero bleeds, and significant reduction in rFVIII consumption. For patients on BAY 94-9027 every-5-days and every-7-days, no differences versus every-4-days N8-GP were observed for the mean ABR for any bleed [IRR=0.90 (95% CI, 0.68‒1.20)] and proportion of patients with zero bleeds [OR=1.06 (95% CI, 0.56‒2.02)].ConclusionBAY 94-9027 prophylaxis demonstrated 26.7% lower annual consumption when compared to N8-GP with similar efficacy in terms of ABR and percentage of patients with zero bleeds.

Health-Related Quality of Life and Satisfaction of Children with Severe Hemophilia a Treated with Turoctocog Alfa Pegol (N8-GP)

Introduction:Hemophilia A is an inherited bleeding disorder characterized by deficiency of factor VIII resulting in recurrent and spontaneous musculoskeletal bleeding. Treatment-related challenges including development of inhibitors to FVIII, venous access problems, and pain at infusion site can impact a patient's quality of life and may subsequently affect patient satisfaction with treatment. Recent advances have extended the half-life of factor replacement therapy which can allow less frequent dosing. The health-related quality of life (HRQOL) and satisfaction with treatment are reported in children with severe hemophilia A who were treated with turoctocog alfa pegol, a novel recombinant FVIII product.Methods: Children with severe hemophilia A aged 0-12 years who participated in the single-arm phase III pathfinder™5 trial were included in this analysis. In the main phase of the trial, 68 children were treated using 60 IU/kg turoctocog alfa pegol IV twice weekly for 26 weeks. HRQOL was assessed by children and their parents using age-specific versions of the Hemophilia-Quality of Life questionnaire (HAEMO-QOL-I for ages 4-7 and HAEMO-QOL-II for ages 8-12). Satisfaction was assessed by parents using the Hemophilia Satisfaction questionnaire (HEMO-SAT). HAEMO-QOL and HEMO-SAT scores range from 0 to 100, with a lower score reflecting a better QOL or higher treatment satisfaction. Changes in the HAEMO-QOL and HEMO-SAT scores from baseline to the end of the main phase of the trial were assessed only for those individuals who completed the questionnaires at both time points.Results: Sixty-eight children participated in the trial (20 aged 0-3 years, 23 aged 4-7 years, 25 aged 8-12 years). Table 1 presents the change in scores of the individuals who completed the questionnaires at both time points in each age group. As reported by the children aged 4-7 and their parents, the mean HAEMO-QOL-I total score decreased (reflecting an improvement for the group) from baseline to end of the trial (29.6 to 22.3 for children; 31.2 to 20.5 for parents). Change in individual scores (N=7 children; N=14 for parents), reflected improvement of HRQOL in 6 out of the 8 domains and in the total score (mean change -14.0±13.9) for the children and in 7 out of the 8 domains and in the total score (mean change -11.5±12.8) for the parents. As reported by the children aged 8-12 and their parents, the mean HAEMO-QOL-II total score decreased (reflecting an improvement for the group) from baseline to end of the trial (21.7 to 17.9 for children; 29.2 to 20.4 for parents). Changes in individual scores (N=21 for children; N=21 for parents), reflected improvement of HRQOL in 8 out of the 10 domains and in the total score (mean change -3.6±9.2) for the children and in 9 out of the 10 domains and in the total score (mean change -8.6±10.0) for the parents. Parents reported low scores in all domains of the HEMO-SAT at both baseline (N=19 for aged 0-3 years, N=20 for aged 4-7 years, N=22 for aged 8-12 years) and end of main phase (N=16 for aged 0-3 years, N=18 for aged 4-7 years, N=21 for aged 8-12 years) indicating that they maintained a high level of satisfaction during the initial 26 weeks of treatment with turoctocog alfa pegol.Conclusions: Overall, children with severe hemophilia A who were treated with turoctocog alfa pegol consistently reported improvement in HRQOL and maintained a high level of satisfaction by the end of the 26-week main phase of the trial. [Display omitted] DisclosuresKearney:Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pham:Novo Nordisk: Consultancy. Adalsteinsson:Novo Nordisk: Employment. Landorph:Novo Nordisk: Employment. Raffini:CSL Behring: Consultancy; Genetech: Consultancy; Green Cross Inc: Consultancy; Bayer: Consultancy.

PRO32 Extended Half-Life (EHL) Recombinant Factor VIII (RFVIII) for the Treatment of Hemophilia a in Italy: Cost of Treatment Comparison

Several recombinant factors VIII (rFVIII) with extended half-life (EHL) have recently been approved in Italy. The present analysis aims to estimate the annual cost of treatment of the EHL rFVIIIs reimbursed in Italy. The perspective of the National Healthcare Service (NHS) was adopted. For each regimen, a literature review was conducted to find the latest available studies reporting the mean annual IU (international unit) consumption. From the calculation of the mean annual IU consumption, annual treatment costs were estimated by using the prices published in the Italian Official Journals and an average weight per patient of 70kg. Compared to turoctocog alfa and efmoroctocog alfa, rurioctocog alfa pegol is the drug associated with the lowest mean annual IU consumption: 4,343 IU for rurioctocog alfa pegol, 4,550 IU for turoctocog alfa and 4,878 IU for efmoroctocog alfa. This was translated into an annual cost per patient of about €219,000 for rurioctocog alfa pegol, €229,000 for turoctocog alfa and €246,000 for efmoroctocog alfa. The adoption of rurioctocog alfa pegol produces a predictable budget forecast, representing a sustainable option for the NHS, in addition to its effectiveness. Further analyses considering real world dosages are needed to confirm the findings of the present work.

Calibration–free concentration analysis for quantification of anti-drug specific antibodies in polyclonal positive control antibodies and in clinical samples

Highly sensitive assays for anti–drug antibodies (ADAs) are both a regulatory requirement and requisite for proper evaluation of the effects of immunogenicity on clinical efficacy and safety. Determination of ADA assay sensitivity depends on positive control antibodies to represent naturally occurring or treatment–induced ADA responses. An accurate determination of the proportion of drug–specific antibodies in these polyclonal positive control batches is critical for correct evaluation of assay sensitivity.Target purification of positive control antibodies is commonly applied but infers the risk to lose a proportion of the antibodies. This may lead to an incorrect estimate of the ADA assay sensitivity, especially if high–affinity antibodies are lost that may be representative of natural ADAs with clinical implication.The Surface Plasmon Resonance platform on the Biacore™ systems offers methods for real–time analysis of biomolecular interactions without introducing any modifications to the analysed material. Calibration–free concentration analysis (CFCA) is such an application for determination of the proportion of drug–specific antibodies, which allows direct determination of active antibody concentrations, as defined by the ligand, in a flow–based system.Here, we present a novel CFCA method for ADA quantification developed and validated using polyclonal positive control antibodies against endogenous human insulin, insulin degludec (Tresiba®) and turoctocog alfa (NovoEight®).We find that CFCA precisely and accurately measures concentrations of drug–specific IgG antibodies with a precision of ±10% and 90%–112% recovery of expected values of monoclonal positive control antibodies. Additionally, we have achieved a more accurate measure of the sensitivity of a cell–based bioassay for in vitro neutralising ADAs using the specific concentration determined with CFCA. Moreover, we effectively quantified serum anti–insulin antibodies in high–titre clinical samples from individuals with diabetes mellitus. This application extends the relevance of the CFCA technology to analysis of immunogenicity for accurate quantification of ADAs in both the polyclonal positive control and in clinical samples.