Octocog Alfa Research Articles

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.

Real-World Use of Octocog Alfa and Damoctocog Alfa Pegol in Women with Hemophilia a from the ATHNdataset

Background and rationale Women and girls with one or two abnormal alleles of clotting factor genes can experience hemophilia symptoms, but a lack of data exists on the treatment of women with hemophilia. We used the ATHNdataset to identify female patients who received octocog alfa (BAY 81-8973/Kovaltry®) or damoctocog alfa pegol (BAY 94-9027/Jivi®) between January 1, 2010 and April 30, 2022. Baseline demographics, treatment history and medical history of patients aged ≥12 years with hemophilia A for damoctocog alfa pegol and all ages for octocog alfa were collected. The HIPAA-compliant, de-identified database, ATHNdataset, is a national database sponsored by the American Thrombosis and Hemostasis Network. This repository contains patient data, including of those with hemophilia A, gathered from ATHN-affiliated hemophilia treatment centers across the United States. Results: A total of 354 and 205 patients receiving octocog alfa and damoctocog alfa pegol, respectively, were in the ATHNdataset at the time of data cutoff. Of these, 13 patients receiving octocog alfa and four receiving damoctocog alfa pegol were female. Of the patients receiving octocog alfa, there was one pediatric patient (<12 years), two adolescent patients (12-18 years), and ten adult patients (>20 years) of whom seven were older than 30 years. For damoctocog alfa pegol, there were two adolescent patients (12-18 years) and two adults (>50 years). These patients were treated as listed in Table 1. For the octocog alfa patients, out of 11 patients, only one was treated with octocog alfa for <1 year, and six patients were treated for >3 years. Data regarding length of treatment were missing for two patients. Two patients were treated with damoctocog alfa pegol for <1 year, and two for >1 year with one of them for >3 years (Table 2). Of the octocog alfa patients, there was one patient who had four bleeds; all bleeds were traumatic, including three joint bleeds. One patient receiving damoctocog alfa pegol had one traumatic bleed with no joint bleeds. All other patients had zero bleeds. Eight patients on octocog alfa with known data were previously treated with another product. Five of these eight patients were on a previous standard half-life product. Three of the eight had bleeding episodes, including spontaneous and joint bleeds, on their previous product; one patient with five bleeds had two traumatic bleeds and three joint bleeds. None of these patients had bleeds while using octocog alfa. All these patients were classified as having mild hemophilia; there was also one patient with moderate and two with severe hemophilia. Two patients on damoctocog alfa pegol with known data were previously treated with another product, one episodically with desmopressin and the other prophylactically with an extended half-life product. Neither had any bleed data listed in the dataset. Previous product usage of the patient with one traumatic bleed on damoctocog alfa pegol was unknown. Three patients receiving damoctocog alfa pegol had mild hemophilia and one severe. Conclusions: The real-world data obtained from the ATHNdataset confirm that some women and girls in all age groups are being treated with octocog alfa or damoctocog alfa pegol, and indicate the effectiveness of these treatments in this real-world setting. The majority have mild hemophilia A. Approximately 1/3 of the female patients were treated on some form of prophylaxis with 2/3 of these being classified as mild. Only traumatic bleeds, including traumatic joint bleeds, were noted. Three patients treated with different products before using octocog alfa had spontaneous, joint and traumatic bleeds on their previous therapies. More data are needed on the diagnosis and treatment of women with hemophilia A. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Personalization of Clotting Factor VIII Replacement Therapy Based on Population Pharmacokinetics in Adult Patients with Severe Hemophilia a Who Frequently Switch Factor VIII Concentrates

Interindividual pharmacokinetic differences in clotting factor VIII (FVIII) metabolism impede the dosing regimen optimization in patients with hemophilia A. The population pharmacokinetic (PK) analysis enables the estimation of FVIII pharmacokinetics in individual patients which is used to personalize dosing regimens. Therefore, we conducted a prospective study on adult patients with severe hemophilia A who received different FVIII concentrates for tertiary prophylaxis and whose dosage of FVIII was adjusted based on individual PK results. We aimed to compare the number of bleeding episodes and FVIII consumption before and after dosing adjustment. The study, conducted for 18 months for each participant, was divided into 3 phases: (1) pre-PK: assessments before FVIII dosing adjustment, (2) dosing adjustment based on the PK analysis of FVIII, and (3) assessments after FVIII dosing adjustment. All patients gave informed consent before enrolment, and all procedures were carried out according to the Declaration of Helsinki. During the study patients frequently changed FVIII concentrates (each patient used 3-5 different products) which reflects the standard of care in adult patients with hemophilia in Poland. During phase 1 of the study, over 5-13 months [median: 11.0 months, mean(standard deviation - SD): 10.8(1.9) months], patients recorded FVIII consumption and bleedings using electronic diaries (myPKFiT® licensed for octocog alfa). In phase 2 of the study, a PK analysis (clearance, half-time, time to reach the 1 IU/dl concentration) was performed: following the 72-hour washout period, blood samples were collected, and patients received the infusion of octocog alfa with the mean dose (SD) of 51.1(1.7) IU/kg. Two more blood samples were collected 3-4 h and 24-36 h after the infusion. Plasma FVIII activity was measured with a one-stage clotting assay, and the FVIII inhibitor with the Nijmegen modification of the standard Bethesda method. The myPKFiT® was used to obtain individualized FVIII dosing regimens based on PK analysis results. The dosing adjustment was offered to patients who experienced breakthrough bleeds during phase 1 or in whom the pre-PK treatment did not secure FVIII trough level of >1 IU/dl. In case of favorable PK results and no breakthrough bleeds during phase 1, a less intensive regimen was implemented. In phase 3 of the study (which lasted for 5-13 months, median: 7.7 months, mean(SD): 7.6(1.6) months), patients continued treatment with locally available FVIII concentrates and used electronic diaries to record FVIII consumption and bleedings. All bleeding rates were annualized (annualized bleeding rates - ABR). The final analysis set included 22 male patients, aged 23-68 years. The clearance of octocog alpha ranged from 0.014 to 0.051 dL/h/kg [mean(SD), 0.030±0.010 dL/h/kg; coefficient of variation (CV)=33%], half-life - from 9.1 to 27.9 h (14.6(4.3) h, CV=29%), and time to reach 1 IU/dl - from 51 to 179 h [91(29) h, CV=32%]. Three individuals were categorized as slow metabolizers (clearance of 0.014, 0.018, and 0.019 dL/h/kg), and 2 as fast metabolizers (clearance of 0.048 and 0.051 dL/kg/h). FVIII inhibitor was undetectable (<0.5 BU/ml) in all patients. After the PK analysis, 21 of 22 patients met the criteria of FVIII dosing adjustment. Four patients did not agree to change the regimen. Seventeen patients modified it according to the PK results (10 of them had FVIII trough levels of >1 IU/dl and 7 of them of <1 IU/dl in phase 1 of the study). Changing the dosing regimen in the 17 patients resulted in ABR reduction compared to the pre-PK phase: a decrease of 3.1-fold in total ABR (p=0.045 for dependent samples t-test); 3.2-fold in spontaneous ABR (p=0.046); and 3.1-fold in injury-related ABR (p=0.072). The consumption of FVIII due to bleeds had decreased by 77% (p=0.034). In conclusion, personalizing the FVIII replacement therapy based on population PK models helps to lower bleeding risk and drug consumption in patients with severe hemophilia A. Presented results suggest that prophylaxis regimen based on PK analysis carried out with octocog alfa and myPKFiT® application is clinically effective also with the use of other FVIII concentrates.

Real-World Clinical Outcomes and Replacement Factor VIII Consumption in Patients with Haemophilia A in Italy: A Comparison between Prophylaxis Pre and Post Octocog Alfa (BAY 81-8973).

(1) Background: new generations of rFVIII products offered the possibility to improve personalized therapeutic approaches, reducing the number of infusions or increasing the protection against bleeding risk. The aim of this study was to assess the effectiveness of prophylaxis with BAY 81-8973 (octocog alfa, Kovaltry®, Bayer Pharma AG) in the real-world setting and its impact on FVIII consumption compared to previous standard half-life treatments. (2) Methods: a retrospective observational study was conducted in five Italian Haemophilia Centers. Patients with haemophilia A under prophylactic treatment with BAY 81-8973 for at least one year, and previously on prophylaxis with a different product were included in the study. Annual bleeding rate (ABR) and annual FVIII consumption were compared. (3) Results: forty-four patients were included in the study. After switching to BAY 81-8973, ABR was significantly reduced (1.76 vs. 0.23; p = 0.015), the percentage of patients with zero bleeds increased from 54.6% to 84.1% (p = 0.003), and the overall FVIII consumption decreased by 25,542 (−7.2%, p = 0.046) IU per patient-year. Patients treated every 3 days or 2 times per week increased from 0% to 27.3%. (4) Conclusion: our results suggest that prophylaxis with BAY 81-8973 can improve clinical outcomes and reduce FVIII consumption, in the real-world practice, compared with the previous prophylaxis regimen with standard half-life products.

Analysis of pooled real-world data from Germany, Italy, and the United States of rVIII-SingleChain compared with standard- and long-acting FVIII products for prophylaxis of hemophilia A

Objective To evaluate real-world annualized bleeding rates (ABRs), dosing frequency, and factor consumption of four recombinant FVIII (rFVIII) products using pooled data from centers in the US, Germany, and Italy. Methods De-identified patient medical chart data were collected from 48 hemophilia treatment centers in the US, Germany, and Italy. Patients included in this analysis had hemophilia A and were treated with rVIII-SingleChain, rFVIIIFc, octocog alfa, or BAY 81-8973 for ≥12 weeks. Where possible, patient selection considered age and disease severity in order to balance patient groups across products. Summary statistics were presented descriptively by product for dosing frequency, consumption, ABR/annualized spontaneous bleeding rate (AsBR), and corresponding percentage of patients with zero bleeds. Logistic regression was performed for patients with zero bleeds or zero spontaneous bleeds (vs. patients with any such bleeds). Generalized linear model regression was performed for ABR, AsBR, and consumption. All regression models included the product variable for comparison as well as additional independent variables for adjustment (age, weight, severity, and country for the consumption model, with the addition of consumption for the bleeding outcomes models). Results Overall, 616 patients were included (rVIII-SingleChain, n = 129; rFVIIIFc, n = 159; octocog alfa, n = 181; BAY 81-8973, n = 147). Dosing frequency was ≤2 times a week for 65.9%, 75.5%, 25.4%, and 40.1% of patients treated with rVIII-SingleChain, rFVIIIFc, octocog alfa, and BAY 81-8973, respectively. ABRs were not significantly different among products, with mean (median) values of 1.1 (0.0), 1.0 (0.0), 1.4 (1.0), and 1.9 (1.0) for rVIII-SingleChain, rFVIIIFc, octocog alfa, and BAY 81-8973, respectively. The percentage of patients with zero bleeds was comparable between rVIII-SingleChain and rFVIIIFc (59.7% vs. 62.3%; p =.916) and significantly higher for rVIII-SingleChain compared with octocog alfa (p <.001) and BAY 81-8973 (p =.003). Comparison of mean weekly consumption showed: rVIII-SingleChain (83.0 IU/kg/week) vs. rFVIIIFc (96.9; p =.055) and significantly lower for rVIII-SingleChain vs. octocog alfa (108.6; p <.001) and BAY 81-8973 (104.3; p =.001). The median values for weekly consumption were 85.7, 90.1, 100.1, and 98.5 IU/kg/week for rVIII-SingleChain, rFVIIIFc, octocog alfa, and BAY 91-8973, respectively. Similar trends were observed for all outcomes when analyzing the subgroups of patients aged ≥12 years and patients with severe disease (all age and ≥12 years). Conclusions rVIII-SingleChain prophylaxis may provide improved bleed protection, less frequent dosing, and lower consumption compared with standard-acting FVIII products, and comparable protection and consumption to the other long-acting FVIII product, in patients with hemophilia A.

CTLA4-Ig prevents development of neutralizing antibody formation after continuous treatment with human FVIII in HA rats.

Immunogenicity causing development of anti-drug antibodies (ADAs) are major challenges in the treatment of haemophilia, as well as other diseases where proteins are used for treatment. Furthermore, it is a complication for preclinical testing of such therapies in animal models. To investigate if the immunosuppressive drug CTLA4 immunoglobulin (CTLA4-Ig) can induce tolerance in haemophilia A (HA) rats receiving recombinant human coagulation factor VIII (rhFVIII) treatment. Two different prophylactic rhFVIII compounds were given intravenously to HA rats for 4 weeks. Both rhFVIII compounds were co-administered with commercially available CTLA4-Ig or human IgG subclass 4 (hIgG4) as control, and blood samples were collected. To functionally test if pharmacological efficacy was retained, rats were subjected to a bleeding experiment under anaesthesia at end of study. The mean inhibitory level after 4 weeks in rats receiving rhFVIII and hIgG4 was 85.7 BU for octocog alfa and 37.4 BU for rurioctocog alfa pegol. In contrast, co-administration with CTLA4-Ig during rhFVIII therapy prevented the formation of ADAs (both binding and inhibitory) in 14/14 rats receiving octocog alfa and in 7/7 rats receiving rurioctocog alfa pegol. Moreover, we were able to show that the pharmacological efficacy of rhFVIII was preserved. In a rat model with spontaneous bleeding, co-administration of CTLA4-Ig with rhFVIII prevented antibody formation. No FVIII antibodies were detected, demonstrating that CTLA4-Ig co-administration can be applicable as a method to prevent immunogenicity, when evaluating human proteins in preclinical systems permitting continuous pharmacokinetic and pharmacodynamic assessment.

Clinical outcome and adherence rate in Scandinavian patients with intermediate-intensity prophylaxis before and after the switch of standard half-life FVIII products to BAY 81-8973.

Treatment optimization in haemophilia A can be achieved by choice of FVIII product and knowledge of pharmacokinetics (PK), phenotype and adherence. A favourable PK profile of BAY 81-8973 (octocog alfa) (Kovaltry, Bayer AB) compared to other standard half-life (SHL) FVIII products has been suggested. To evaluate whether the switch to BAY 81-8973, using the same dosing schedule, impact factor consumption and bleed rates, taking arthropathy and adherence into account METHODS: Forty patients on prophylaxis with SHL (median age 40.5 years) attending the haemophilia treatment centres in Malmö and Oslo were enrolled. The annualised bleeding rate (ABR) and joint bleeding rate (AJBR) before and after the switch to BAY 81-8973 was calculated. PK analyses were performed with WAPPS-Hemo. Joint health status and treatment adherence were assessed. The median ABR and AJBR was 0 before and after the switch, at both centres. The median yearly factor consumption was 3,345 IU/Kg/year in the entire study group corresponding to intermediate-intensity prophylaxis in most patients and with significantly more used in Malmö (3,862 IU/Kg/year), compared to Oslo (2,337 IU/Kg/year) (P .006). There was no correlation between arthropathy and bleeding. The median BAY 81-8973 t½ was 15.15h (range 7.5-29h), with significant correlation to VWF levels, and 13.4h after exclusion of VWF outliers. Adherence to treatment was 97%. Concentrate switch, using mainly intermediate-intensity regimens with high adherence rates, preserves excellent prophylaxis outcome using standard half-life FVIII products, indicating the value of individualized prophylaxis and close follow-up.

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Rurioctocog Alfa Pegol Use in Immune Tolerance Induction: Interim Results from an Open-Label Multicenter Clinical Trial in Previously Untreated Patients with Severe Hemophilia a

Rurioctocog Alfa Pegol Use in Immune Tolerance Induction: Interim Results from an Open-Label Multicenter Clinical Trial in Previously Untreated Patients with Severe Hemophilia a

Monitoring of different factor VIII replacement products using a factor VIII one-stage clotting assay on cobas t 511/711 analysers.

IntroductionRecombinant coagulation factor VIII (FVIII) products are the standard of care for patients with haemophilia A. The development of modified FVIII products has provided benefit for patients but presented challenges for monitoring FVIII activity.AimThis single‐centre study evaluated the Roche FVIII one‐stage clotting assay (OSA) in measuring FVIII activity in plasma samples spiked with seven FVIII products at clinically relevant concentrations.MethodsFVIII‐deficient plasma samples were spiked with two batches of recombinant FVIII products (octocog alfa, moroctocog alfa, simoctocog alfa, efmoroctocog alfa, damoctocog alfa pegol, rurioctocog alfa pegol, lonoctocog alfa) at 1–120 IU/dL FVIII activity, according to their labelled potency. Measurement was conducted on the cobas t 511/711 analysers using the Roche FVIII OSA and the Technoclone TECHNOCHROM FVIII:C chromogenic substrate assay (CSA).ResultsUsing the OSA, FVIII activity was close to labelled potency for most analysed FVIII products including a recombinant FVIII Fc fusion protein. PEGylated FVIII product, damoctocog alfa pegol, was marginally above and single‐chain product, lonoctocog alfa, below the predefined acceptance criteria: for FVIII activity < 25 IU/dL: ± 5 IU/dL; for FVIII activity ≥ 25 IU/dL: ± 20% (relative). The different principles of OSA and CSA led to discrepancies in the estimation of all analysed FVIII products. Additionally, in vitro recovery was increased at lower levels of FVIII activity using the OSA, whereas recovery was more consistent using the CSA.ConclusionThese data allow the interpretation of FVIII activity results for different FVIII products using the Roche FVIII OSA on the cobas t 511/711 analysers.

Individualized prophylactic treatment of patients with hemophilia A to improve effectiveness and optimize product consumption on the example of octocog alpha and rurioctocog alpha pegol. A systematic literature review

Objective: to review the data on the efficacy and consumption of octocog alfa and rurioctoctog alfa pegol in standard prophylaxis and individualized prophylaxis in hemophilia A patients based on published international data.Material and methods: a systematic literature search and review were performed. Among 25 sources identified within the systematic search 7 relevant sources describing the comparison of treatment with octocog alfa and rurioctocog alfa pegol in adult and pediatric patients with severe and moderate hemophilia A based on personalized assessment of the pharmacokinetic curve using the interactive tool myPKFit versus the standard (non-personalized) dosage regimen were selected. Data on individual patients, as well as data from secondary subgroups defined by age, bleeding rate, risk of bleeding associated with the daily physical activity were combined and analyzed.Results. In observational studies, adjustments of the dose and administration of octocog alfa in patients with severe hemophilia based on personalized assessment of the pharmacokinetic curve using myPKFit resulted in the reduced consumption and/or increased efficacy of prophylaxis — a reduced annual bleeding rate. In an extended controlled study of rurioctocog alpha pegol a trend toward reduced bleeding rate and increased mean annual consumption of the drug was reported in patients who received myPKFit guided prophylaxis compared to a non-personalized treatment regimen. In the single-cut studies, myPKFiT use resulted in the regimen revisions in less than a quarter of patients.Summary. Personalized dosing for octocog alpha and rurioctocog alpha pegol based on pharmacokinetic curve built using pharmacokinetic population model enables reasonable dose adjustments and improves outcomes.

Matching-Adjusted Indirect Comparison of Efficacy and Consumption of rVIII-SingleChain Versus Two Recombinant FVIII Products Used for Prophylactic Treatment of Adults/Adolescents with Severe HaemophiliaA.

IntroductionGiven the relatively small number of patients with haemophilia A, head-to-head comparisons between recombinant FVIII (rFVIII) products are difficult to conduct. This study compared the efficacy and consumption of rVIII-SingleChain (lonoctocog alfa, AFSTYLA®) with rAHF-PFM (octocog alfa, Advate®) and rFVIIIFc (efmoroctocog alfa, Elocta®), for the prophylaxis and treatment of bleeding episodes in previously treated adolescents/adults with severe haemophilia A, through a matching-adjusted indirect comparison (MAIC).MethodsA systematic literature review identified published clinical trials for rAHF-PFM and rFVIIIFc. Individual patient data for rVIII-SingleChain were used to match baseline patient characteristics to those from published trials, using an approach similar to propensity score weighting. After matching, annualized bleeding rates (ABR), percentage of patients with zero bleeds, and rFVIII consumption were compared across trial populations.ResultsPublished data were identified from two rAHF-PFM trials and one rFVIIIFc trial. rVIII-SingleChain had similar ABR (risk ratio [RR]: 0.74 [0.16; 3.48]; RR: 1.18 [0.85; 1.65]) and percentage of patients with zero bleeds (odds ratio [OR]: 1.34 [0.56; 3.22]; OR: 0.78 [0.47; 1.31]) versus rAHF-PFM and rFVIIIFc, respectively. Annual rVIII-SingleChain consumption was significantly lower than rAHF-PFM (mean difference: − 1507.66 IU/kg/year [− 2011.71; − 1003.61]) and equivalent to rFVIIIFc (RR: 0.96 [0.62; 1.49]).ConclusionAlthough limited to published information for comparator trials, these results suggest that with an annualized rFVIII consumption comparable to rFVIIIFc, but significantly lower than rAHF-PFM, routine prophylaxis with rVIII-SingleChain is able to maintain a similar ABR and percentage of patients with zero bleeds, attesting to the long-acting nature of rVIII-SingleChain.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01853-0.

Pharmacotherapeutic Patterns and Patients’ Access to Pharmacotherapy for Some Rare Diseases in Bulgaria – A Pilot Comparative Study

Provision of the latest innovative and advanced therapies for rare diseases (RDs) patients, following the international therapeutic recommendations, is crucial and necessary for both practitioners and patients. The goal is to assess the access of Bulgarian patients with the most cost-consuming RDs to medicines and to compare the pharmacotherapeutic patterns in Bulgaria and the relevant European professional associations. Pharmaco-therapeutic guidelines for treating the most cost-consuming RDs in Bulgaria were analyzed to assess their compliance with the European ones. Market entrance was evaluated through analysis of the availability of medicines in the Positive Drug List (PDL) and their date of inclusion since marketing authorization. Guidelines’ compliance index was calculated and patient access was analyzed through evaluation of the National Health Insurance Fund (NHIF) standards, which provide additional criteria for treatment initiation. The analyzed guidelines follow the adopted recommendations by the relevant European professional associations. NHIF have exclusion and inclusion criteria for initiating treatment with medicines for rare diseases and for continuation. The average time-lag between centralized procedure approval and inclusion in the Bulgarian PDL for orphan medicinal products (MPs) is 6.75 years (SD = 4.96) with the longest time observed for eptacog alfa (20 years) and the shortest for rurioctocog alfa pegol, octocog alfa and simoctocog alfa (1 year). Bulgarian patients with cystic fibrosis with pulmonary manifestation had a wait time of only 1.6 years to get access to innovative, centrally authorized medicines, whereas the period for access to acromegaly treatment was 8.2 years. The main factors influencing market entrance and patient access are the time to inclusion in the PDL and the NHIF criteria.

Switching Kogenate FS® to Kovaltry® for the Treatment of Severe Haemophilia A Patients: A Successful Single Center Experience

Background: Haemophilia A is an X-linked hereditary disorder caused by deficient levels of the coagulation protein factor VIII (FVIII). Standard therapy for haemophilia A comprises replacement of FVIII with plasma-derived or recombinant FVIII concentrate, which can be administered as on-demand or prophylaxis regimen. The most challenging complication of replacement therapy in hemophilia A is the occurrence of alloantibodies against infused factor FVIII, thus predisposing the patients to an increased morbidity and disability. Historically, first FVIII was isolated from cryoprecipitated plasma concentrates. Thirty years ago, after the cloning of F8 gene, therapy for hemophilia A patients underwent a new exciting era that developed technological strategies aimed to improve haemostatic efficacy and safety of the replacement factor. In this line, a new recombinant FVIII, BAY 81-8973 (octocog alfa; Kovaltry®, Bayer) has recently been introduced onto pharmaceutical market for treatment of these patients. Kovaltry® is an unmodified, full-length, recombinant FVIII concentrate with the same amino acid sequence as Kogenate FS® (Bayer), but produced with innovative manufacturing technologies that include production without addition of human- or animal-derived raw materials from purification or formulation processes, inclusion of a higher degree of sialic acid capping of N-terminal glycans on the molecular surface, coexpression of the human chaperone protein heat shock protein 70, and a 20-nm nanofiltration step to remove small non-enveloped viruses and potential protein aggregates. On this basis we considered beneficial for our patients changing Kogenate FS® therapy for Kovaltry®.Objective: We aimed to demonstrate that switching from Kogenate FS® to Kovaltry® could be easily performed without increasing the risk of bleeding or FVIII consumption in severe haemophilia A patients.Methods: Sixty two adult and pediatric patients with severe haemophilia A, without inhibitors, treated with Kogenate FS® either on on-demand treatment (n=13) or on prophylaxis regimen (n=49), were recruited. On November 2016, we began to switch Kogenate FS® treatment to Kovaltry® in these patients.The trend of prophylaxis with Kovaltry® was evaluated by determining mean injection frequency (per week), mean dose of each injection (IU/kg), mean total dose injected/week (IU), baseline and post-infusion levels of FVIII and annual bleeding rate (ABR). Same data for Kogenate FS® were collected retrospectively from clinical histories of patients.For determining baseline and post-infusion levels of Kovaltry®, whole blood was collected in 3.2% sodium citrate tubes (BD Vacutainer, Becton Dickinson, San José, CA, USA) at pre-dosing and 30 minutes after Kovaltry® infusion. Plasma FVIII:C was measured by chromogenic assay.Results: Switching from Kogenate FS® to Kovaltry® caused no changes, except in two patients, either in mean injection frequency or mean dose of each injection or mean total dose injected/week or baseline and post-infusion levels of FVIII or annual bleeding rate. Increment observed in mean total dose injected/week in two of the pediatric patients was due to an increased physical activity (patient 2) and to weight gain (patient 8). For sake of example, Table 1 shows these variables for 10 pediatric patients under prophylactic treatment.None of the patients treated with Kovaltry® developed inhibitors.Conclusion: Changing severe haemophilia A treatment from Kogenate FS® to Kovaltry® can be performed easily and did not pose any risk to the patient since Kovaltry® proved to be equally effective than Kogenate FS® to prevent bleeding episodes and did not induce the occurrence of inhibitors. [Display omitted] DisclosuresÁlvarez-Roman:Novo Nordisk: Consultancy; Shire: Consultancy. Jimenez-Yuste:Novo Nordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy.

A comparison of MyPKFiT and WAPPS-Hemo as dosing tools for optimizing prophylaxis in patients with severe haemophilia A treated with Octocog alfa.

MyPKFiT and the Web-Accessible Population Pharmacokinetic service-Hemophilia (WAPPS-Hemo) are web-based population-based applications developed for helping physicians individualize and optimize replacement therapy. Although MyPKFiT is intended for Octocog alfa and Rurioctocog alfa pegol use only, the WAPPS-Hemo is applicable to all factor VIII concentrates. To compare MyPKFiT and WAPPS-Hemo as dosing tools for optimizing treatment of patients with severe haemophilia A on regular prophylaxis with Octocog alfa in a real-world setting. Fourteen patients with severe haemophilia A (median age 30.8years; range 20-71) were enrolled. The FVIII activity was measured twice after a regular dose of Octocog alfa by the chromogenic and the one-stage assays. PK analyses were performed using each tool and dosing estimations to reach trough levels of 1%, 3% or 5% after 48h. Findings were calculated and compared. The two PK algorithms yielded similar t½ independent of the type of FVIII assay used. However, there were significant differences in the time to reach 1%, 3% and 5%. The WAPPS-Hemo generated 10-12h longer time to a trough of 1% and up to 4h for the troughs of 3% and 5%. Accordingly, the doses estimated by WAPPS-Hemo for a daily regimen were between 28% and 100% of those proposed by MyPKFiT. MyPKFiT and WAPPS-Hemo provided similar half-life estimations for Octocog alfa independent of the FVIII assay used. The doses suggested by WAPPS-Hemo to reach specific troughs were overall lower, which may have implications for treatment optimization.

Determining the value contribution of emicizumab (hemlibra®) for the prophylaxis of haemophilia a patients without inhibitors in Spain by multi-criteria decision analysis (MCDA)

Objective: Determining the value of emicizumab compared to octocog alfa (OA) and efmoroctocog alfa (EA) in the prophylaxis of severe Haemophilia A (HA) patients without inhibitors using Multi-Criteria Decision Analysis (MCDA). Methodology: The EVIDEM framework adapted to orphan drugs and weighted by a sample of 98 national and regional Spanish evaluators was used. Two structured evidence matrices were developed: emicizumab against octocog alfa (OA) and emicizumab against efmoroctocog alfa (EA). A multidisciplinary team of haemophilia experts rated each one of the criteria. Mean and standard deviation was calculated by each criterion and discussed among all participants. Results: Relative quality of life and therapeutic benefit were the most valued criteria for emicizumab. HA without inhibitors was perceived as a serious disease (4.3±0.5) with unmet needs, especially for severe HA patients with higher probability of FVIII inhibitors development (3.3±0.9). When compared with OA and EA, emicizumab had higher therapeutic benefit (4.3±0.9 emicizumab/OA, 4.2±1.0 emicizumab/EA) with greater patient reported outcomes (4.0±1.2 emicizumab/OA, 4.3±0.9 emicizumab/EA) and relative efficacy (3.7±1.6 emicizumab/OA and 3.3±1.4 emicizumab/EA). Comparative safety and tolerability were perceived as similar for all the alternatives (2.1±2.1 emicizumab/OA and 1.6±1.5 emicizumab/EA). Quality of evidence (3.9±0.9 emicizumab/OA and 3.8±0.8 emicizumab/EA) and expert consensus (3.0±1.3) were also positive. All contextual criteria were valued positively for emicizumab. Conclusions: Emicizumab adds higher therapeutic value and improves patients’ quality of life compared to the current prophylaxis agents for severe HA without inhibitors and satisfies important unmet needs such as higher efficacy, improved posology and subcutaneous administration. Keywords: haemophilia A; drug value; multicriteria decision analysis, emicizumab

PRO66 PHARMACOKINETIC PARAMETER DRIVEN OUTCOMES MODEL PREDICTS A REDUCTION IN BLEEDS WITH OCTOCOG ALFA VERSUS ANTIHEMOPHILIC FACTOR (RECOMBINANT)

Spontaneous joint bleeding and repeated hemarthroses in haemophilia are common complications leading to hemophilic arthopathy. Prophylactic administration of clotting factor concentrates may prevent this. The aim of this analysis is to compare the long-term clinical outcomes for octocog alfa and antihemophilic factor (recombinant) based on differences in the pharmacokinetic (PK) profiles.

Critical Review of the Pivotal Studies of Four rFVIII Products for the Treatment of Hemophilia A Patients: The Role of Octocog Alfa

INTRODUCTION: Hemophilia A is a rare congenital bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). The severe form of the disease is characterized by spontaneous bleeds, especially into the joints. Prophylaxis, based on regularly intravenous administration of the missing factor to avoid hemorrhages, represents the gold standard of treatment. In recent years, new products that significantly improve the treatment management options for patients with hemophilia have become available in the market.OBJECTIVE: To critically evaluate the pivotal studies of recombinant FVIII (rFVIII) products, approved in Europe within the first half of 2018 having obtained the indication for a prophylaxis dosing regimen based also on a twice weekly infusion frequency or even less, highlighting their limitations or strengths.METHODS: A systematic literature search was conducted, and several databases (PubMed and Embase) were consulted.RESULTS: Nine clinical trials involving patients with severe hemophilia A without inhibitor were included in this analysis. Four rFVIII products (Elocta®, Biogen, Cambridge, MA, USA; Kovaltry®, Bayer HealthCare Pharmaceuticals, Germany; Afstyla®, CSL Behring GmbH, Germany; Adynovi®, Baxalta Innovation GmbH, Austria) with different pharmacokinetic profiles were evaluated. The trials included in this analysis had different designs and heterogeneous methods were utilized to assess the study outcomes. The baseline characteristics of the patients enrolled in the studies were also often different and sometimes not adequately described. LEOPOLD II, a trial to compare prophylaxis to on-demand therapy with an unmodified rFVIII product (Kovaltry®, octocog alfa), was the only completely randomized trial that enrolled a more critical patient population in terms of compromised joint condition than the other studies. Based on these side-by-side comparison, Octocog alfa reported similar efficacy, in terms of annualized bleeding rate, to the other rFVIII products, including extended half-life.CONCLUSIONS: Even without structural modifications, octocog alfa may be considered a useful treatment option for two times a week prophylaxis in a selected population of haemophilia patients.

Assessing prophylactic use and clinical outcomes in hemophilia A patients treated with rVIII-SingleChain and other common rFVIII products in Germany.

ObjectiveTo evaluate real‐world outcomes with rVIII‐SingleChain and other commonly used recombinant FVIII (rFVIII) products.MethodsHemophilia treatment centers in Germany (n = 21) contributed patient chart data. Inclusion criteria were prophylactic treatment with one of five rFVIII products for ≥8 weeks.ResultsMale patients (n = 225) were included: rVIII‐SingleChain (n = 40), rFVIIIFc (n = 47), octocog alfa (rFVIII; n = 58), octocog alfa (BAY 81‐8973; n = 40), or moroctocog alfa (n = 40). In patients with severe disease (n = 76), 66.6%, 70.0%, 20.0%, 7.7%, and 27.3% were dosed ≤2×/week, respectively. Irrespective of dosing frequency, mean annualized bleed rates (ABRs)/annualized spontaneous bleed rates (AsBRs) were 0.3/0.1, 0.8/0.4, 1.1/0.5, 1.5/0.8, and 1.4/0.6, and mean FVIII consumption (IU/kg/week) was 83.2, 97.2, 92.5, 104.0, and 102.1, respectively. Results for all patients were similar. Of the patients on prophylaxis with prior therapy and after switching to rVIII‐SingleChain (n = 21), mean ABR/AsBRs were 0.7/0.3 and 0.2/0.0, respectively. After switching to rVIII‐SingleChain, mean FVIII consumption reduced (109.4 vs 74.5 IU/kg/week), and percentage of patients dosed ≤2×/week increased (0% to 71.4%).ConclusionsrVIII‐SingleChain prophylaxis provides excellent bleeding protection, with potentially lowest factor consumption among the products assessed. Patients who switched to rVIII‐SingleChain prophylaxis reduced dosing frequency and consumption compared with prior treatment, with similar or potentially lower bleeding rates.

Status of Recombinant Factor VIII Concentrate Treatment for Hemophilia a in Italy: Characteristics and Clinical Benefits.

The current interest in recombinant factor VIII (rFVIII) products stems from the fact that they offer a technological solution to prolonging the half-life of and reducing the risk of formation of alloantibodies (inhibitors) against FVIII in treated patients with hemophilia A (HA). The Italian health care system has authorized the use of a wide range of rFVIII concentrates of the first, second, and third generation, as well as new innovative rFVIII preparates with an extended half-life (EHL) (Kogenate FS®-Bayer, belonging to the second generation and replaced since 2017 by a product consisting of the same modified molecule; because it is only available until the end of the current year, it will not be considered in this review). Some of these products have unique pharmacodynamic and pharmacokinetic (PK) profiles, including an EHL. The first-generation full-length rFVIII (FL-rFVIII), octocog alfa (Recombinate® Baxter/BIOVIIIx), although the oldest rFVIII product, has several desirable features. Third-generation products include two modified octocog alfa molecules (Advate®, Shire; Kovaltry®, Bayer) as well as the B domain-deleted rFVIII (BDD-rFVIII) moroctocog alfa (ReFacto®-Pfizer). The B domain-truncated (BDT-rFVIII) turoctocog alfa (NovoEight®, Novo Nordisk), the BDD-rFVIII simoctocog alfa (Nuwiq®, Kedrion), the single-chain BDT-rVIII lonoctocog alfa (Afstyla®, CSL Behring), and the BDD-rFVIIIFc efmoroctocog alfa (Elocta®, Sobi-Biogen) are new, innovative products. Simoctocog alfa, because its peculiarities, is considered a fourth-generation rFVIII concentrate. Turoctocog alfa, simoctocog alfa, and lonoctocog alfa have a high affinity for von Willebrand factor (vWF) that reduces renal clearance and prolongs the half-life of rFVIII. Efmoroctocog alfa, a first-in-class rFVIII-Fc fusion protein (rFVIIIFc), has a half-life 1.5–1.8 times longer than that of conventional plasma-derived FVIII (pd-rFVIII) and other rFVIII products. Clinical studies have evaluated the efficacy, safety, and inhibitor development of all these innovative concentrates in both previously treated (PTPs) and untreated patients (PUPs). This review considers the rFVIII products that are indicated for the treatment of patients with severe HA, focusing on those that are commercially available in Italy. Their PK characteristics, immunogenicity, and clinical benefits are discussed and compared.