Octocog Alfa Research Articles

Evaluation of FVIII pharmacokinetic profiles in Korean hemophilia A patients assessed with myPKFiT: a retrospective chart review

PurposeThis study aimed to investigate the pharmacokinetics (PK) of factor VIII (FVIII) in Korean patients, as limited information is available on the PK of FVIII in this population.MethodsWe collected the FVIII PK results from patients with moderate-to-severe hemophilia A using myPKFiT. PK variations were assessed according to age, blood type, inhibitor history, von Willebrand factor antigen (vWF:Ag) level, and body mass index. Additionally, the correlation between the PK profile and prophylaxis regimen was specifically analyzed for each product in severe cases.ResultsThe PK data of 48 and 81 patients treated with octocog alfa and rurioctocog alfa pegol, respectively, were obtained. The median half-lives of octocog alfa and rurioctocog alfa pegol were 9.9 (range: 6.3–15.2) h and 15.3 (range: 10.4–23.9) h, respectively. The PK profiles for each product did not differ according to age group; however, blood type-O patients had shorter half-lives and time to 1% compared to non-blood type-O patients. In regression analysis, the PK of octocog alfa showed a statistically significant difference according to age, whereas the PK of rurioctocog alfa pegol correlated with vWF:Ag. Only the frequency of rurioctocog alfa pegol use showed a statistically significant difference in relation to time to 1%, although the coefficient of determination was small.ConclusionThis study confirmed significant interpatient variation in the PK of FVIII among Korean patients with hemophilia A. To achieve optimized prophylaxis, personalizing the regimen based on the PK profile of each individual patient is essential.

Comprehensive laboratory assessment of lonoctocog alfa versus octocog alfa in severe haemophilia A.

Lonoctocog alfa is a single-chain factor VIII (FVIII) molecule with high binding affinity to von-Willebrand-factor. While it is well known that its plasma activity is underestimated by one-stage clotting assays (OSCA), there is a lack of knowledge on the post-infusion performance of lonoctocog alfa in global coagulation assays or its potential impact on the haemostatic balance in vivo. To characterize lonoctocog alfa versus octocog alfa in pre- and post-infusion samples obtained from patients undergoing repeated investigation of incremental recovery (IR). Eighteen patients with severe haemophilia A (lonoctocog alfa: 10, octocog alfa: 8) were included. A panel of factor-specific and global coagulation assays was applied, comprising a FVIII OSCA, two FVIII chromogenic substrate assays (CSA), rotational thrombelastography and thrombin generation (TG). Potential activation of coagulation was assessed by measuring plasma thrombin markers and levels of activated protein C. Comparable IRs were found for lonoctocog alfa and octocog alfa (2.36 [IU/dL]/[IU/kg] vs. 2.55 [IU/dL]/[IU/kg], respectively). Lonoctocog alfa activities were found to be underestimated by the FVIII OSCA while also the two FVIII CSAs showed statistically significant assay discrepancies on lonoctocog alfa. Effects of both FVIII products on rotational thrombelastography were less distinct than those on TG parameters. No elevated pre- or significantly shifting post-infusion plasma levels of coagulation biomarkers were detected. Lonoctocog alfa and octocog alfa showed comparable recovery and safety in vivo as well as similar impacts on TG in vitro. Observed assay discrepancies on lonoctocog alfa demonstrated variability of results also between different FVIII CSAs.

Canadian clinical experience on switching from standard half-life recombinant factor VIII (rFVIII), octocog alfa, to extended half-life rFVIII, damoctocog alfa pegol, in persons with haemophilia A ≥ 12 years followed in a Comprehensive Hemophilia Care Program in Canada.

Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an extended half-life recombinant factor (F)VIII replacement, indicated for the treatment of haemophilia A in patients aged ≥12 years. Following introduction of damoctocog alfa pegol in Canada in 2020, there have been no reports on routine clinical effectiveness and satisfaction, when switching from a previous FVIII product in Canada. To report changes in pharmacokinetics, effectiveness, utilization and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973, Kovaltry®) treatment. A single-centre, intra-patient comparison of pharmacokinetics and clinical outcomes was performed. Blood samples drawn once pre-dose and ≥2 times post-dose were measured by a one-stage assay to assess pharmacokinetic parameters including area under the curve (AUC, primary endpoint). Patient-reported outcomes data were collected using the Patient-Reported Outcomes, Burdens and Experiences questionnaire (PROBE). Clinical outcomes included annualized bleeding rate (ABR) and factor utilization. Dose-normalized AUC was significantly increased after switch to damoctocog alfa pegol from octocog alfa. Median (quartile [Q]1; Q3) annualized bleeding rates were 0.67 (0.00; 1.33) with damoctocog alfa pegol and 1.33 (0.00; 2.67) with octocog alfa. Half of the patients receiving damoctocog alfa pegol prophylaxis experienced zero bleeds (n=9, 50.0%) versus 38.9% (n=7) of patients treated with octocog alfa. Patients' good quality of life was maintained. This study provides routine clinical evidence supporting the benefits of switching from octocog alfa to damoctocog alfa pegol for patients with severe haemophilia A.

A Generative and Causal Pharmacokinetic Model for Factor VIII in Hemophilia A: A Machine Learning Framework for Continuous Model Refinement.

In rare diseases, such as hemophilia A, the development of accurate population pharmacokinetic (PK) models is often hindered by the limited availability of data. Most PK models are specific to a single recombinant factor VIII (rFVIII) concentrate or measurement assay, and are generally unsuited for answering counterfactual ("what-if") queries. Ideally, data from multiple hemophilia treatment centers are combined but this is generally difficult as patient data are kept private. In this work, we utilize causal inference techniques to produce a hybrid machine learning (ML) PK model that corrects for differences between rFVIII concentrates and measurement assays. Next, we augment this model with a generative model that can simulate realistic virtual patients as well as impute missing data. This model can be shared instead of actual patient data, resolving privacy issues. The hybrid ML-PK model was trained on chromogenic assay data of lonoctocog alfa and predictive performance was then evaluated on an external data set of patients who received octocog alfa with FVIII levels measured using the one-stage assay. The model presented higher accuracy compared with three previous PK models developed on data similar to the external data set (root mean squared error = 14.6 IU/dL vs. mean of 17.7 IU/dL). Finally, we show that the generative model can be used to accurately impute missing data (< 18% error). In conclusion, the proposed approach introduces interesting new possibilities for model development. In the context of rare disease, the introduction of generative models facilitates sharing of synthetic data, enabling the iterative improvement of population PK models.

The effectiveness and safety of octocog alfa in patients with hemophilia A: up to 7-year follow-up of the real-world AHEAD international study.

Real-world data assessing treatment outcomes in patients with hemophilia A in routine clinical practice are limited. To evaluate the effectiveness and safety of octocog alfa in patients with moderate/severe hemophilia A receiving treatment in clinical practice. The international Antihemophilic Factor Hemophilia A Outcome Database study is an observational, noninterventional, prospective, multicenter study. This planned interim data read-out was conducted following 7 years of observation of patients receiving octocog alfa (cut-off, 30 June 2020). The primary endpoint was joint health status, assessed by the Gilbert Score. Secondary endpoints included annualized bleeding rates (ABRs), Hemophilia Joint Health Score (HJHS), health-related quality of life, consumption, and safety. This post hoc analysis stratified data by hemophilia severity at baseline [moderate, factor VIII (FVIII) 1-5%; severe, FVIII <1%]. Of the 711 patients in this analysis, 582 (82%) were receiving prophylaxis with octocog alfa at enrollment, and 498 (70%) had severe disease. Median Gilbert Scores were higher with on-demand therapy versus prophylaxis and scores were comparable in moderate and severe disease. In patients receiving prophylaxis, there was an improvement in HJHS Global Gait Score over 7 years of follow-up overall and in patients with severe disease. ABRs and annualized joint bleeding rates were low across all 7 years. An ABR of zero was reported in 34-56% of prophylaxis patients versus 20-40% in the on-demand group. ABRs were similar in severe and moderate disease. In total, 13/702 (1.9%) patients experienced 18 treatment-related adverse events. These data demonstrate the long-term effectiveness and safety of octocog alfa in patients with moderate and severe hemophilia A, especially in those receiving prophylaxis. The high number of patients receiving on-demand treatment experiencing zero bleeds could be due to selection bias within the study, with patients with less severe disease more likely to be receiving on-demand treatment. ClinicalTrials.gov: NCT02078427.

Chronic Disease Outcomes As Predictors of Quality of Life in Patients with Hemophilia Α: Data from the Real-World AHEAD International Study

Background: Hemophilia A (HA), a genetic disorder caused by deficient or defective factor VIII (FVIII) clotting protein, has a significant impact on patients' quality of life (QoL).The international Antihemophilic factor Hemophilia A outcome Database (AHEAD) study (NCT02078427) is an ongoing prospective, non-interventional, multicenter study evaluating the long-term safety and effectiveness of FVIII replacement in patients with HA receiving either octocog alfa or rurioctocog alfa pegol (ADVATE®; ADYNOVATE® [US] / ADYNOVI™ [Europe]; Baxalta US Inc., a Takeda company Lexington, MA, USA) in routine clinical practice. Aim: This analysis aimed to evaluate the association between chronic disease outcomes and QoL in patients with moderate or severe HA without an active inhibitor and treated with octocog alfa. Methods:Male patients aged ≥18 years with moderate (FVIII 1-≤5%) or severe (FVIII &amp;lt;1%) HA without an active inhibitor and receiving octocog alfa were included in the analysis. Data were included across study years 1 to 5 for patients with all model variables reported in at least one study year. Cut off was set at year 5 as smaller sample sizes in later years did not allow for appropriate statistical modelling due to natural attrition and loss to follow up. The association between chronic disease outcomes and QoL was estimated using a Mixed Effects Model with repeated measures. The model assessed the impact of chronic pain (classified as no pain [used as the reference], mild pain, moderate pain, or severe pain) and number of problem joints (PJs; identified through the reporting of relevant components of the hemophilia joint health score, Gilbert Score and/or Petterson score) on EQ5D 3L index score (calculated using UK value set), controlling for clinical and demographic characteristics (annualized bleeding rate [ABR], HA severity, body mass index [BMI], and age at visit), in addition to individual patient effect, via the random effects component. The random effects component allows the model to control and account for individual patient effects that may not be measured by available independent variables but that may influence the output of the analysis. Results:The final analysis included 175 adult male patients with an average (range) of 2.1 (1-5) study years. The majority (70%) of patients had severe HA. At study year 1, the mean ± SD age was 33.6 ± 12.7 years and the mean ± SD number of PJs was 3.8 ± 2.0, while 47% of patients reported some level of chronic pain, with 20% of patients reporting moderate or severe pain levels. Mean ± SD EQ5D 3L index score was 0.77 ± 0.21 at study year 1. Overall, after controlling for demographic and clinical characteristics, and any individual patient effect, chronic outcomes (chronic pain and number of PJs) were found to have a statistically significant negative association with QoL (Table). The negative association of chronic pain with EQ5D 3L index score was greater with increasing pain level (mild, -0.082; moderate, -0.135; severe -0.169; P≤0.001). Number of PJs was also negatively associated with EQ5D 3L index score (P=0.005) with a decrease of -0.018 for each additional problem joint. Age at visit also showed a negative association with EQ5D 3L index score (-0.004; P=0.002). ABR, HA severity, and BMI did not have a statistically significant association with EQ5D 3L index score. Conclusions: In this Mixed Effects Model, chronic pain level and number of PJs both had a statistically significant negative association with QoL, highlighting the importance of managing these chronic outcomes with effective treatment.

Successful Management of Intracranial Hemorrhage with Emicizumab in a Newborn with Severe Hemophilia a: A Case Report

Introduction Intracranial hemorrhage (ICH) is the second most common first hemorrhage in neonates with congenital Hemophilia, with an incidence of 3.4-4.0%. Nearly half (41%) of ICHs occur within the first week of life. ICH is the most feared complication of hemophilia with a high rate of morbidity and up to 20% of mortality. Timely diagnosis and prompt treatment are critical, even though the clinical signs of ICH in neonates are difficult to assess. Most studies recommend infusion of Factor VIII (FVIII) rising its plasma level to 100% as soon as possible. Unfortunately, approximately 25% to 40% of neonates develop inhibitors against FVIII after substitutive treatment; the percentage may be even higher in neonates with ICH requiring prolonged continuous treatment over days to weeks. We report a case of ICH in a newborn with severe haemophilia A (HA) treated with an initial-single dose of FVIII concentrate and then only with emicizumab. Case report A male neonate, born at 38+4 weeks of gestation by cesarean delivery, presented abnormal bleeding on his third day of life after heel blood sampling. Activated Partial Thromboplastin test resulted 147 seconds and FVIII was less then 1%. Family history for bleeding disorders was negative. A cerebral ultrasound scan documented a brain area suspicious for intracranial hemorrhage. Before transferring the neonate to the neonatal intensive care unit (NICU), he received an additional intravenous dose of vitamin K and 10 ml/kg fresh frozen plasma. On admission in NICU, the neonate presented alert and responsive with stable hemodynamics and vital signs. A second brain ultrasound and head MRI confirmed an intracerebral hemorrhage in the left parieto-occipital area near the splenium of the corpus callosum associated with subdural hematoma in the left temporo-occipital, occipito-mesial area, in falx cerebri and left tentorium cerebelli. Neonate received tranexamic acid infusions 40 mg/kg die and 50 IU/Kg of intravenous recombinant factor VIII concentrate (octocog alfa). Then, it was decided to start treatment with Emicizumab, a bispecific antibody mimicking FVIII, at a dose of 3 mg/kg subcutaneously once a week for 4 weeks, continuing prophylaxis at 1.5 mg/kg once a week.Serial brain ultrasound revealed progressive reduction of the ICH extension over the following weeks; one month later, brain MRI confirmed the improvement. The neonate's clinical condition remained always stable; he never showed seizures or neurological signs of impaired consciousness and his neurodevelopment is appropriate for age. MRI performed at three months of age documented complete resolution of the cerebral hemorrhage. Discussion Intensive FVIII replacement therapy for ICH in pups is associated with a high risk of inhibitor formation.Emicizumab, a humanised bispecific monoclonal antibody, is indicated for routine prophilaxis in patients with severe HA with and without antibodies to FVIII. Emicizumab is attractive due to its weekly or even longer dosing intervals and subcutaneous route of administration but, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Theoretically, it needs few days to be hemostatically effective but its in vitro coagulant potential in neonate is heterogeneous, thus we can not completely explain the therapeutic success with only one dose of FVIII. Conclusions The combined use of emicizumab and antifibrinolytics was successful in treating acute intracranial hemorrhage. To the best of our knowledge, this is the first pediatric case of successful management of intracranial hemorrhage with emicizumab in a newborn with severe HA.

A global comparative field study to evaluate the factor VIII activity of efanesoctocog alfa by one-stage clotting and chromogenic substrate assays at clinical haemostasis laboratories.

Structural and chemical modifications of factor VIII (FVIII) products may influence their behaviour in FVIII activity assays. Hence, it is important to assess the performance of FVIII products in these assays. Efanesoctocog alfa is a new class of FVIII replacement therapy designed to provide both high sustained factor activity levels and prolonged plasma half-life. Evaluate the accuracy of measuring efanesoctocog alfa FVIII activity in one-stage clotting assays (OSAs) and chromogenic substrate assays (CSAs). Human plasma with no detectable FVIII activity was spiked with efanesoctocog alfa or a full-length recombinant FVIII product comparator, octocog alfa, at nominal concentrations of 0.80 IU/mL, 0.20 IU/mL, or 0.05 IU/mL, based on labelled potency. Clinical haemostasis laboratories (N=35) tested blinded samples using in-house assays. Data from 51 OSAs (14 activated partial thromboplastin time [aPTT] reagents) and 42 CSAs (eight kits) were analyzed. Efanesoctocog alfa activity was reliably (±25% of nominal activity) measured across all concentrations using OSAs with Actin FSL and multiple other aPTT reagents. Under- and overestimation of FVIII activity occurred with some reagents. No specific trend was observed for any class of aPTT activators. A two- to three-fold overestimation was consistently observed using CSAs and the OSA with Actin FS as the aPTT reagent across evaluated concentrations. Under- or overestimation occurred with some specific OSAs and most CSAs, which has been previously observed with other modified FVIII replacement products. Efanesoctocog alfa FVIII activity was measured with acceptable accuracy and reliability using several OSA methods and commercial plasma standards.

Characterization of an Anti-Factor VIII Inhibitor Related To P.Arg2178Cys Mutation in A Patient with Mild Haemophilia A

In patients with inherited mild haemophilia treated with clotting factor concentrates, the risk of inhibitor development is lower than in severe haemophilia. We report the observation of a 38-year-old man, with mild haemophilia A, previously treated for mucosal bleeding, who presented no major immunization risk factors except an exon 23 missense mutation p.Arg2178Cys in the F8 gene in the C1 domain. He developed an inhibitor against Octocog alfa. The implication of the mutation in this particular immunization process is well known. Characterization of this inhibitor has been extended as a type I inhibitor with classical epitope mapping and solely directed against exogenous factor VIII. Due to the occurrence of an anamnestic response associated with a high titre inhibitor, we had recourse to Eptacog alfa during a critical bleeding situation.

PB0636 Clinical Outcomes Following Treatment with Octocog Alfa in Patients with Severe Hemophilia A and Pre-Existing Target Joints: 9-year Interim Read-Out of the Real-World AHEAD International Study

PB0636 Clinical Outcomes Following Treatment with Octocog Alfa in Patients with Severe Hemophilia A and Pre-Existing Target Joints: 9-year Interim Read-Out of the Real-World AHEAD International Study

PB0666 Clinical Outcomes Following Treatment with Octocog Alfa in Patients with Hemophilia A: 9-Year Interim Read-Out of the Real-World AHEAD International Study

PB0666 Clinical Outcomes Following Treatment with Octocog Alfa in Patients with Hemophilia A: 9-Year Interim Read-Out of the Real-World AHEAD International Study

PB0632 Quality of Life Outcomes Following Treatment with Octocog Alfa in Patients with Hemophilia A: 9-Year Interim Read-Out of the Real- World AHEAD International Study

PB0632 Quality of Life Outcomes Following Treatment with Octocog Alfa in Patients with Hemophilia A: 9-Year Interim Read-Out of the Real- World AHEAD International Study

PB1268 Clinical Outcomes with Octocog Alfa in Patients with Hemophilia A in China: 1-year of Follow-up of the AHEAD International Study

PB1268 Clinical Outcomes with Octocog Alfa in Patients with Hemophilia A in China: 1-year of Follow-up of the AHEAD International Study

PB0213 Efanesoctocog Alfa vs. Standard Half-Life (Octocog Alfa) FVIII Therapies for Prophylaxis in Adolescents and Adults with Severe Hemophilia A: A Matching-Adjusted Indirect Comparison and Meta-Analysis

PB0213 Efanesoctocog Alfa vs. Standard Half-Life (Octocog Alfa) FVIII Therapies for Prophylaxis in Adolescents and Adults with Severe Hemophilia A: A Matching-Adjusted Indirect Comparison and Meta-Analysis

Effects of PK-guided prophylaxis on clinical outcomes and FVIII consumption for patients with moderate to severe Haemophilia A.

In recent years, there has been increased focus on individualizing treatment for persons with hemophilia including pharmacokinetic-guided (PK) dosing. In this retrospective study clinical outcomes before and after PK-guided prophylaxis were examined. Eight Haemophilia Treatment Centres from the United States participated in the study and included 132 patients classified into two cohorts: those undergoing a PK-assessment for product switch (switchers) or to optimize treatment (non-switchers). Subset analyses for the two most common products and patients with dosing per prescription label were included for annual bleeding rates (ABR), mean weekly consumption outcomes, and annualized cost of prophylaxis. The most common products before and after index date were octocog alfa, rurioctocog alfa pegol, and efmoroctocog alfa. Seventy-four (56%) patients were identified as switchers and 58 (44%) patients were classified as non-switchers. The majority of patients (78.0%) experienced either a decrease in ABR post-index or maintained 0 ABR during pre- and post-index time periods, with similar proportions identified in both switchers (77.0%) and non-switchers (79.3%) populations. Non-switchers were identified as having no significant change in cost of therapy, while switchers experienced increased cost of therapy driven by higher price of extended half-life products. Within subset analyses, patients receiving rurioctocog alfa pegol and efmoroctocog alfa had mean ABR under 1 after index date. PK-guided prophylaxis has the potential to improve clinical outcomes without increase in cost of therapy for patients maintaining product and can aid in maintaining effective protection against bleeds in those switching product.

Switching from Sucrose-Formulated rFVIII to Octocog Alfa (BAY 81-8973) Prophylaxis Improves Bleed Outcomes in the LEOPOLD Clinical Trials.

Previous clinical trials established the efficacy and safety of sucrose-formulated recombinant factor (F) VIII (rFVIII-FS/Kogenate FS®/Helixate FS®) and octocog alfa (BAY 81-8973/Kovaltry®; LEOPOLD trials). To report the results of a post hoc subgroup analysis assessing efficacy and safety outcomes in patients with hemophilia A who were receiving rFVIII-FS prior to enrolling into the LEOPOLD I Part B and LEOPOLD Kids Part A clinical trials and switching to octocog alfa. LEOPOLD I Part B (NCT01029340) and LEOPOLD Kids Part A (NCT01311648) were octocog alfa Phase 3, multinational, open-label studies in patients with severe hemophilia A aged 12-65 years and ≤12 years, respectively. Annualized bleeding rate (ABR) was the efficacy endpoint for both studies. Safety endpoints included adverse events (AEs) and development of FVIII inhibitors. Of the 113 patients in both LEOPOLD trials, 40 (35.4%) patients received rFVIII-FS prophylaxis pre-study and had data available for pre-study total ABR. In LEOPOLD I Part B (n = 22, 35.5%), median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) pre-study to 1.0 (0.0; 6.8), and from 1.0 (0.0; 6.0) pre-study to 0.0 (0.0; 6.02) in LEOPOLD Kids Part A (n = 18, 35.3%). Octocog alfa was well tolerated, and no patients had drug-related serious AEs or inhibitors. Treatment with octocog alfa prophylaxis appeared to have a favorable risk-benefit profile compared with rFVIII-FS and thus could be an effective and improved alternative strategy for individualized treatment for children, adolescent and adult patients with severe hemophilia A currently on rFVIII-FS treatment.

Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3.

Recombinant von Willebrand factor (rVWF, vonicog alfa, Vonvendi/Veyvondi, Takeda Pharmaceuticals USA, Lexington, MA) and several plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrates are available for treating bleeding episodes in patients with von Willebrand disease (VWD). To develop population pharmacokinetic (PK)/pharmacodynamic (PD) models that describe VWF:ristocetin cofactor (VWF:RCo) activity and its relationship with FVIII activity (FVIII:C) over time following intravenous administration of either rVWF or a pdVWF/FVIII concentrate (VWF:RCo/FVIII:C 2.4:1) in patients with VWD; to use the final PK/PD models for an in silico comparison of rVWF and pdVWF/FVIII. The population PK model for rVWF was based on data from four clinical studies in which rVWF was administered to adult patients with VWD type 1, 2 or 3 (phase 1: NCT00816660; phase 3: NCT01410227 and NCT02283268) or severe hemophilia A (phase 1: EudraCT 2011-004314-42). The PK and PK/PD models for pdVWF/FVIII were based on data from the phase 1 study (NCT00816660) in patients with type 3 VWD who received either rVWF plus recombinant FVIII (rFVIII, octocog alfa, ADVATE®, Takeda Pharmaceuticals USA, Lexington, MA, USA) or pdVWF/FVIII. There was a marked difference in clearance following rVWF administration compared with pdVWF/FVIII in type 3 VWD, leading to a ~1.75 longer mean residence time (ie, persistence of VWF:RCo activity in the body) and half-life for rVWF versus pdVWF/FVIII. Simulations showed that following repeated administration of rVWF (50 IU/kg), a FVIII:C activity of >40 IU/dL can be maintained for the full 72 h dosing interval. The slower elimination of VWF:RCo following rVWF administration results in a prolonged effect on FVIII turnover compared with pdVWF/FVIII administration.

Pharmacokinetics of recombinant factor VIII in adults with severe hemophilia A: fixed-sequence single-dose study of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa

BackgroundEfanesoctocog alfa is a new class of factor (F) VIII replacement therapy designed to provide high sustained factor levels for longer by overcoming the von Willebrand factor half-life ceiling. ObjectivesTo assess the pharmacokinetics and safety of standard half-life (octocog alfa) and extended half-life (rurioctocog alfa pegol) FVIIIs and efanesoctocog alfa. MethodsThis phase 1 study (NCT05042440; EudraCT 2021-000228-37) enrolled previously treated adult men with severe hemophilia A. Patients received sequential single 50-IU/kg doses of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa after appropriate washout periods between each dose. ResultsThirteen participants were enrolled. Geometric mean elimination half-life of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa was 11.0, 15.4, and 43.3 hours, respectively, and area under the FVIII activity-time curve was 1670, 2820, and 10,100 IU × h/dL, respectively. Efanesoctocog alfa maintained mean FVIII activity levels of >40 IU/dL for up to 4 days and at ∼10 IU/dL on day 7. Corresponding times for >40 IU/dL and >10 IU/dL were <1 and <2 days, respectively, for octocog alfa and 1 day and <3 days, respectively, for rurioctocog alfa pegol. No serious treatment-emergent adverse events were reported for efanesoctocog alfa, and no inhibitor development to FVIII was detected. ConclusionEfanesoctocog alfa had 3- to 4-fold longer elimination half-life and 3- to 6-fold greater exposure (area under the FVIII activity-time curve, 6.03 and 3.57 folds) than octocog alfa and rurioctocog alfa pegol. Efanesoctocog alfa provided high sustained FVIII activity in the normal-to-near-normal range (>40 IU/dL) for up to 4 days after the dose and at ∼10 IU/dL on day 7.

Relationship between factor VIII levels and bleeding for rFVIII-SingleChain in severe hemophilia A: A repeated time-to-event analysis.

Publications on the exposure-effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII-SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII-SingleChain prophylaxis from three clinical trials were combined. The published rFVIII-SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time-to-event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one-stage assay FVIII levels from 241 persons (median age 19 years) followed for median 1090 days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow-up and a FVIII level of 8.9IU/dL (95% confidence interval: 6.9-10.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre-study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3IU/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0-17) or one (90% PI: 0-11) bleeds per year, respectively. In conclusion, the developed PK-RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII-SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81-8973 (octocog alfa) and BAY 94-9027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding.

Budget impact of prophylactic treatment of rVIII-SingleChain in moderate and severe hemophilia A in Italy

IntroductionrVIII-SingleChain, a recombinant factor VIII (rFVIII), has demonstrated safety and efficacy in patients with hemophilia A in clinical trials and real-world evidence. This analysis aimed to estimate the potential budget impact of increasing the usage of rVIII-SingleChain for the prophylactic treatment of hemophilia A over 3 years in Italy.MethodsPatients with moderate and severe hemophilia A receiving prophylaxis were included in the analysis. Epidemiological data were obtained from published literature. Mean product consumption and mean annual bleeding rate for rVIII-SingleChain, rFVIIIFc, octocog alfa and BAY 81-8973 were based on pooled real-world data from Italy, Germany and US. A budget impact model has been developed in order to compare two scenarios: a base-case scenario where current rVIII-SingleChain shares are kept constant over 3 years and an alternative scenario where rVIII-SingleChain shares increase by taking from other rFVIII products. Analysis 1 was based on the current Italian list prices and Analysis 2 considered current regional acquisition prices for both scenarios.ResultsAnnually, adult patients treated with rVIII-SingleChain prophylaxis are expected to consume 324,589 units per patient, resulting in annual costs of €240,196 per patient. In Analysis 1, comparing the base case (constant market share of 9% rVIII-SingleChain over time) with the alternative scenario (higher rVIII-SingleChain market share and increasing from 15% in the first year to 25% in the third year), the total expenditure for prophylaxis using rFVIII products is expected to decrease by €1.4 million in Year 1, by €3.1 million in Year 2 and by €5.4 million in Year 3. In Analysis 2 based on regional prices, the results remained consistent.Discussion/ConclusionThis analysis suggests that increasing utilization of rVIII-SingleChain in hemophilia A patients may lead to cost savings as a result of reduced consumption with uncompromised efficacy in bleed protection.