Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial.

Importance: Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption. Objective: To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion. Design, Setting, and Participants: Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021. Interventions: Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines. Main Outcomes and Measures: The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety). Results: Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03). Conclusions and Relevance: Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion. Trial Registration: ClinicalTrials.gov Identifier: NCT03218722.

Hemostatic Management in an Infant With Neuroblastoma and Severe Hemophilia B With Extended Half-life Recombinant Factor IX Fusion Protein.

In the rare co-occurrence of childhood cancer and severe hemophilia, hemostatic management is of paramount therapeutic importance. We present the case of an 11-month-old boy with severe congenital hemophilia B, who was diagnosed with metastatic high-risk neuroblastoma. He consequently developed paraneoplastic coagulopathy with life-threatening tumor hemorrhage and intracranial hemorrhage, showing central nervous system relapse. Management consisted of factor IX replacement with extended half-life factor IX fusion protein, adjusted to bleeding risk. Additional interventions included factor XIII, fibrinogen, fresh frozen plasma, tranexamic acid, and platelet transfusions. The half-life of factor IX products was markedly reduced requiring close factor IX monitoring and adequate replacement. This intensified treatment allowed chemotherapy, autologous stem cell transplantation, and GD2 antibody immune therapy without bleeding or thrombosis.

How do we optimally utilize factor concentrates in persons with hemophilia?

The current mainstay of therapy for hemophilia is to replace the deficient clotting factor with the intravenous administration of exogenous clotting factor concentrates. Prophylaxis factor replacement therapy is now considered the standard of care in both pediatric and adult patients with hemophilia with a severe phenotype to protect musculoskeletal health and improve quality of life. Heterogeneity in bleeding presentation among patients with hemophilia due to genetic, environmental, and treatment-related factors has been well described. Accordingly, the World Federation of Hemophilia recommends an individualized prophylaxis regimen that considers the factors mentioned above to meet the clinical needs of the patient, which can vary over time. This review focuses on the practical points of choosing the type of factor concentrate, dose, and interval while evaluating appropriate target trough factor levels and bleeding triggers such as level of physical activity and joint status. We also discuss the use of a pharmacokinetics assessment and its incorporation in the clinic for a tailored approach toward individualized management. Overall, adopting an individualized prophylaxis regimen leads to an optimal utilization of factor concentrates with maximum efficacy and minimum waste.

Réévaluation de RebinynMC (nonacog bêta pégol): hémophilie de type B / RebinynTM (nonacog beta pegol): type B Hemophilia (re-evaluation)

MANDAT: À la demande du fabricant Novo Nordisk Canada Inc., l'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à la réévaluation du produit du système du sang RebinynMC (nonacog bêta pégol), un facteur IX (FIX) de coagulation humain recombinant à demi-vie prolongée qui s'administre par voie intraveineuse. Au Canada, le nonacog bêta pégol est indiqué pour la maîtrise et la prévention des épisodes hémorragiques ainsi que pour la maîtrise et la prévention des saignements dans un contexte périopératoire chez les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas). Il est aussi indiqué pour la prophylaxie de routine afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence chez les patients de 18 ans et plus atteints d'hémophilie B. Les indications visées pour cette réévaluation sont identiques à celles reconnues par Santé Canada. Le nonacog bêta pégol a déjà été évalué par l'INESSS (avis de juin 2020). Lors de son évaluation précédente, l'INESSS a formulé une recommandation défavorable à son ajout sur la Liste des produits du système du sang du Québec, car la valeur thérapeutique n'avait pas été reconnue par le Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription (CSEMI). Il s'agit de la deuxième évaluation de ce produit. Les cinq FIX suivants sont présentement inscrits sur la Liste des produits du système du sang du Québec et ont servi de comparateurs : BeneFIXMC (nonacog alfa; FIX recombinant à action standard), RixubisMC (nonacog gamma; FIX recombinant à action standard), AlprolixMC (eftrénonacog alfa; FIX recombinant à demi-vie prolongée), IdelvionMC (albutrepenonacog alfa; FIX recombinant à demi-vie prolongée), ImmunineMC (FIX d'origine plasmatique). DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du nonacog bêta pégol. Des données contextuelles et expérientielles issues de la consultation d'experts sont également présentées. DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du nonacog bêta pégol. Des données contextuelles et expérientielles issues de la consultation d'experts sont également présentées. BESOIN DE SANTÉ: L'hémophilie B, causée par une défaillance du FIX, se manifeste par des temps de coagulation plus longs que la normale. Dans les cas sévères, le déficit en FIX mène à des épisodes de saignement fréquents aux articulations, appelés hémarthroses, et aux tissus mous même sans traumatisme. La prophylaxie à l'aide de FIX plasmatique ou recombinant constitue le traitement privilégié. Celle-ci consiste en plusieurs injections intraveineuses hebdomadaires pour remplacer le FIX manquant. Malgré une bonne prise en charge de l'hémophilie B au Québec, certaines lacunes liées aux traitements actuels demeurent. Outre le souhait d'un traitement curatif permanent, les besoins suivants ont été reconnus par les experts rencontrés : une meilleure prévention contre le développement d'inhibiteurs (anticorps neutralisants contre le FIX), la prévention d'arthropathies hémophiliques et des douleurs chroniques, des traitements offrant une protection hémostatique supérieure qui perdure plus longtemps et l'atténuation des contraintes liées aux injections intraveineuses répétées. RÉSULTATS: La combinaison des données d'une étude canadienne en contexte réel de soins, des données du rapport de surveillance postcommercialisation du nonacog bêta pégol et des données des études cliniques évaluées aux fins de l'avis précédent a été considérées. PERSPECTIVE DES EXPERTS: À la lumière des données présentées dans le cadre de cette réévaluation, les experts consultés sont d'avis que l'efficacité de la prophylaxie avec le nonacog bêta pégol est comparable à celle des comparateurs, soit tous les FIX inscrits à la Liste. Selon les experts, le profil de l'innocuité du nonacog bêta pégol est comparable à celui des autres options disponibles pour la population ciblée. De plus, les préoccupations relatives à l'accumulation potentielle de PEG dans le plexus choroïde demeurent théoriques chez l'humain et ne les empêcheraient pas d'utiliser le produit chez la population québécoise indiquée. RECOMMANDATIONS DE L'INESSS SUR LE NONACOG BÊTA PÉGOL: À la lumière des informations disponibles, l'INESSS recommande d'ajouter RebinynMC (nonacog bêta pégol) à la Liste des produits du système du sang du Québec pour la maîtrise et la prévention des épisodes hémorragiques et la maîtrise et la prévention des saignements dans un contexte périopératoire chez les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas) ainsi que pour la prophylaxie de routine afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence chez les patients de 18 ans ou plus atteints d'hémophilie B. Précision sur la recommandation: Dans une perspective de justice distributive, le remboursement du nonacog bêta pégol pour l'indication demandée constituerait une décision responsable, juste et équitable si le coût d'utilisation du nonacog bêta pégol ne surpasse pas celui des FIX à demi-vie prolongée lors du prochain appel d'offres.

MANDATE: At the request of the manufacturer Novo Nordisk Canada Inc., the Institut national d'excellence en santé et en services sociaux (INESSS) re-evaluated the blood system product RebinynTM (nonacog beta pegol), an intravenously injected recombinant factor IX (FIX) indicated in adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. The indications assessed for this re-evaluation are identical to those accorded by Health Canada. INESSS previously evaluated nonacog beta pegol (evaluation of June 2020). During the first evaluation, INESSS issued an unfavourable recommendation for the addition of the product to the Liste des produits du système du sang du Québec because the therapeutic value had not been recognized by the Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscriptions (CSEMI). This is the second evaluation of this product. The following five FIX currently listed on the Liste des produits du système du sang du Québec were used as the comparators of nonacog beta pegol: BeneFIXTM (nonacog alfa; standard half-life recombinant FIX), RixubisTM (nonacog gamma; standard half-life recombinant FIX), AlprolixTM (eftrénonacog alfa; extended half-life recombinant FIX), IdelvionTM (albutrepenonacog alfa; extended half-life recombinant FIX), ImmunineTM (plasma-derived FIX). EVALUATION PROCESS: Published trials and manufacturer data were reviewed to document the efficacy, safety and efficiency of nonacog beta pegol. Experiential and contextual data from expert consultations and patients are presented as well. HEALTH NEED: Type B hemophilia is caused by a deficiency in FIX and is characterized by longer clotting times. In severe cases, FIX deficiency leads to frequent bleeding episodes in joints (hemarthrosis) and soft tissue in the absence of trauma. Prophylaxis with plasma or recombinant FIX is the preferred treatment. This consists of several weekly intravenous injections to replace the missing FIX. Despite a good management of Quebecers living with type B hemophilia, the need for new treatment remains. In addition to permanent curative treatment, the following needs were identified by the experts consulted: better prevention of inhibitor development (neutralizing antibodies against FIX), prevention of hemophilic arthropathies and chronic pain, treatments that provide superior hemostatic protection that lasts longer and alleviates the stresses associated with repeated intravenous injections. RESULTS: Combined data from a real-world Canadian study, a post-market surveillance report on nonacog beta pegol, as well as previously evaluated clinical studies were considered for this evaluation. RECOMMANDATIONS DE L'INESSS SUR LE NONACOG BÊTA PÉGOL: In light of the available data, INESSS recommends that RebinynTM (nonacog beta pegol) be added to the Liste des produits du système du sang du Québec for the treatment of hemophilia B (congenital factor IX deficiency or Christmas disease) in adults and children for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Precision regarding the recommendation: From a distributive justice perspective, the reimbursement of nonacog beta pegol for the requested indication would constitute a responsible, fair and equitable decision if the cost of using nonacog beta pegol does not exceed that of extended half-life FIX during the next call for tenders.

Bleeding outcomes and factor utilization after switching to an extended half-life product for prophylaxis in haemophilia A in Austria.

To prevent bleeding in severe haemophilia A [SHA, defined as factor VIII (FVIII) activity < 1%] regular prophylactic FVIII replacement therapy is required, and the benefits of factor products with extended half-life (EHL) over traditional standard half-life (SHL) are still being debated. We performed a multi-centre, retrospective cohort study of persons with SHA in Austria aiming to compare clinical outcomes and factor utilization in patients with SHA, who switched from prophylaxis with SHL to an EHL. Data were collected from haemophilia-specific patient diaries and medical records. Twenty male persons with SHA (median age: 32.5 years) were included. The most common reason for switching to the EHL was a high bleeding rate with SHL. Switch to rFVIII-Fc resulted in a significantly decreased annualized bleeding rate (ABR; median difference (IQR): - 0.3 (- 4.5-0); Wilcoxon signed-rank test for matched pairs: Z = - 2.7, p = 0.008) and number of prophylactic infusions per week (- 0.75 (- 1.0-0.0); Z = - 2.7, p = 0.007). Factor utilization was comparable to prior prophylaxis with SHL (0.0 (- 15.8-24.8) IU/kg/week; Z = - 0.4, p = 0.691). In summary, switch to EHL (rFVIII-Fc) was associated with an improved clinical outcome, reflected by ABR reduction, and less frequent infusions, without significantly higher factor usage.

First open-label, single-arm, prospective study of real-world use of FIX replacement therapy in a predominantly pediatric hemophilia B population in China.

BACKGROUND: Nonacog alfa (recombinant factor IX [FIX]) is approved in China for the control and prevention of bleeding events in patients with hemophilia B. This was the first study to assess prophylaxis and on-demand therapy with recombinant FIX replacement in a real-world setting in China. This study aimed to evaluate the safety and efficacy of nonacog alfa in Chinese patients with hemophilia B. METHODS: In this open-label, multicenter study (clinicaltrials.gov identifier NCT02336178), patients received on-demand or prophylactic treatment with intravenous nonacog alfa for approximately 6 months or 50 exposure days, whichever occurred first. The primary safety outcome was medically important events (i.e., development of FIX inhibitors, allergic reactions, and thrombotic events). Key secondary efficacy outcomes included the annualized bleeding rate for on-demand treatment and prophylaxis, response to on-demand treatment, the number of infusions per bleeding event, and the number of breakthrough bleeding events within 48 hours of prophylaxis. RESULTS: Seventy male patients (mean [standard deviation] age 7.8 [7.2] years) were enrolled (on-demand, n = 37; prophylaxis, n = 57 [24 patients were included in both groups]). Thirty-eight (54%) patients had up to 50 FIX exposure days before the study. The only medically important event was a transient low-titer FIX inhibitor (incidence 1.4%, 95% confidence interval, 0-7.7). The mean annualized bleeding rate was 26.3 for on-demand treatment and 6.5 for prophylaxis. A mean (standard deviation) of 1.5 (1.7) nonacog alfa infusions were given per bleeding episode; 78.8% of episodes resolved with 1 infusion. Response was "excellent" or "good" for 88% of the on-demand infusions. Twenty-three bleeding events (n = 11 patients) occurred within 48 hours of 2032 prophylaxis doses (1.13%). CONCLUSION: In the real-world setting, nonacog alfa is safe and effective for on-demand treatment and for prophylaxis for patients with hemophilia B in China.

In silico comparison of pharmacokinetic properties of three extended half-life factor IX concentrates.

PURPOSE: Pharmacokinetic (PK) differences between the extended half-life (EHL) factor IX (FIX) concentrates for hemophilia B exist, which may influence hemostatic efficacy of replacement therapy in patients. Therefore, we aimed to evaluate the PK properties of three EHL-FIX concentrates and compare them to a standard half-life (SHL) recombinant FIX (rFIX) concentrate. METHODS: Activity-time profiles of PEGylated FIX (N9-GP), FIX linked with human albumin (rIX-FP), FIX coupled to human IgG1 Fc-domain (rFIXFc), and SHL rFIX were simulated for 10,000 patients during steady-state dosing of 40 IU/kg once weekly (EHL-FIX) and biweekly (rFIX) using published concentrate specific population PK models. RESULTS: Half-lives were respectively 80, 104, and 82 h for N9-GP, rIX-FP, and rFIXFc versus 22 h for rFIX. Between the EHL concentrates, exposure was different with area under the curve (AUC) values of 78.5, 49.6, and 12.1 IU/h/mL and time above FIX target values of 0.10 IU/mL of 168, 168, and 36 h for N9-GP, rIX-FP, and rFIXFc, respectively. N9-GP produced the highest median in vivo recovery value (1.70 IU/dL per IU/kg) compared with 1.18, 1.00, and 1.05 IU/dL per IU/kg for rIX-FP, rFIXFc, and rFIX, respectively. CONCLUSIONS: When comparing EHL products, not only half-life but also exposure must be considered. In addition, variation in extravascular distribution of the FIX concentrates must be taken into account. This study provides insight into the different PK properties of these concentrates and may aid in determination of dosing regimens of EHL-FIX concentrates in real-life.

Continuous infusion factor replacement in haemophilia B during and after cardiac surgery: the better choice?

A 57-year-old man with mild haemophilia B was admitted for coronary artery bypass graft surgery. His factor IX (FIX) activity was 15% on admission. Our goal was to maintain his FIX activity at 80%-100% for post-op days (PODs) 0-3, and at 60%-80% for PODs 4-14. Preoperatively, the patient was given recombinant FIX (rFIX) bolus using the formula:Dosage needed=%(desired FIX level-current level of FIX)×weight (kg)×1.3.This increased his activity to 100%. One IU of rFIX increased FIX activity by 0.8%; the half-life of rFIX is 18-24 hours. The rFIX infusion was started intraoperatively and continued after surgery to maintain target FIX activity. He was discharged on POD 9 on rFIX bolus dosing of 5000 IU every 12 hours for an additional 5 days. Using continuous factor infusion, we managed to decrease the amount rFIX used by >60% while maintaining steady state FIX activity level.

Clinical, pharmacokinetic and economic analysis of the first switch to an extended half-life factor IX (albutrepenonacog alfa, rFIX-FP) in Spain.

Extended half-life of factor IX (FIX) demonstrated clinical benefit and lower treatment burden than standard half-life FIX products in clinical trials. We analysed the impact in efficacy, pharmacokinetics (PKs) and costs of the switch from nonacog alfa (rFIX) to albutrepenonacog alfa (rFIX-FP) in the first patient with haemophilia B (HB) treated in Spain outside clinical trials. A 7-year-old boy presented with HB with poor venous access and repetition infections using rFIX, which was switched to rFIX-FP. Prophylaxis was adjusted by PKs using WAPPS-Hemo tailoring from 100 IU/kg/week of rFIX to 80 IU/kg/3 weeks of rFIX-FP. Comparing 6 months before, rFIX-FP reduced 68.5% FIX consumption/kg and 58.3% infusion frequency, but total costs/weight showed a slight increase. Ratio of half-life between rFIX and rFIX-FP was 3.4-3.7. This case report revealed that switch to rFIX-FP decreased frequency and FIX consumption, without adverse events and bleeds.

Preclinical evaluation of a next-generation, subcutaneously administered, coagulation factor IX variant, dalcinonacog alfa.

INTRODUCTION: The rapid clearance of factor IX necessitates frequent intravenous administrations to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous administration has historically been limited by low bioavailability and potency. Dalcinonacog alfa was developed using a rational design approach to be a subcutaneously administered, next-generation coagulation prophylactic factor IX therapy. AIM: This study aimed to investigate the pharmacokinetic, pharmacodynamic, and safety profile of dalcinonacog alfa administered subcutaneously in hemophilia B dogs. METHODS: Two hemophilia B dogs received single-dose daily subcutaneous dalcinonacog alfa injections for six days. Factor IX antigen and activity, whole blood clotting time, and activated partial thromboplastin time were measured at various time points. Additionally, safety assessments for clinical adverse events and evaluations of laboratory test results were conducted. RESULTS: There was an increase in plasma factor IX antigen with daily subcutaneous dalcinonacog alfa. Bioavailability of subcutaneous dalcinonacog alfa was 10.3% in hemophilia B dogs. Daily subcutaneous dosing of dalcinonacog alfa demonstrated the effects of bioavailability, time to maximal concentration, and half-life by reaching a steady-state activity sufficient to correct severe hemophilia to normal, after four days. CONCLUSION: The increased potency of dalcinonacog alfa facilitated the initiation and completion of the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B.

Treatment patterns and bleeding outcomes in persons with severe hemophilia A and B in a real-world setting.

The current standard of care treatment for severe hemophilia A and B (SHA and SHB) is the prophylactic intravenous replacement of coagulation factor VIII or IX (FVIII/FIX) to prevent spontaneous bleeding. Persons with hemophilia without prophylactic treatment receive therapy in case of bleeding, i.e., on demand. To assess treatment patterns, utilization of products, and bleeding outcomes in a real-world cohort of persons with SHA and SHB, defined as FVIII or FIX activity < 1%, data was retrospectively collected from hemophilia-specific patient diaries used for home treatment, medical records, and entries into the Austrian Hemophilia Registry from the year 2012 to 2017. Fifty-three male persons with SHA (n = 47) and SHB (n = 6) were included; 26 with SHA and 5 with SHB were on prophylaxis, 8 and 1 switched therapy regimen, and 13 and 0 received on-demand therapy. Persons on prophylaxis used a mean factor FVIII or FIX dose of 71.7 and 40.1 IU/kg/week. Median (IQR) annualized bleeding rates (ABR) in SHA were 28.0 (23.4-31.3) in the on-demand, 4.9 (1.6-13.5) in the prophylaxis group, and 3.0 (2.0-6.8) in the prophylactic group of SHB. Three persons with SHA had zero bleeds during the observation period. On-demand therapy and hepatitis B and C were associated with higher ABR but not age, weight, and HIV positivity. Bleeding rates and the proportion of on-demand therapy in persons with hemophilia were high in our real-world cohort. Further improvement is needed, which might be facilitated with the advent of factor products with extended half-life or non-factor therapies.

The Evolution of Hemophilia Care: Clinical and Laboratory Advances, Opportunities, and Challenges.

Hemophilia A (HA) and B (HB) are X-linked bleeding disorders caused by mutations in the F8 or F9 gene that result in the absence, or reduced activity, of the corresponding clotting factor. The severity of bleeding and related complications is proportional to the amount of residual circulating functional factor. The development of a safe and effective hemophilia treatment lasted several decades and has been mainly based on clotting factor replacement. Advances in the engineering and manufacturing of clotting concentrates have led to the widespread availability of extended half-life products that reduced the number of intravenous infusions needed to achieve adequate trough levels. The recent development of new nonfactor replacement treatments and biotechnology techniques has offered therapeutic alternatives for hemophilia patients with and without inhibitors. These are characterized by an easier route of administration, low immunogenicity, and, regarding gene therapy and cell-based treatments, potential long-term protection from bleeding after a single treatment course. In this review, we analyze recent progresses in the management of hemophilia and discuss opportunities and challenges.

High adherence to prophylaxis regimens in haemophilia B patients receiving rIX-FP: Evidence from clinical trials and real-world practice.

INTRODUCTION: Adherence to prophylaxis regimens is essential for bleed prevention in haemophilia but remains a challenge due to the need for frequent infusions. AIM: To evaluate patient adherence to prophylaxis regimens with a long-acting recombinant factor IX (rIX-FP; IDELVION® ) in clinical studies and real-world practice. METHODS: In two phase 3 clinical studies, patients with haemophilia B (FIX ≤2%) recorded their dose, dosing frequency and rIX-FP consumption in an e-diary. Adherence to prescribed prophylaxis regimens was assessed in all patients and to prescribed dose in patients ≥12 years only. Additionally, adherence to rIX-FP prophylaxis regimens in real-world practice was captured. RESULTS: In clinical studies, 94.9% (n = 56/59) of patients ≥12 years and 100% (n = 27) of paediatric patients received ≥80% of the expected number of infusions for their assigned prophylaxis schedule. Overall, mean adherence rate was 95.5% across all prophylaxis regimens in patients ≥12 years and 97.9% with a 7-day regimen in paediatric patients. In patients ≥12 years, 85.7% (n = 54/63) were dose adherent, defined as receiving within 10% of their prescribed dose ≥80% of the time. In real-world practice, adherence was observed in 100% (n = 14 and n = 15, respectively) of patients in two haemophilia treatment centres and 57.1% (n = 4/7) of patients in a third centre; non-adherence (n = 3/7) was linked to insurance-related and parental issues. CONCLUSION: In clinical studies, patients with haemophilia B had high adherence rates to rIX-FP prophylaxis regimens with a variety of dosing intervals, enabling them to achieve very low bleeding rates. High adherence may also be achievable in real-world practice.

Model-Based Evaluation of Linear Limited and Bayesian Sparse Sampling for Therapeutic Monitoring of Recombinant Coagulation Factor IX.

Dosing of coagulation factor products is mainly determined based on a patient's body weight; however, several studies have reported high interindividual variability in their pharmacokinetics (PK). The objective of this study was to develop and evaluate 2 sparse sampling methods for the estimation of AUC of recombinant factor IX (BeneFIX) as proof of concept for dose individualization. A population pharmacokinetic model was used to generate the plasma factor IX activity-versus-time data. The linear limited sampling model (LLSM) was developed based on the correlation of factor IX activity versus AUC0-72 hours following screening of several blood sampling times in adolescent and adult subjects (n = 90 subjects). Factor IX trough concentrations were predicted from a relationship established from AUC versus factor IX activity measured 72 hours postdosing. Using the best selected sampling time, the LLSM and Bayesian model were validated in separate data sets (n = 75 subjects). Using the LLSM and Bayesian analysis, a blood sample at 24 hours predicted AUC with bias and root mean square error < 5% and < 15%, respectively. The predicted trough concentrations were ≥1 IU/dL in 99% and 100% of subjects by the LLSM and Bayesian model, respectively. The average factor IX dose for a target AUC of 800 IU·h/dL was 61, 60, and 63 IU/kg using the extensive (reference), LLSM and Bayesian model, respectively. Overall, the AUC, trough concentrations and individualized dosing of recombinant factor IX could be reasonably predicted using the LLSM and Bayesian model.

The availability of new drugs for hemophilia treatment.

INTRODUCTION: A number of new FVIII/IX concentrates enriched the portfolio of products available for the treatment of hemophilia A/B patients. Due to the large inter-patient variability, accurate tailoring of the therapy became essential to improve patients' adherence, clinical outcomes, and cost/effectiveness ratio. Recently, non-replacement therapies have taken the limelight and succeeded in decreasing the bleedings of patients. AREAS COVERED: The PK characteristics, efficacy, and safety of the new rFVIII and rFIX concentrates and of non-replacement therapy, are reported in detail in the published clinical trials. EXPERT OPINION: Outstanding improvements of rFIX concentrates' pharmacokinetics and pharmacodynamics have allowed to reduce the bleedings in hemophilia B patients, in order to increase their adherence to prophylaxis and quality of life. Less significant are the effects of pegylation or Fc fusion on the pharmacokinetics of the new rFVIII concentrates. The new non-replacement therapy is achieving the favor of many treaters and patients, in particular those with Factor VIII inhibitors. Great attention must be paid to the dangerous synergy of APCC and emicizumab, responsible for some fatal events during the clinical trials and compassionate use of this drug. So far, replacement therapy should be the standard of care for hemophilia patients without inhibitors or difficulties in venous access.

RebinynMC, Facteur IX de coagulation (recombinant): nonacog bêta pégol / RebinynTM (nonacog beta pegol): coagulation factor IX (recombinant)

MANDAT: L'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à l'évaluation du produit du système du sang RebinynMC (nonacog bêta pégol, N9-GP), un facteur IX recombinant (FIXr) administré par injection intraveineuse. Le nonacog bêta pégol est indiqué chez les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas) pour la maîtrise et la prévention des épisodes hémorragiques et la maîtrise et la prévention des saignements dans un contexte périopératoire ainsi que chez les patients de 18 ans ou plus atteints d'hémophilie B pour la prophylaxie de routine, afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence. Quatre FIX recombinants sont présentement inscrits à la Liste des produits du système du sang du Québec et ont été utilisés comme comparateurs : BeneFIXMC (nonacog alfa), RixubisMC (nonacog gamma), AlprolixMC (eftrénonacog alfa) et IdelvionMC (albutrepenonacog alfa). DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du nonacog bêta pégol. Des données expérientielles et contextuelles issues de la consultation d'experts et de patients sont également présentées. BESOIN DE SANTÉ: L'hémophilie B est une pathologie génétique récessive liée au chromosome X et caractérisée par un déficit congénital en facteur IX (FIX). Ce déficit se traduit par un temps de coagulation prolongé menant à des épisodes de saignements fréquents aux articulations (hémarthroses), aux muscles, ainsi qu'aux muqueuses. Certains épisodes de saignements peuvent mettre en danger la vie de l'individu ou mener à des handicaps moteurs importants. Les traitements de remplacement par FIX actuels permettent aux hémophiles de type B du Québec de prévenir et de traiter leurs épisodes de saignements. Parmi les besoins recensés auprès des experts et patients consultés, on retrouve une meilleure prévention contre le développement d'inhibiteurs, la prévention d'arthropathies hémophiliques et des douleurs chroniques, des traitements offrant une protection hémostatique supérieure qui perdure plus longtemps et l'atténuation des contraintes liées aux injections intraveineuses répétées. RÉSULTATS: Les résultats d'efficacité du nonacog bêta pégol sont basés sur quatre études de phase III ouvertes et non contrôlées. En raison de la restriction de l'indication du nonacog bêta pégol, les résultats de l'efficacité de la prophylaxie à long terme pour les moins de 18 ans n'ont pas été considérés. La force de la preuve de l'efficacité du nonacog bêta pégol a été jugée très faible. DÉLIBÉRATION SUR LE NONACOG BÊTA PÉGOL: Délibération RebinynMC: Les membres du Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription sont unanimement d'avis que la valeur thérapeutique de RebinynMC n'est pas démontrée pour les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas) pour la maîtrise et la prévention des épisodes hémorragiques et la maîtrise et la prévention des saignements dans un contexte périopératoire ainsi que chez les patients de 18 ans ou plus atteints d'hémophilie B pour la prophylaxie de routine, afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence. MOTIFS DE LA POSITION UNANIME: Les membres du Comité ont reconnu l'importance du fardeau associé à la prise en charge de la maladie. Ils ont également reconnu que la fréquence réduite des injections représente un avantage pour les patients. Néanmoins, après un examen minutieux de l'ensemble de la preuve, les constats suivants ont été établis: En raison de la faiblesse de la preuve, les études disponibles ne permettent pas de reconnaitre une valeur thérapeutique non inférieure à RebinynMC par rapport aux autres produits actuellement disponibles; Des préoccupations ont été soulevées par les membres en lien avec l'accumulation de PEG dans le cerveau des animaux observée lors d'études précliniques ainsi qu'aux risques potentiels à long terme leur étant associés; Considérant la disponibilité d'autres options de traitement bien établies, les membres préconisent la prudence. CONSIDÉRANT LA DISPONIBILITÉ D'AUTRES OPTIONS DE TRAITEMENT BIEN ÉTABLIES, LES MEMBRES PRÉCONISENT LA PRUDENCE: À la lumière des informations disponibles, l'INESSS ne recommande pas l'ajout de RebinynMC (nonacog bêta pégol) à la Liste des produits du système du sang du Québec puisque la valeur thérapeutique du produit n'a pas été démontrée. Davantage de données d'efficacité et d'innocuité provenant d'études avec un meilleur niveau de preuve sont requises pour soutenir une reconnaissance de la valeur thérapeutique.

MANDATE: The Institut national d'excellence en santé et en services sociaux (INESSS) evaluated the blood system product RebinynTM (nonacog beta pegol), an intravenously injected recombinant factor IX (FIX) indicated in adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. The following four recombinant FIX, currently indicated for the treatment of hemophilia B and listed in the Liste des produits du système du sang du Québec, served as comparators: BeneFIXTM (nonacog alfa), RixubisTM (nonacog gamma), AlprolixTM (eftrenonacog alfa) et IdelvionTM (albutrepenonacog alfa). EVALUATION PROCESS Published trials and manufacturer data were reviewed to document the efficacy, safety and efficiency of nonacog beta pegol. Experiential and contextual data from expert consultations and patients are presented as well. HEALTH NEED: Hemophilia B is an X chromosome-linked recessive genetic disease characterized by coagulation factor IX (FIX) deficiency. This deficiency prolongs coagulation times, which can lead to frequent bleeding episodes in the joints (hemarthrosis), muscles and mucus membranes. Some bleeding events can also lead to severe motor handicaps or even be life-threatening. The current FIX replacement therapies enable Quebecers who are type B hemophiliacs to prevent or stop their bleeding episodes. Experts and patients were queried about health needs in the hemophilia B community. Treatments that better prevent the development of inhibitors, hemophiliac arthropathies and chronic pain, and therapies that provide superior, longer-lasting hemostatic protection with fewer intravenous injections were among the needs mentioned most frequently. RESULTS: Efficacy: The efficacy evaluation for nonacog beta pegol was based on four phase III, open-label and non-controlled trials. As a result of the restriction of the indication, efficacy results for the prophylactic use of nonacog beta pegol in children and adolescents under 18 years f age were not considered. The overall efficacy evidence was considered very low. DELIBERATION ON NONACOG BETA PEGOL: Deliberation on RebinynTM: Members of the Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription (CSEMI) unanimously share the opinion that the therapeutic value of RebinynTM (nonacog beta pegol) has not been demonstrated for the treatment of hemophilia B (congenital factor IX deficiency or Christmas disease) in adults and children for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Reasons for the unanimous position: Members of the Committee recognized the considerable burden associated with the disease. They also recognized that the reduced injection frequency is considered an advantage for patients. Nevertheless, after careful examination of all the evidence, the following observations were made: Given the weakness of the evidence, the available studies do not permit us to conclude that the therapeutic value of nonacog beta pegol is noninferior to that of the other recombinant FIXs currently available; Concerns were raised by the members of the CSEMI regarding the accumulation of PEG in the brain of animals during preclinical studies as well as the potential risks associated with long term deposits of PEG; Considering the availability of safer therapeutic options, the members advise caution. INESSS' recommendation regarding RebinynTM: In light of the available data, INESSS recommends that RebinynTM (nonacog beta pegol) not be added to the Liste des produits du système du sang du Québec since the product's therapeutic value has not demonstrated. Additional efficacy and safety data with a higher level of evidence are required to support the therapeutic value for the proposed indications.

A hemophilia A mouse model for the in vivo assessment of emicizumab function.

The bispecific antibody emicizumab is increasingly used for hemophilia A treatment. However, its specificity for human factors IX and X (FIX and FX) has limited its in vivo functional analysis to primate models of acquired hemophilia. Here, we describe a novel mouse model that allows emicizumab function to be examined. Briefly, FVIII-deficient mice received IV emicizumab 24 hours before tail-clip bleeding was performed. A second infusion with human FIX and FX, administered 5 minutes before bleeding, generated consistent levels of emicizumab (0.7-19 mg/dL for 0.5-10 mg/kg doses) and of both FIX and FX (85 and 101 U/dL, respectively, after dosing at 100 U/kg). Plasma from these mice display FVIII-like activity in assays (diluted activated partial thromboplastin time and thrombin generation), similar to human samples containing emicizumab. Emicizumab doses of 1.5 mg/kg and higher significantly reduced blood loss in a tail-clip-bleeding model using FVIII-deficient mice. However, reduction was incomplete compared with mice treated with human FVIII concentrate, and no difference in efficacy between doses was observed. From this model, we deducted FVIII-like activity from emicizumab that corresponded to a dose of 4.5 U of FVIII per kilogram (ie, 9.0 U/dL). Interestingly, combined with a low FVIII dose (5 U/kg), emicizumab provided enough additive activity to allow complete bleeding arrest. This model could be useful for further in vivo analysis of emicizumab.

Long-Term Safety and Efficacy of Nonacog Beta Pegol (N9-GP) Administered for at Least 5 Years in Previously Treated Children with Hemophilia B.

Long-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis (N = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%).

Factor VIII and IX assays for post-infusion monitoring in hemophilia patients: Guidelines from the French BIMHO group (GFHT).

Replacement therapy with plasma-derived or recombinant FVIII and FIX (pdFVIII/pdFIX or rFVIII/rFIX) concentrates is the standard of treatment in patients with haemophilia A and B, respectively. Measurement of factor VIII (FVIII:C) or factor IX (FIX:C) levels can be done by one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). The French study group on the Biology of Hemorrhagic Diseases (a collaborative group of the GFHT and MHEMO network) presents a literature review and proposals for the monitoring of FVIII:C and FIX:C levels in treated haemophilia A and B patients, respectively. The use of CSA is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. Except for rFVIII-Fc, great caution is required when measuring FVIII:C levels by OSA in patients substituted by EHL-rFVIII. The OSA is recommended for the monitoring of patients treated with pdFIX or rFIX. Large discordances in the FIX:C levels measured for extended half-life rFIX (EHL-rFIX), depending on the method and reagents used, must lead to great attention when OSA is used for measuring FIX:C levels in patients substituted by EHL-rFIX. Data of most of recent studies, obtained with spiked plasmas, deserve to be confirmed in plasma samples of treated patients.

Real-world assay variability between laboratories in monitoring of recombinant factor IX Fc fusion protein activity in plasma samples.

INTRODUCTION: Monitoring of factor IX (FIX) replacement therapy in haemophilia B relies on accurate coagulation assays. However, considerable interlaboratory variability has been reported for one-stage clotting (OSC) assays. This study aimed to evaluate the real-world, interlaboratory variability of routine FIX activity assays used in clinical haemostasis laboratories for the measurement of recombinant FIX Fc fusion protein (rFIXFc) activity. METHODS: Human FIX-depleted plasma was spiked with rFIXFc at 0.80, 0.20 or 0.05 IU/mL based on label potency. Participating laboratories tested samples using their own routine OSC or chromogenic substrate (CS) assay protocols, reagents and FIX plasma standards. Laboratories could perform more than one measurement and method, and were not fully blinded to nominal activity values. RESULTS: A total of 142 laboratories contributed OSC results from 175 sample kits using 11 different activated partial thromboplastin time (aPTT) reagents. The median recovered FIX activity for the 0.80, 0.20 and 0.05 IU/mL samples was 0.72 IU/mL, 0.21 IU/mL and 0.060 IU/mL, respectively. Across all OSC reagents, interlaboratory variability (% CV) per aPTT reagent ranged from 9.4% to 32.1%, 8.2% to 32.6% and 12.2% to 42.0% at the 0.80, 0.20 and 0.05 IU/mL levels, respectively. CS results showed excellent median recoveries at all nominal levels (87.5% to 115.0%; n = 11) with low interlaboratory variability (CV 3.6% to 15.4%). CONCLUSION: This large, real-world data set indicates that rFIXFc activity in plasma samples can be accurately measured with the majority of routine OSC and CS assay methods. Given the variation in FIX assay procedures between sites, it is important that individual laboratories qualify their in-house methods for monitoring of rFIXFc activity.