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PUPs B-LONG evaluated the safety and efficacy of recombinant factor IX Fc fusion protein (rFIXFc) in previously untreated patients (PUPs) with hemophilia B. In this open-label, phase 3 study, male PUPs (age 85%) bleeding episodes required only 1 infusion for bleed resolution. In this first study reporting results with rFIXFc in pediatric PUPs with hemophilia B, rFIXFc was well tolerated, with the adverse event profile as expected in a pediatric hemophilia population. rFIXFc was effective, both as prophylaxis and in the treatment of bleeding episodes. This trial was registered at www.clinicaltrials.gov as #NCT02234310.

Introduction: The recombinant factor FVIII Fc fusion protein (rFVIIIFc) is a first-in-class extended half-life FVIII product to treat patients with hemophilia A. The safety, efficacy and prolonged half-life of rFVIIIFc was demonstrated in the phase 3 studies A-LONG, Kids A-LONG and the extension study ASPIRE. Despite robust efficacy and safety data of rFVIIIFc therapy from clinical trials, evidence on the effectiveness of rFVIIIFc use in real-world remains scarce. Our analysis aimed at investigating the effectiveness of prophylactic rFVIIIFc treatment in routine clinical use in Germany. Material and Methods: Twenty-seven patients with severe hemophilia A, who switched from prophylaxis with conventional recombinant factor VIII (rFVIII) products to rFVIIIFc, were included. Annualized bleeding rates, factor consumption, number of injections and adherence to prophylaxis were compared. The retrospective period prior switching to rFVIIIFc was three years, while the mean follow-up period after switching to rFVIIIFc was 24.9 months. Results: Switching to rFVIIIFc led to a 33.7% reduction in mean annualized number of injections and a 18.3% reduction in mean annualized factor consumption while maintaining low bleeding rates. The mean annualized bleeding rate (ABR) was 2.5 and 1.7 for rFVIII and rFVIIIFc, respectively. The adherence improved from 87% to 94%. During the follow-up period eleven surgeries were performed; all with a hemostatic response rated as excellent. No FVIII inhibitor formation after switching to rFVIIIFc has been detected. Conclusion: Real-world treatment with rFVIIIFc was associated with substantial reductions in consumption and injection frequenies while maintaining low bleeding rates supporting safety and efficacy data from clinical trials.

Introduction In 2017, all people with severe haemophilia B (PWSHB) in Ireland switched from standard half-life (SHL) recombinant FIX (rFIX) to rFIX Fc fusion protein (rFIXFc) prophylaxis. Aims To evaluate prophylaxis regimens, bleeding rates and factor usage for two years of rFIXFc prophylaxis in a real-world setting. Methods Data collected retrospectively from electronic diaries and medical records of PWSHB for a two-year period on rFIXFc prophylaxis were compared with paired baseline data on SHL rFIX treatment. Results 28 PWSHB (≥18 years) were enrolled, and at switchover 79% were receiving prophylaxis and 21% episodic treatment with SHL rFIX. At 24 months following switchover, all remained on rFIXFc prophylaxis with reduced infusion frequency; median dose per infusion once weekly (55 IU/kg, 20/28), every 10 days (63 IU/kg, 2/28) or every 14 days (98 IU/kg, 6/28). Median annualised bleed rate improved significantly on rFIXFc prophylaxis (2.0 versus 3.3 on SHL FIX) (p = 0.01). Median FIX trough level with once-weekly infusions was 0.09 IU/ml (0.06-0.14 IU/ml). Management of bleeding episodes was similar with rFIXFc and SHL rFIX; one infusion was sufficient to treat 74% and 77% of bleeds, respectively, with similar total median treatment per bleeding episode. Factor consumption reduced by 28% with rFIXFc prophylaxis (57 IU/kg/week, range 40-86 IU/kg/week) compared with SHL rFIX (79 IU/kg/week, range 44-210 IU/kg/week) (p = 0.002). Conclusion This study provides important insights into real-world experience of switching to rFIXFc prophylaxis in an adult population, demonstrating high rates of prophylaxis, with reduced infusion frequency, bleeding and FIX consumption.

Objective: To evaluate the efficacy of recombinant factor VIII FC fusion protein in haemophilia A patientreceiving on demand treatment only. Study Design: Comparative cross sectional study. Place and Duration of Study: Department of Hematology, Armed Forces Institute of Pathology and PakistanHemophilia Welfare Society, Rawalpindi, from Jun to Dec 2017. Methodology: Eighty-nine male patients of Hemophilia A already receiving recombinant factor VIII (20-30 Units/kg) on demand, with no history of inhibitors were included in study. Patients were divided as per age into paediatric and adult group and also on the basis of their basal factor VIII levels into severe, moderate and mild groups. Same patients were switched to recombinant factor VIII FC fusion protein (20-30 Units/kg) and its efficacy was measured and compared with recombinant Factor VIII in terms of dose requirement, injections, bleeds in six month period, presence of inhibitors and side effects. Results: Eighty nine male patients were studied. There was significant reduction in dose from median value of5750 units for group I to 4000 units for group II. Number of bleed in six month period were reduced from 5.3 ingroup I to 4.5 in group II. Number of injections were reduced on average to 1-2 injection per bleed in group II. No inhibitors were detected in group II. Conclusion: rFVIII Fc fusion protein has prolong activity and results in reduction of total dose, number of bleed,dose per bleed and has reduced antigenecity.

Introduction In sub-Saharan Africa, access to clotting factor concentrates (CFCs) is often extremely limited and published data on people with haemophilia on prophylaxis are almost not existent. Aims and methods To assess the feasibility, barriers and outcomes of a low-dose and low-frequency prophylaxis with extended half-life (EHL) recombinant Fc fusion FVIII and FIX in Ivorian children on a two-year period in the setting of the World Federation of Hemophilia's (WFH) humanitarian aid programme. Results Twenty-five boys with haemophilia were included. Mean (SD) age at inclusion was 5.6 (2.5) years. The median [range] follow-up duration was 17 [11-24] months. Regimen of prophylaxis was 20 IU kg-1 1×/week in haemophilia A and every 10 days in haemophilia B. We observed a maximal reduction by 87.6% of the annual spontaneous joint bleeding rate and a slight decrease in the total HJHS scores (p = .047). Adherence problems related to parents' low education level and shortage in CFCs were the main issues to carry out the programme. Inhibitors occurred in 12.5%. Conclusion This study confirms the feasibility and efficacy of low-dose and low-frequency prophylaxis in young Ivorian children with haemophilia treated with EHL CFCs donated through the WFH humanitarian aid programme. This work also highlights the crucial role of adherence and the need for appropriate education to achieve prophylaxis. Finally, it reminds the paramount objective of achieving self-sufficient, sustainable and available haemophilia replacement therapy for all worldwide.

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.

Objectives: To study the pharmacokinetics, safety and immunogenicity of Recombinant Human Tumor Necrosis Factor-α Receptor II: IgG Fc Fusion Protein for Injection (QL0902) and evaluate the pharmaco...

Introduction The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half‐life treatment for severe haemophilia A were demonstrated in the Phase 3 A‐LONG and Kids A‐LONG studies. Eligible subjects who completed A‐LONG and Kids A‐LONG could enrol in ASPIRE (NCT01454739), an open‐label extension study. Aim To report the long‐term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. Methods Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. Results A total of 150 subjects from A‐LONG and 61 subjects from Kids A‐LONG enrolled in ASPIRE. Most subjects received the IP regimen (A‐LONG: n = 110; Kids A‐LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A‐LONG and Kids A‐LONG was 3.9 (0.1‐5.3) years and 3.2 (0.3‐3.9) years, respectively. No inhibitors were observed (0 per 1000 subject‐years; 95% confidence interval, 0‐5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was

To investigate the effectiveness of low dose secondary/tertiary prophylaxis in severe Hemophilia A children and determine improvements in their daily life. Thirty Hemophilia A children (≤ 12 y) with factor VIII

INTRODUCTION: Recurrent bleeding in severe haemophilia B causes painful hemarthroses and reduces capacity for physical activity. Recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis results in low annualised bleeding rates, with the potential to improve patients' health-related quality of life (HRQoL). AIM: To present a post hoc analysis of data from B-LONG describing change over time in patient-reported outcomes associated with pain and physical activity. METHODS: Patients (≥12 years) who received weekly dose-adjusted or interval-adjusted rFIXFc prophylaxis and completed the Haemophilia-Specific QoL questionnaire for adolescents (Haemo-QoL) or adults (Haem-A-QoL) at baseline (BL) and end of study (EoS). Individual level changes in items of the 'Physical Health' and 'Sports and Leisure' domains, categorised as 'never/rarely/seldom' or 'sometimes/often/all the time', were analysed using McNemar's test to compare distribution of responses at EoS versus BL. RESULTS: At EoS versus BL, a significantly greater proportion of patients did not experience painful swellings (64% vs. 44%; P = .004), painful joints (44% vs. 28%; P = .003) or pain when moving (54% vs. 41%; P = .026). Additionally, at EoS versus BL, patients were less likely to avoid participating in sports like football (30% vs. 8%; P = .002), avoid sports due to their haemophilia (47% vs. 27%; P = .007), or experience difficulty walking as far as they wanted (63% vs. 43%; P = .001). The proportion of patients who played sports as much as the general population was numerically increased (52% vs. 37%; P = .033) at EoS versus BL. CONCLUSION: Results of the analysis suggest that over time, rFIXFc prophylaxis is associated with significant improvements in pain and physical functioning. This contributes to previous evidence of overall HRQoL improvements in patients with haemophilia B treated with rFIXFc.

International audience; Background: Recombinant factor VIII Fc fusion protein (rFVIIIFc) is the first extended half-life (EHL) recombinant clotting factor with marketing authorization; it has been available in France since October 2016. However, data and literature about rFVIIIFc in clinical practice are scarce.Objective: We propose a 1-year clinical and economic outcome evaluation in patients with hemophilia A taking into consideration treatment adherence.Patients and methods: We reviewed the diaries of all patients treated with rFVIIIFc at Marseille Hemophilia Center for 1 year. All the data were related to the patients' infusion (i.e., annual number of infusions, weekly dose/kg, and annual consumption) and bleeding reports. The clotting factor costs were considered, whereas additional costs (e.g., infusion devices and nurse intervention) were neglected.Results: A total of 34 patients were evaluated. Their median age was 18 years (IQR = 18). Treatment adherence was observed in 62% for FVIII and 66% for rFVIIIFc. The analysis revealed a negligible decrease in the annual clotting factor consumption following the switch (- 2%, p = 0.7339). These data were combined with a significant reduction in the annual number of infusion (- 22.5%, median = 138.5, IQR = 65.8 for FVIII; median = 105, IQR = 24 for rFVIIIFc, p < 0.0001) and bleeding (- 50%, median = 5, IQR = 7.5 for FVIII; median = 1, IQR = 4 for rFVIIIFc, p < 0.0001). With regard to the cost, a decreasing trend was observed (- 8%, p = 0.1300).Conclusion: The analysis in a real-life setting revealed that the input of switches toward rFVIIIFc in different treatment (age of patients and regimen) patterns seems to corroborate previous studies. The results suggest that switches have a beneficial effect in terms of efficacy, clotting factor consumption, and cost.

Introduction The one‐stage clotting assay is used to measure factor IX (FIX) activity in patients’ plasma samples and in FIX products for hemophilia treatment. However, the diversity of reagents and instruments has resulted in significant FIX assay variability. Methods The accuracy of the one‐stage clotting assay to measure recombinant FIX Fc fusion protein (rFIXFc) activity was evaluated by major Japanese hemophilia treatment centers and commercial laboratories that measure factor IX activity for a majority of hemophilia B patients in Japan. Plasma‐derived FIX (pdFIX) and recombinant FIX (rFIX) products were used as comparators. FIX‐deficient plasma was spiked with four levels of FIX products based on label potency and measured under blinded conditions by routine one‐stage clotting assay procedures in 19 participating laboratories. Interlaboratory coefficient of variation and spike recovery were calculated. Results Interlaboratory coefficient of variation of rFIXFc was not significantly different from that of rFIX, but appeared larger than that of pdFIX. Mean spike recovery for rFIXFc was generally comparable to rFIX and pdFIX. However, larger discrepancies between pdFIX and rFIX were observed in three of nine laboratories using ellagic acid‐based activated partial thromboplastin time reagents. Conclusion Recombinant FIX Fc fusion protein activity was found to be similar to that of rFIX or pdFIX by the one‐stage clotting assay. However, minimizing interlaboratory variability is vital for optimizing future patient care.

The goal of the Sexually Transmitted Infection Clinical Trial Group’s (STI-CTG) Antimicrobial Resistance (AMR) in Neisseria gonorrhoeae (NG) meeting was to assemble experts from academia, government, non-profit and industry to discuss the current state of research, gaps and challenges in research and technology as well as priorities and new directions to address the contsinued emergence of multi-drug resistant NG infections. Topics discussed at the meeting, that will be the focus of this article, include AMR NG global surveillance initiatives, the use of whole genome sequencing (WGS) and bioinformatics to understand mutations associated with AMR, mechanisms of AMR, and novel antibiotics, vaccines and other methods to treat AMR NG. Key points highlighted during the meeting include: (i) US and International surveillance programs to understand AMR in NG. (ii) The US National Strategy for combating antimicrobial resistant bacteria. (iii) Surveillance needs, challenges and novel technologies. (iv) Plasmid- and chromosomally-mediated mechanisms of AMR in NG, (v) Novel therapeutic (e.g., sialic acid analogs, FH/Fc fusion molecule, monoclonal antibodies, topoisomerase inhibitors, fluoroketolides, LpxC inhibitors) and preventative (e.g., peptide mimic) strategies to combat infection. The way forward will require renewed political will, new funding initiatives and collaborations across academic and commercial research and public health programs.

Recombinant factor VIII and factor IX Fc fusion proteins (rFVIIIFc and rFIXFc) were developed with an extended half-life (EHL) to improve the management of people with hemophilia A (PwHA) and B (PwHB), respectively. This survey gathered physician-reported treatment decisions and physician views on outcomes in PwHA or PwHB who switched to rFVIIIFc or rFIXFc in the 12 months prior to study completion. Physicians (N = 37) considered bleeds, pharmacokinetic parameters, joint health and adherence the most important factors to assess both in routine care and when deciding to switch to an EHL therapy. In the 12 months prior to study completion, 37 physicians switched 113 PwHA to rFVIIIFc and 25 physicians switched 36 PwHB to rFIXFc. Most PwH (>90%) had moderate or severe hemophilia and many (>60%) switched within 6 months of the survey. The main reason for switching PwHA to rFVIIIFc was to allow fewer injections (49%), while the main reason for switching PwHB to rFIXFc was the product becoming available for use (36%). Overall, 96% of PwHA and 89% of PwHB who were switched remained on these EHL products at the time of survey. Mean total weekly dose, injection frequency and annualized bleeding rate were reported to have reduced following switching. This survey provides valuable insight into reasons for, and challenges to, the use of EHL products in clinical practice. Physicians perceived that switching to treatment with rFVIIIFc or rFIXFc can improve quality of life, treatment burden, disease control and adherence.

Recombinant factor VIII Fc fusion protein (rFVIIIFc) has been indicated for adults and children with hemophilia A. The objective of this article was to build a population pharmacokinetic (PK) model using adult and pediatric data sets and explore relevant dosing scenarios across all ages. The activity-time profiles of rFVIIIFc from 3 clinical studies (all trials registered at https://www.clinicaltrials.gov: NCT01027377, NCT01181128, and NCT01458106) were characterized, and covariates that determine variability of rFVIIIFc PK in children and adults were identified and implemented. Data sets were pooled to estimate population PK parameters. Simulations were conducted to generate activity-time profiles at steady state (SS). The proportion of subjects maintaining SS trough1 and3 IU/dL and time10 IU/dL were estimated. The rFVIIIFc model was a two-compartment model that identified weight and von Willebrand factor as significant covariates. Model-predicted SS peaks and troughs of rFVIIIFc activity-time profiles confirmed the necessity of modifying dosing in pediatric subjects. The model also predicted that the average subject in the adult and adolescent group dosed with 40 IU/kg every 2 days maintained factor VIII activity10 IU/dL for the entire duration. Children aged6 years and aged 6 to12 years receiving this dose maintained factor VIII activity of10 IU/dL for nearly two-thirds and three-quarters of their time, respectively. In conclusion, these population PK analyses characterize activity-time profiles for rFVIIIFc among pediatric and adult subjects. The model was used for simulation of clinically relevant dosing scenarios, which can provide better protection and better clinical outcomes.

Prophylaxis with factor VIII (FVIII) is the current therapeutic approach for people with haemophilia A. However, standard half‐life (SHL) FVIII products must be injected frequently, imposing a substantial burden on the individual and making it difficult to tailor therapy according to patient need and lifestyle, which could impact adherence. Recombinant FVIII Fc fusion protein (rFVIIIFc; Elocta®, Sobi; Eloctate®, Sanofi) is a recombinant fusion protein that undergoes slower clearance from the body than SHL FVIII products. This pharmacokinetic property of rFVIIIFc allows prophylactic administration every 3‐5 days, or once weekly in selected patients, with doses adjusted to patient needs and clinical outcomes. Higher FVIII levels can be achieved maintaining dosing frequency similar to that usually applied with SHL FVIII. This review provides a summary of recent data from the A‐LONG, Kids A‐LONG, ASPIRE and PUPs A‐LONG studies and recently published real‐world experience relevant to rFVIIIFc use in individualised regimens. The review also introduces ongoing studies of rFVIIIFc, including its use for induction of immune tolerance, and discusses some aspects to consider when switching patients to rFVIIIFc and managing ongoing treatment. In summary, rFVIIIFc is suitable for individualised prophylaxis regimens that can be tailored according to patient clinical needs and lifestyle.

International audience; Introduction Recombinant factor IX Fc fusion protein (rFIXFc) has demonstrated efficacy for treatment of haemophilia B in the Phase 3 B-LONG and Kids B-LONG studies. However, long-term rFIXFc safety and efficacy data have not yet been reported.Aim To report long-term rFIXFc safety and efficacy in subjects with haemophilia B.Methods B-YOND (NCT01425723) was an open-label extension for eligibl previously treated subjects who completed B-LONG or Kids B-LONG. Subjects received >= 1 treatment regimen: weekly prophylaxis (WP), individualized interval prophylaxis (IP), modified prophylaxis or episodic treatment. Subjects could switch regimens at any time. The primary endpoint was inhibitor development.Results Ninety-three subjects from B-LONG and 27 from Kids B-LONG (aged 3-63 years) were enrolled. Most subjects received WP (B-LONG: n = 51; Kids B-LONG: n = 23). For subjects from B-LONG, median (range) treatment duration was 4.0 (0.3-5.4) years and median (range) number of exposure days (EDs) was 146 (8-462) EDs. Corresponding values for paediatric subjects were 2.6 (0.2-3.9) years and 132 (50-256) EDs. No inhibitors were observed (0 per 1000 subject-years; 95% confidence interval, 0-8.9) and the overall rFIXFc safety profile was consistent with prior studies. Annualized bleed rates remained low and extended-dosing intervals were maintained for most subjects. Median dosing interval for the IP group was approximately 14 days for adults and adolescents (n = 31) and 10 days for paediatric subjects (n = 5).Conclusions B-YOND results confirm the long-term (up to 5 years, with cumulative duration up to 6.5 years) well-characterized safety and efficacy of rFIXFc treatment for haemophilia B.

Only a few studies on real-world clinical use of recombinant factor VIII -fusionned with Fc (rFVIIIFc, efmoroctocog alpha) have been performed to date, with data on the annual bleeding rate (ABR), the prophylaxis regimen, and FVIII consumption. The aim of our study was to report the real-world clinical application of rFVIIIFc with additional elements, both biological and clinical. A prospective monocentric study has been conducted in the Haemophilia treatment center (HTC) of the Strasbourg university hospital among the severe haemophilia A patients. Thirty male patients were enrolled in the study. After injection of rFVIIIFc, the average time spent above 5%, 2% and 1% of FVIII was respectively almost 3, 4 and 5 days. The average half-life was 15.8 hours. A strong linear correlation between incremental recovery of rFVIIIFc and weight and between rFVIIIFc half-life and basal VWF:Ag level was observed. FVIII activity measurement for rFVIIIFc showed similar results than those previously published. In the follow-up, residual FVIII activity was on average the one of a mild haemophilia patient, corroborated by the results of endogenous thrombin potential of the thrombin generation assay. In clinical practice, rFVIIIFc was well tolerated and patients were mostly satisfied or indifferent of the switch. A single failure was however noticed. No FVIII inhibitor has been detected. Decrease in FVIII consumption was observed, with reduced or unchanged ABR. The switch was an actual success for almost all of the 30 patients, corroborated by satisfactory clinical and biological results.

International audience; Introduction Recombinant factor IX Fc fusion protein (rFIXFc) is an extended half-life concentrate for the treatment of haemophilia B (HB). rFIXFc activity monitoring is crucial in several clinical situations. However, differences were observed between one-stage clotting (OSC) and chromogenic assays, but not for all factor IX (FIX) concentrations.Aims To compare rFIXFc measurements obtained using different instruments and common OSC and chromogenic asssays.Methods FIX:C measurements were performed in rFIXFc-spiked plasma aliquots (targeted FIX levels of 1.5, 1, 0.5, 0.2, 0.05, 0.02 and 0.01 IU/mL) and plasma samples collected from two patients with HB at various time points after rFIXFc infusion, using three instruments (STA-R MAX, ACLTOP700 and CS2100i) and common clotting and chromogenic FIX:C assays.Results The same reagent could give different FIX:C measurements when adapted to different instruments. Moreover, the same reagent/instrument combination could give different results depending of the FIX concentration. For OSC assays, only STA-Cephascreen on STA-R MAX and CS2100i, SynthAFax on ACLTOP 700 and Actin on CS2100i provided acceptable recoveries for all rFIXFc concentrations. The chromogenic assays ROX-FIX and Biophen FIX:C underestimated rFIXFc for concentrations lower than 0.05 and 0.2 IU/mL, respectively.Conclusions Our study demonstrates that the same reagent adapted to different instruments could lead to different rFIXFc values. As rFIXFc under/overestimation could be associated with inappropriate treatment or biased calculation of pharmacokinetic parameters, the reagent/instrument combination used by haemostasis laboratories should be considered and regularly evaluated by external quality assessment programmes.

Primary prophylaxis with FVIII is the therapeutic regimen of choice in severe hemophilia A; it reduces joint bleeding and associated chronic damage and helps prevent fatal bleeds. However, the high...

International audience; Although the primary reason for recombinant factor VIII Fc fusion protein (rFVIIIFc) development was to reduce treatment burden associated with routine prophylaxis, new evidence suggests additional benefits of Fc fusion technology in the treatment of people with haemophilia A. Preclinical research has been utilized to characterize the potential immunomodulatory properties of rFVIIIFc, including an ability to reduce inflammation and induce tolerance to factor VIII. This has since been expanded into clinical research in immune tolerance induction (ITI) with rFVIIIFc, results of which suggest the potential for rapid tolerization in first-time ITI patients and therapeutic benefit in patients undergoing rescue ITI. The potential for improved joint health through the anti-inflammatory properties of rFVIIIFc has also been suggested. In addition, a new avenue of research into the role of rFVIIIFc in promoting bone health in patients with haemophilia A, potentially through reduced osteoclast formation, has yielded encouraging results that support further study. This review summarizes the existing preclinical and clinical studies of immunomodulation and tolerization with rFVIIIFc, as well as studies in joint and bone health, to elucidate the potential benefits of rFVIIIFc in haemophilia A beyond the extension of factor VIII half-life.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action.

Introduction Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. Aim Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. Methods Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. Results Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. Conclusions Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.

Introduction Hemophilia A is a rare bleeding disorder characterized by coagulation Factor VIII (FVIII) deficiency. Symptoms are primarily bleeding episodes that occur spontaneously or following injury, trauma, or surgical procedure. The treatment for hemophilia A involves replacement of FVIII for on-demand or prophylactic care. The aim of this analysis was to describe treatment outcomes and patterns between patients with hemophilia A who switch to emicizumab (Hemlibra®), Fc fusion protein (rFVIIIFc; Eloctate®), or other factor therapy using specialty pharmacy data from the US. Methods This was a retrospective observational descriptive study conducted between November 2014 and January 2021 using specialty pharmacy data including over 5,000 total patients with hemophilia A in the US. Patients included in the analysis were male, had a diagnosis of hemophilia A without a history of inhibitors, and had a minimum of 6 months baseline pre-index data and 6 months follow-up data post-index. Index date was defined as the first dispense of emicizumab after October 2018 or rFVIIIFc after May 2015. Patient reported and claims-based treatment outcomes assessed pre- and post-treatment included: annualized bleeding rate (ABR, calculated from patient bleed logs), any factor usage including on-demand FVIII use, prescribed and dispensed dosage of treatment, and frequency. Wastage as a percentage was a calculated as: (prophylaxis logged - prophylaxis prescribed)/prophylaxis dispensed. Results 118 patients treated with emicizumab and 55 patients treated with rFVIIIFc were included in the analysis. Additionally, 26 patients switched from rFVIIIFc to emicizumab, and therefore met inclusion criteria for both treatment groups (these patients are described separately). Baseline characteristics are reported in Table 1; the majority of patients in all cohorts had severe hemophilia and prior prophylaxis therapy. The most frequently prescribed dosing patterns for patients in the emicizumab cohort was once every 2 weeks (Q2W) for 56 patients (47.5%) and once weekly (Q1W) for 51 patients (43.2%). Whereas the most frequently prescribed dosing patterns for the rFVIIIFc only cohort was twice per week (BIW) in 27 patients (49.1%), every 4 days (Q4D) in 15 patients (27.3%), and Q1W in 2 patients (3.6%). Total mean (95% confidence intervals [CI]) weekly prophylaxis consumption was 1.68 (1.65; 1.72) mg/kg in the emicizumab cohort and 83.17 (72.06; 94.29) IU/kg in the rFVIIIFc cohort post index. Mean (95% CI) weekly dispensed dosage for prophylaxis was 1.81 (1.76; 1.86) mg/kg emicizumab and 83.83 (72.55; 95.11) IU/kg rFVIIIFc post index. Mean (95% CI) total supplied FVIII for on-demand factor on hand was 5.14 (2.92; 7.35) IU/kg in the emicizumab cohort and 11.76 (9.06; 14.46) IU/kg in the rFVIIIFc cohort post index. Weekly percentage of supplied dosage wasted was 6.03% (4.50; 7.57; p Mean (95% CI) change in overall ABR pre- and post-treatment was -1.14 (-2.16; -0.18) in the rFVIIIFc cohort and -0.91 (-1.36; -0.50) in the emicizumab cohort (Table 2). Mean (95% CI) changes in spontaneous ABR and spontaneous joint ABR pre- and post-treatment were -0.36 (-1.12; 0.27) and -0.16 (-0.70; 0.31), respectively, in patients treated with rFVIIIFc, whereas within the emicizumab group they were -0.40 (-0.71; -0.13) and -0.37 (-0.66; -0.12). Conclusion Patients were prescribed emicizumab labeled dosing primarily on a Q1W or Q2W pattern, whereas patients prescribed rFVIIIFc had more individualized dosing primarily being prescribed Q4D or BIW. FVIII for on-demand treatment use was found post index in both the factor and non-factor treated cohorts. Overall product wastage with emicizumab is higher than previously reported. Product wastage was highest among emicizumab patients under 12 years, but wastage was still considerable in patients 12 or older. This descriptive analysis indicated that both treatments remained effective with lower bleed rates than prior FVIII therapies. Figure 1 Figure 1. Disclosures Cockerham: Sanofi: Current Employment, Current equity holder in publicly-traded company. Wilson: Sanofi: Current Employment, Current equity holder in publicly-traded company; Alexion: Current equity holder in publicly-traded company. Frick: Trio Health, Inc.: Current Employment; Sanofi S.A.: Research Funding. Dasmahapatra: Sanofi: Current Employment, Current equity holder in publicly-traded company.

Introduction Recombinant factor VIII (rFVIII) products with extended half-lives have the potential to improve adherence and outcomes in haemophilia beyond the results obtained with conventional rFVIII products. Aim In the absence of head-to-head comparisons, annualized bleed rates (ABRs) and weekly factor consumption with rFVIII Fc fusion protein (rFVIIIFc) and conventional rFVIII products were indirectly compared using studies of continuous prophylaxis. Methods A systematic literature review was conducted to identify studies of rFVIII products for comparison with rFVIIIFc in the continuous prophylactic treatment of previously treated adolescents and adults with moderate and severe haemophilia A. Mean ABRs were compared between rFVIIIFc and individual rFVIII studies and between rFVIIIFc and a pooled measure for rFVIII estimated by meta-analysis. Comparisons of factor consumption were based on mean or median weekly factor consumption. Results Results from seven studies of conventional rFVIII products (injections 2–4 times week−1) were compared with rFVIIIFc (injections 1.4–2.4 times week−1). The pooled mean ABR for rFVIII products was significantly higher compared with rFVIIIFc (difference = 2.0; P = 0.007). Compared with most rFVIII studies, the reported weekly factor consumption was lower with rFVIIIFc [mean differences = 15.5–21.8 IU kg−1 week−1 (17–26%); median differences = 12.7–29.8 IU kg−1 week−1 (16–37%)]. In one comparison, mean weekly factor consumption with rFVIII was significantly lower but mean ABR was significantly higher than rFVIIIFc. Conclusion Prophylaxis with rFVIIIFc may be associated with improved bleeding rates and lower weekly factor consumption than more frequently injected rFVIII products. Relative to rFVIII products with similar bleeding rates, results indicate that rFVIIIFc is associated with reduced weekly factor consumption while requiring fewer prescribed injections.

SummaryThe safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents ≥12 years) and Kids B-LONG (children Supplementary Material to this article is available online at www.thrombosis-online.com.

Introduction PBPK models incorporate complex drug and system (ie, physiology) information into a mathematical framework to support dose selection while considering various patient factors (eg, age, sex, and comorbidity). Through "predict-learn-confirm cycles," PBPK models enable dose prediction to optimize clinical study design. BIVV001 (rFVIIIFc-VWF-XTEN), a new class of FVIII replacement therapy designed to break the von Willebrand factor (VWF) half-life ceiling (Chhabra et al.Blood. 2020; Konkle et al.Blood. 2018), consists of a single recombinant FVIII fused to dimeric Fc (to permit recycling of BIVV001 by a naturally occurring pathway via Fc neonatal receptors [FcRn]), a VWF D′D3 domain, and two XTEN® polypeptides (XTEN® is a registered trademark of Amunix Pharmaceuticals, Inc.). In a Phase 1 study (Lissitchkov et al.Blood. 2019), four once-weekly BIVV001 50 IU/kg infusions provided high sustained FVIII activity with a mean half-life of 41.3 hours. We aimed to build and verify an initial PBPK model to characterize BIVV001 activity levels in adults with severe hemophilia A. Methods To our knowledge, this is the first time that a PBPK model has been studied in hemophilia. We assumed that the distribution of BIVV001 and recombinant FVIII Fc fusion protein (rFVIIIFc) (Eloctate®) involves the FcRn recycling pathway that is similar to monoclonal antibodies. First, to evaluate the feasibility of the modeling approach, we built a PBPK model (Simcyp, Sheffield, UK) that captured FcRn-dependent recycling of Fc fusion proteins. Model input parameters were adjusted to capture observed rFVIIIFc activity levels with a prediction error of Results To fit the BIVV001 data, the PBPK model input parameters, KD1, vascular reflection coefficient (σv), and Kup, were modified compared with those used for the rFVIIIFc PBPK model. The PBPK model captured observed BIVV001 exposure with a low prediction error ( Conclusions We have developed a PBPK model that accurately predicts the high sustained FVIII activity levels observed with BIVV001 exposure in adults with severe hemophilia A. The PBPK model framework can be a useful tool in the development of FVIII replacement therapies for hemophilia A. Disclosures Xia: Sanofi:Current Employment, Current equity holder in publicly-traded company.Katragadda:Sanofi:Current Employment, Current equity holder in publicly-traded company.Teutonico:Sanofi:Current Employment, Current equity holder in publicly-traded company.Macha:Sanofi:Current Employment, Current equity holder in publicly-traded company.Demissie:Sanofi:Current Employment, Current equity holder in publicly-traded company.Benson:Sanofi:Current Employment, Current equity holder in publicly-traded company.

Fc fusion proteins and Fc fusion peptides or peptibodies are chimeric molecules composed of an active pharmacological protein or peptide and the Fc fragment of an immunoglobulin. The primary aim of this drug construct is to prolong the half-life of the active component. This molecular architecture is seen in drugs, such as etanercept, romiplostim, and the recombinant factor VIII (efmoroctocog alfa). A considerable number of Fc fusion proteins and peptibodies are currently in pre-clinical and clinical development. The isolated effect of the Fc fragment has been studied intensively during last years, but is still poorly understood in the clinical setting and in relation with the active drug and underlying disease. In this short review, we will propose new hypotheses of possible immunomodulatory functions of the Fc fragment of romiplostim in patients with primary immune thrombocytopenia.

TPS3147 Background: Productive antitumor immune responses in nonclinical models depend on a type of dendritic cell (DC), conventional DC subtype 1 (cDC1), which in the context of cancer, primes tumor-reactive T cells through presentation of tumor-derived antigens. FMS-related tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that binds to and activates FLT3 on terminally differentiated DCs. Activated FLT3 promotes proliferation, inhibits cell death, and is required for the differentiation, expansion, and maintenance of DCs in peripheral and lymphoid organs. GS-3583 is a fusion protein composed of the extracellular domain of recombinant human FLT3L fused to an engineered fragment crystallizable (Fc) region of human immunoglobulin G4. GS-3583 has PK properties that support sustained cDC in patients and potential combination with established immunotherapies. This phase 1b, open-label, multicenter, dose-finding study will evaluate safety, tolerability, PK, and preliminary efficacy of GS-3583 monotherapy in patients with advanced solid tumors (NCT04747470). Methods: Approximately 33 adults aged ≥18 years with a histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor that is refractory to or intolerant of standard therapy or for which no standard therapy is available will be enrolled. The study employs a 3+3 dose escalation design in which GS-3583 is administered intravenously for up to 52 weeks or until progressive disease or unacceptable toxicity. Up to five dose escalation cohorts have been planned. The maximum tolerated dose is the highest dose with incidence of DLT in < 33% of 6 or more patients in the first 28 days of GS-3583 dosing; recommended phase 2 dose will be determined. Assessments include safety, PK, pharmacodynamics including cDCs, immunogenicity, and efficacy by RECIST 1.1 in CT/MRI imaging conducted every 8 weeks. Accrual at approximately 3-4 centers in the US is ongoing. Clinical trial information: NCT04747470.

5566 Background: AVB-500 is a first-in-class Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. Both GAS6 and AXL are highly expressed in high-grade serous ovarian cancer (HSGOC). This study evaluated safety, tolerability, and preliminary efficacy of AVB-500 in combination with pegylated liposomal doxorubicin (PLD) and paclitaxel (Pac) and determine the recommended Phase 2 dose (RP2D). Methods: Patients were enrolled in escalating dose cohorts of AVB-500 10mg/kg to 20mg/kg q2 weeks in combination with weekly Pac 80mg/m2 D1, 8, 15 q28 days or PLD 40mg/m2 D1 q28 days and assess for safety, pharmacokinetics, pharmacodynamics, and response by investigator, via RECIST v1.1. Results: A total of 53 patients with platinum-resistant HGSOC (PROC) were enrolled. A total of 23 patients received Pac + AVB-500 and 30 patients received PLD + AVB-500. Grade 3 or 4 treatment-related adverse events were observed in 4/23 (17%) and 2/30 (7%) PAC and PLD, respectively. No patients discontinued therapy due to an adverse event. Most events were related to known chemotherapy side effects. RP2D was identified as 15mg/kg. Confirmed overall response rate (ORR) with Pac+AVB-500 was 35% (8/23) including 2 CRs and 11% (3/28) in the PLD+AVB-500 subgroup. ORR was 19% (3/16) in patients with platinum free interval (PFI) of < 3 months versus (vs) 23% (8/35) in patients with PFI of 3-6 months. ORR was 11% (2/18) in patients with 1 prior treatment vs 27% (9/33) in patients with 2-3 prior lines of therapy. ORR in patients without prior bevacizumab was 33% (9/27) vs 8% (2/24) in those with prior bevacizumab. Patients treated with Pac combination and whose AVB-500 trough levels were above the minimal efficacious concentration (MEC) of 13.8mg/L achieved the greatest benefit with ORR, median PFS, and median OS of 43% (6/14), 3.9 months, and 17.8 months vs 22% (2/9), 2.8 months, and 8.7 months observed in those whose trough was below the MEC. Among the Pac treated subgroup, the ORR was 47% (13% CR) vs 0% for those with sAXL/GAS6 ratios > 0.773 compared to ratios 0.773. Conclusions: AVB-500 is a novel Fc fusion protein that binds the GAS6 ligand and inhibits AXL signaling. AVB-500 was well-tolerated in combination with Pac or PLD. This Ph1b trial suggested a higher ORR in the Pac treated subgroup, with C1D15 trough levels > 13.8mg/L (most consistently achieved at the 15mg/kg dose level). Exploratory analyses suggested that improved ORR may be observed in patients who have not been exposed to bevacizumab. The serum sAXL/GAS6 ratio may be a potential biomarker of pathway activation and identify patients who most benefit from Pac+AVB-500. The ORR in patients with PFI < 3 months or who had > 1 line of prior therapy were similar to those with 3-6 months PFI or ≤1 lines of therapy. Further development of AVB-500 15 mg/kg q2 weeks in combination with Pac is warranted in PROC. Clinical trial information: NCT03639246.

2559 Background: Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor specific CD8+ T cells and their recruitment to tumor microenvironment (TME). However, cDC1s are often underrepresented in the TME. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L), a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to expansion of cDC1s in the periphery which can then be recruited into the TME. We hypothesize that FLT3 pathway stimulation using GS-3583, a FLT3 agonist Fc fusion protein, has the potential to promote T cell mediated anti-tumor activity. Methods: This was a first-in-human placebo-controlled study of GS-3583 in healthy volunteers to evaluate the safety, PK, and PD of escalating single doses (ranging from 75μg to 2000μg) of GS-3583. The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8-12 healthy subjects who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in the phase 1 unit for 15 days and then for 12 weeks as outpatients. As part of the PD evaluation, we investigated the changes in the number of cDC1s and cDC subtype 2 (cDC2) cells. Results: As of 8th Feb 2021, selected safety, PK and PD data from the first 3 cohorts were available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have been no serious or grade 3 or higher adverse events. Preliminary PK analysis suggested dose-dependent increase in GS-3583 exposure (AUC and Cmax). Preliminary PD analysis shows that administration of GS-3583 resulted in dose-dependent increases in cDC1/cDC2 cells that peaked at day 5 or day 8 and returned to baseline within three weeks of drug administration. Conclusions: GS-3583 was safe and well tolerated and induced dose dependent expansion of dendritic cells in the periphery. In patients with cancer, this increase in dendritic cells can be utilized to enhance anti-tumor responses to immuno-oncology therapies.[Table: see text]

Introduction In haemophilia, prophylactic infusion of replacement factor can result in improvements in health-related quality of life (HRQoL) when compared with episodic treatment. The Haemophilia-specific Quality of Life (Haem-A-QoL) questionnaire assessed HRQoL in adults with severe haemophilia A or B who received prophylactic or episodic treatment with recombinant factor VIII or IX Fc fusion protein (rFVIIIFc or rFIXFc) in the A-LONG or B-LONG clinical studies. Aims Understand changes in HRQoL during the A-LONG and B-LONG trials. Methods Group-level and individual-level changes over time for the Haem-A-QoL key domains of ‘Physical Health’ and ‘Sports & Leisure,’ and ‘Total Score’ were evaluated in adults through baseline and 6-month HRQoL assessments. Previously determined responder definitions (RDs) were used for evaluating meaningful subject-level HRQoL improvements. Results The analysis included 67 A-LONG and 51 B-LONG subjects who completed the Haem-A-QoL (baseline and 6 months). While HRQoL improvements were observed among all treatment groups, greater improvements in HRQoL were observed among subjects who received episodic treatment pre-study (and prophylaxis on-study) compared to those who received hyphenate prophylaxis. Applying the RDs for interpreting 6-month changes, 47.4%/33.3% (‘Physical Health’), 35.9%/50.0% (‘Sports & Leisure’) and 23.9%/33.3% (‘Total Score’) of A-LONG subjects who received individualized or weekly prophylaxis were classified as HRQoL responders. In B-LONG, 69.2%/57.9% (‘Physical Health’), 44.4%/56.7% (‘Sports & Leisure’) and 41.7%/44.1% (‘Total Score’) of subjects who received individualized or weekly prophylaxis were classified as HRQoL responders. Conclusion Changes in Haem-A-QoL key domains and ‘Total Score’ suggest that prophylaxis with long-acting rFVIIIFc or rFIXFc resulted in meaningful HRQoL improvements.

Introduction: Recent haemophilia treatment advances include new recombinant FVIII (rFVIII) products with improved pharmacokinetic (PK) properties that aim to reduce the burden of prophylaxis. These treatments are commonly referred to as extended half-life rFVIII products (EHL rFVIII). There is no uniform definition of what constitutes an EHL rFVIII. Such a definition would help physicians, patients and funders understand the properties of standard and EHL rFVIIIs and thus provide clarity when selecting an EHL in clinical settings. Aim: To critically assess the published evidence on new and emerging rFVIII products in order to propose a definition to classify EHL rFVIIIs. Methods: We systematically searched PubMed, EMBASE and regulatory authorities (FDA/EMA/Health Canada) websites for publications and regulatory submissions describing prospective crossover PK studies evaluating rFVIIIs that demonstrate improved PK parameters in adults and adolescents with severe haemophilia A. Results: Following critical analyses of the published data, we developed a holistic approach to defining rFVIIIs as EHLs, which requires all of the following: (i) using technology designed to extend rFVIII half-life; (ii) lacking bioequivalence with a standard rFVIII comparator-above the FDA/EMA cut-off of 125% for the 90% confidence intervals for area under the curve ratio; and (iii) having an extended half-life ratio measured in a PK comparator crossover study. Conclusion: In this systematic review, a pragmatic definition of EHL rFVIII has been proposed that should provide better clarity in clinical discussions surrounding the appropriate use of rFVIII products. At present, only products using PEGylation or Fc fusion half-life extension technology meet the proposed criteria for definition of EHL rFVIII. (Less)

Objective Hybrid Fc-fused rhGH (GX-H9) is a long-acting recombinant human growth hormone (GH) under clinical development for both adults and children with GH deficiency (GHD). We compared the safety, pharmacokinetics and pharmacodynamics of weekly and every other week (EOW) dosages of GX-H9 with those of daily GH administration in adult GHD (AGHD) patients. Design This was a randomized, open-label, active-controlled and dose-escalation study conducted in 16 endocrinology centers in Europe and Korea. Methods Forty-five AGHD patients with or without prior GH treatment were enrolled. Patients with prior GH treatments were required to have received the last GH administration at least 1 month prior to randomization. Subjects were sequentially assigned to treatment groups. Fifteen subjects were enrolled to each treatment group and randomly assigned to receive either GX-H9 or Genotropin (4:1 ratio). GX-H9 dosage regimens for Groups 1, 2 and 3 were 0.1 mg/kg weekly, 0.3 mg/kg EOW and 0.2 mg/kg EOW, respectively. All Genotropin-assigned subjects received 6 µg/kg Genotropin, regardless of treatment group. Main outcome analyses included measurements of serum insulin-like growth factor 1 (IGF-I), safety, pharmacokinetics, pharmacodynamics and immunogenicity. Results Mean GX-H9 peak and total exposure increased with an increase in dose after a single-dose administration. The mean IGF-I response was sustained above baseline over the intended dose interval of 168 h for the weekly and 336 h for the EOW GX-H9 groups. Safety profiles and immunogenicity were not different across the treatment groups and with Genotropin. Conclusions GX-H9 has the potential for up to twice-monthly administration.

Introduction The safety, efficacy and prolonged half-life of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously treated patients with severe haemophilia A was demonstrated in the phase 3 A-LONG and Kids A-LONG studies. Here, we report interim safety and efficacy data from the rFVIIIFc extension study, ASPIRE (ClinicalTrials.gov #NCT01454739). Methods Eligible subjects could enrol in ASPIRE upon completing A-LONG or Kids A-LONG. There were four treatment groups: individualized prophylaxis; weekly prophylaxis; modified prophylaxis (for subjects in whom optimal treatment could not be achieved with individualized or weekly prophylaxis); and episodic treatment. The primary endpoint was development of inhibitors. Results A total of 150 A-LONG subjects and 61 Kids A-LONG subjects enrolled in ASPIRE. As of the interim data cut (6 January 2014), the median time on study was 80.9 (A-LONG) and 23.9 (Kids A-LONG) weeks. The majority of subjects (A-LONG, 92.0%; Kids A-LONG, 57.4%) had ≥100 cumulative rFVIIIFc exposure days. No inhibitors were observed. Adverse events were generally consistent with those expected in the general haemophilia A population. Median annualized bleeding rates (ABRs) were low with individualized [A-LONG: 0.66; Kids A-LONG: 0.00 (

Prophylactic infusion of factor VIII (FVIII) prevents joint bleeding and other hemorrhages in patients with hemophilia A. Conventional FVIII concentrates have a short half-life, with an average of about 12 h in adults, ranging in individual patients between 6 and 24 h, and even shorter in younger children. Therefore, effective prophylaxis requires frequent intravenous injection, usually three times per week or every other day. Several technologies are currently under investigation to extend the half-life of FVIII, including Fc fusion (Eloctate, Elocta, efmoroctocog alfa), addition of polyethylene glycol (turoctocog alfa pegol [N8-GP], BAY 94-9027, BAX 855), and a single-chain construct (CSL627). This review summarizes characteristics of products in clinical development and discusses their potential benefits.

Stefan R. Schmidt consolidates the hugely diverse field of fusion proteins and their application in the creation of biopharmaceuticals. The text is replete with case studies and clinical data that inform and intrigue the reader as to the myriad possibilities available when considering the creation of a fusion protein. This valuable text will serve the novice as a broad introduction or the seasoned professional as a thorough review of the state of the art. The first marketed therapeutic recombinant protein was human insulin (Humulin® R). Its approval in 1982 was followed by other such products, including erythropoietin (EPO), interferon (IFN), and tissue plasminogen activator (tPa). Since the 1980s, the number and general availability of recombinant products that replace natural proteins harvested from animal or human sources has increased considerably. Following the initial success, researchers started de novo designs of therapeutic proteins that do not occur in nature. The first of these new drugs to be ...

A robust, economical process should leverage proven technology, yet be flexible enough to adopt emerging technologies which show significant benefit. Antibody and Fc-fusion processes may capitalize on the high selectivity of an affinity capture step by reducing the total number of chromatographic steps to 2. Risk associated with this approach stems from the potentially increased time frame needed for process development as well as unforeseen changes in impurity profile during first scale-up of drug substance (DS) for animal toxicology and clinical phase I trials (FIH) production, which could challenge a two-step process to the point of failure. Two different purification strategies were pursued during process development for an FIH process of a dAB-Fc fusion protein. A two-step process was compared to a three-step process. The two-step process leveraged additives to maximize impurity reduction during affinity capture. While wash additives in combination with a mixed mode chromatography met all impurity reduction requirements, HCP levels were still higher as compared to the three-step process. The three-step process was implemented for manufacture of clinical material to mitigate risk.

SummaryThe use of plasma-derived and recombinant coagulation factors for the treatment of haemophilia A and B is well established and permits patients to live a relatively normal life. In order to improve treatment options, several products are in development, which have a prolonged duration of action, thus enabling less frequent prophylactic dosing and aiming to reduce the burden of treatment. Several innovative approaches are being pursued to extend the half-life of factor VIIa, factor VIII and factor IX, utilising technologies such as Fc fusion, recombinant albumin fusion and addition of polyethyleneglycol (PEG) (PEG ylation). These methods prolong the time in the circulation by reducing degradation and elimination. This review summarises the technologies and products in development and their stages of development, and also discusses their pros and cons.

Monoclonal antibodies (mAbs) and fusion proteins with an Fc portion of immunoglobulin G (IgG) are emblematic of the remarkable expansion of biopharmaceuticals. Despite their biological origin, these products display an interindividual variability in their efficacy and/or side effects, which must be taken into consideration. Biological monitoring allowing for adapted prescription and dose adjustments may lead to therapeutic optimization and limitation of the high costs of these drugs. Herein, we review the biological theranostic of mAbs and Fc fusion proteins, including pre-treatment analyses, monitoring of efficacy, therapeutic drug monitoring, and monitoring of side effects. Supported by concrete evidence, a specific interest is given to individualised therapeutic monitoring that combines intention to treat, biomarkers of efficacy and adaptation of serum concentrations.