Extended Half-life Products Research Articles

Current and emerging factor VIII replacement products for hemophilia A.

Hemophilia A is a congenital X-linked bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. Routine infusion of factor replacement products is the current standard of care; however, the development of alloantibodies against FVIII remains a challenge. The treatment of hemophilia has undergone major advances over the past century to improve safety, effectiveness, manufacturing, and convenience of factor products. Major recent advances in the treatment of hemophilia A include the emergence of extended half-life products, factor VIII orthologs, and gene therapy products. Extended half-life products were designed to decrease the frequency of infusions, but only modest half-life extension is achieved. Factor VIII orthologs featuring lower cross-reactivity with anti-FVIII antibodies may be less susceptible to inactivation by inhibitors. Meanwhile, gene therapy may potentially provide a cure for hemophilia A, thus abrogating the need for protein-based factor replacement. This review aims to discuss current and emerging FVIII replacement products for hemophilia A.

Perioperative management of haemophilia B: A critical appraisal of the evidence and current practices.

While there is substantial literature addressing the principles of general management of haemophilia, literature on perioperative management of haemostasis is scarce. The aim of this study was to better understand perioperative management among congenital haemophilia B patients (without inhibitors) and to gain insights into real-world surgical practices. A systematic literature review, with an emphasis on haemophilia B, was conducted using EMBASE® , Medline® and the Cochrane Library. Studies from 1974 to June 2015 were accessed, and 132 studies were eligible for the full-study review. An international expert panel with five haematologists and one surgeon reviewed the resulting literature and provided further insights. The literature review revealed that documented experience in the perioperative management of bleeding risk in haemophilia B patients is relatively scarce. Therefore, the review was amended to provide a comprehensive overview of the perioperative management for haemophilia A and B patients; the expert panel applied a particular focus to haemophilia B. Several gaps were identified in the literature including the lack of consensus on defining surgery in terms of bleeding risk, optimal factor levels during surgery and lack of robust evidence on surgical outcomes. The ensuing discussions with the expert panel provided validation of some of the results from the systematic literature review and proposed future directions for perioperative management. Suggestions included collaboration with haemophilia treatment centres (HTCs) to collect real-world data on perioperative management, establishing the need for optimal factor level monitoring practice, and the appropriate adoption of extended half-life products in clinical settings.

Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches?

Hemophilia A (HA) is a common bleeding disorder caused by the deficiency of factor VIII (FVIII) with an incidence of ~1 in 5000 male births. Replacement of FVIII is necessary to prevent and treat bleeding episodes. However, with multiple new drugs in addition to old standards, choosing among the different FVIII treatment options is harder than ever. There are FVIII products that are plasma derived or recombinant, FVIII products designed to extend the half-life of FVIII, and the first single-chain FVIII product, recombinant factor VIII single chain (rFVIII-SC). As development of inhibitors to FVIII continues to be a major problem in the care of HA patients, recent studies showing lower rates of inhibitor development with plasma-derived FVIIII products versus recombinant FVIII products have made choosing among the many options now available even more complex. Although still unproven, extended half-life (EHL) products may provide the hope of decreased immunogenicity but need further testing in previously untreated patients (PUPs). This review highlights some of the differences between FVIII products currently available and hopefully assists the clinician to decide which FVIII product to choose for their patients.

Haemophilia patients' unmet needs and their expectations of the new extended half-life factor concentrates.

National Member Organisations (NMO) of persons with haemophilia (PWH) from the DACH Region (D = Germany, A = Austria, CH = Switzerland) were interested to better understand PWH's expectations and concerns of extended half-life (EHL) factor concentrates (FC) before availability in these countries. Based on an expert meeting and focus groups conducted across Germany a survey for haemophilia patients and their parents was developed and was sent out to 2,644 PWH. One thousand and seven questionnaires were sent back (38.1%); 743 adults and 262 parents. Most patients had haemophilia A (84.5%), were severely affected (73.7%), received prophylaxis (57%) and used recombinant FC (60.2%). One-quarter did not know the correct half-life of their FC [HA/FVIII: 26%, HB/FIX: 31.1%]. Four percent were unsatisfied with their current FC, mainly with short half-life of FC and difficult manageability. They expected from new EHL products less frequent injections (55.2%), better efficacy (32.1%) and safety/no side effects (15.7%); 59.5% would be willing to switch to new products if they have a prolonged half-life and the same safety of the current FC. They wish more information about half-life (84.4%), possible side-effects (81.3%) and efficacy (77%) and wanted to receive information about new products from their haemophilia treater (76.3%) and the newsletter of their NMO (74.3%). Significant differences across countries were found. The representative survey could show that although PWH were generally satisfied with their current FC, the majority would be willing to switch to EHL products assuming half-life is prolonged and has the same safety of the current FC.

Exploring some intersections between pharmacokinetics, factor VIII measurement and human morphometrics – impact of recent advances in haemophilia study design on our understanding of optimal haemophilia treatment

Exploring some intersections between pharmacokinetics, factor <scp>VIII</scp> measurement and human morphometrics – impact of recent advances in haemophilia study design on our understanding of optimal haemophilia treatment

WITHDRAWN: Primary prophylaxis in haemophilia care: Guideline update 2016

This paper reviews the current status on recommendations or guidelines for primary prophylaxis based on recent published papers from organizations or group of experts as well as some original key papers. A rather uniform view exists that prophylaxis should be initiated at an early age before or after no more than a single joint bleed and, if possible, preferably be continued for life. The dose and dose frequency of prophylaxis is dependent on the goal of treatment, bleeding phenotype, compliance, venous access and economic resources in the health care system and should be tailored individually based on clinical outcome and pharmacokinetics. For children, the effectiveness of prophylaxis is more dependent on maintaining minimum trough levels than in adults. Novel extended half-life products are being introduced, which should not affect the decision on when to start prophylaxis nor the initial dose, but which may be helpful for patients with difficult venous access and which may enable higher trough levels of factor VIII.

Primary prophylaxis in haemophilia care: Guideline update 2016

This paper reviews the current status on recommendations or guidelines for primary prophylaxis based on recent published papers from organizations or group of experts as well as some original key papers. A rather uniform view exists that prophylaxis should be initiated at an early age before or after no more than a single joint bleed and, if possible, preferably be continued for life. The dose and dose frequency of prophylaxis is dependent on the goal of treatment, bleeding phenotype, compliance, venous access and economic resources in the health care system and should be tailored individually based on clinical outcome and pharmacokinetics. For children, the effectiveness of prophylaxis is more dependent on maintaining minimum trough levels than in adults. Novel extended half-life products are being introduced, which should not affect the decision on when to start prophylaxis nor the initial dose, but which may be helpful for patients with difficult venous access and which may enable higher trough levels of factor VIII.

Expectations and Concerns Towards New Extended Half-Life (EHL) Products - Results of Surveys Among Haemophilia Patients from the Dach Region

Background: In Western Europe most patients with haemophilia (PWH) have the opportunity to get regular prophylaxis and can life normal lives due to the availability and funding of factor concentrates. The majority of haemophilia patients have to inject themselves every other day or three times a week.The need of frequent injections may impact negatively patients' treatment adherence which might result in increased annual bleeding rate and impaired quality of life. Therefore there is a need for half-life extended (EHL) products which will be launched in the next years in Europe for treatment of haemophilia A and B and are expected to improve patients' quality of life. However, little is known about patients' perspectives on the use of these new EHL products and their willingness to switch to these products.Aim: National Member Organisations (NMO) of haemophilia patients from the DACH Region (D=Germany, A=Austria, CH=Switzerland) were interested to better understand PWH's expectations and concerns towards these new EHL products in order to adapt haemophilia treatment to real patients' needs.Methods: A systematic postal survey was sent out to 2,644 patients and parents of children with haemophilia A or B in Germany (2015), Switzerland (2016) and Austria (2016). The postal survey included questions concerning demographic and clinical data of the patient, knowledge about half-life of actual factor concentrates (FC) and attitudes towards FC in terms of satisfaction with actual factor concentrate, expectation towards new EHL products, willingness to switch to new EHL products, required information for decision making, preferred information sources and facilitation of therapy in general.Results: In total 1,013 questionnaires were sent back (38.3%); 2 patients had to be excluded from further analysis since these patients had VWD. 747 adult haemophilia patients and 262 parents of haemophilic children participated, 2 respondents could not be classified. The majority of patients had haemophilia A (84.1%), were severely affected (73%), received prophylaxis (56.6%), mostly three times a week (40.9%) and used recombinant products (59.4%). 14% had a history of an inhibitor (past, actual). Most of the patients and parents did not know the correct half-life of the actual FC [FVIII: 30%, FIX: 75%]. In general they were satisfied (M=4.4±0.8) with their actual FC; only 4.1% were unsatisfied, mainly with difficult manageability and short half-life of FC. They expected from the new products to provide less frequent injections, better efficacy and safety/no side effects. 59.6% would be willing to switch to new products if they have a prolonged half-life and have the same safety of the actual FC. Reasons for not willing to switch were fear of inhibitor development and no side effects of actual FC. They had almost no information about the new up-coming products, wish more information about half-life, possible side-effects and efficacy and would consider changing product if the prolongation of the half-life is at least double as high as the actual FC. 20.6% would switch already with a half-life prolongation of 1.2-1.5 times longer; 3.3% would not switch at all. The majority wanted to receive information about new products from their haemophilia treater (77.1%), newsletter of their NMO (73.4%) and information letter from their HTC/NMO (35.7%). They would wish smaller packages, different mode of administration and better manageability of the product in order to facilitate their therapy.There was a significant difference across countries regarding treatment regimen (p<.0001) and used product category (p<.0001); in Germany more patients were on prophylaxis (71.3%) and in Switzerland more patients used recombinant products (75.8%). No differences were found for the satisfaction with their actual product, their willingness to switch to new EHL products in general and the time of required half-life prolongation. In Switzerland more patients required information on costs of the new EHL products for an adequate decision making process for switching (p<.0001).Conclusions: In this representative survey among patients and parents of children with haemophilia of the DACH Region it could be shown that even though they were generally satisfied with their actual FC the majority would be willing to switch from their actual FC to the new up-coming EHL products assuming the half-life is prolonged and has the same safety of the actual FC. Disclosuresvon Mackensen:Shire: Research Funding; SOBI: Research Funding. Kalnins:SOBI: Research Funding. Lino:SOBI: Research Funding. Joerg:SOBI: Research Funding. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Weiss:Shire: Research Funding.

Real World Data Analysis of Coagulation Factor IX Costs in Specific Patients with Hemophilia B Switching from Standard Half-Life to Extended Half-Life Products

Introduction: Hemophilia B, an X-linked genetic disease characterized by low clotting factor IX (FIX) levels, leads to spontaneous and traumatic bleeding in affected individuals. Intravenous FIX replenishment is administered to maintain adequate levels. The recent introduction of an extended half-life (EHL) FIX replacement product provided the opportunity to compare costs of care associated with treatment with an EHL product versus a standard half-life (SHL) product.Methods: The Truven Marketscan US claims database (Oct 2010 - Apr 2016) was used to identify factor concentrate charges for patients who had claims data for at least 3 months prior to and after switching from SHL to EHL products. Additionally, available data for up to 12 months pre- and post-switch on these identified patients were analyzed.Results: Thirteen patients, ranging from 3-64 years of age (median 18) were included in the analyses. Factor concentrate costs were higher after switch from SHL to EHL in each of the time periods examined (Table). Median costs were used since they were less influenced by isolated outliers and were similar to means in most cases. The median costs were 238% higher in the 3 months just after switching to the EHL product compared to the 3 months just prior to switching from the SHL product. Median costs were $51,881, $79,654, $75,695 and $61,515 in the 12-10, 9-7, 6-4 and 3-1 months prior to switch respectively compared to $173,515, $147,061, $149,971 and $207,973 in the corresponding quarterly month intervals post switch.Conclusion: This analysis of real world administrative data following individual patients through the switch from SHL to EHL products continuum suggests that switching from an SHL to an EHL product is associated with increased median factor costs throughout the 12 months following the switch, and that further analysis with larger numbers of patients should be explored. [Display omitted] DisclosuresTortella:Pfizer Inc: Employment. Fogarty:Pfizer Inc: Employment. Alvir:Pfizer Inc: Employment. McDonald:Pfizer Inc: Employment. Spurden:Pfizer Inc: Employment. Pleil:Pfizer Inc: Employment.

2017 Clinical trials update: Innovations in hemophilia therapy.

A surge in therapeutic clinical trials over recent years is paving the way for transformative treatment options for patients with hemophilia. The introduction of recombinant factor concentrates in the early 1990s facilitated the use of prophylactic replacement as standard care for hemophilia rather than on-demand treatment. This has revolutionized health outcomes for hemophilia patients, enabling participation in physical activities and reducing debilitating, chronic joint damage. Challenges of prophylactic factor infusion include the frequency of infusions needed to maintain factor levels greater than 1%, patient adherence, reliable intravenous access, and development of neutralizing alloantibodies ("inhibitors"). Novel therapeutics seek to improve upon current factor concentrates by several different mechanisms: (1) extending the half-life of circulating exogenous factor protein, (2) replacing the gene necessary for production of endogenous factor protein, (3) employing bispecific antibody technology to mimic the coagulation function of factor VIII, (4) disrupting anticoagulant proteins, such as tissue factor pathway inhibitor (TFPI) or antithrombin (AT3) with antibodies, aptamers, or RNA interference technology. Emerging treatment options may reduce the frequency of (extended half-life products) or eliminate (gene therapy) the need for scheduled factor concentrate infusions, or provide a subcutaneous administration option (bispecific antibody, AT3, and TFPI targeting therapies). In addition, the nonfactor replacement strategies provide a promising treatment option for patients with inhibitors, presently the greatest unmet medical need in hemophilia. This review highlights current and recently completed clinical trials that are driving a paradigm shift in our approach to hemophilia care for patients with and without inhibitors. Am. J. Hematol. 91:1252-1260, 2016. © 2016 Wiley Periodicals, Inc.

Prophylaxis for Hemophilia in the Era of Extended Half-Life Factor VIII/Factor IX Products.

There are two main bioengineering approaches to extending the half-life of factor (F)VIII or FIX products used for hemophilia replacement therapy. These are fusion to Fc-immunoglobulin G (FVIII and FIX) or to albumin (FIX) or pegylation/glycopegylation (FVIII and FIX). Four FVIII and three FIX products are in clinical development or have recently been licensed in regions of the world. The reported half-life extension is approximately 1.5-fold for FVIII and 2.5-fold, or even longer, for FIX. Clinical trials have shown promising results with respect to extension of dose intervals and efficacy in the treatment and prevention of bleeding events. The role of these products in clinical practice has been discussed in terms of either improving convenience and adherence through prolongation of the interval between infusions or maintaining current intervals thereby increasing trough levels and the safety margin against bleeds. This review of extended half-life products addresses the possibilities and problems of their introduction in hemophilia treatment.

A Method for Deriving Pharmacokinetic Constants for Factor VIII and IX from Limited Blood Sampling

IntroductionThe treatment of hemophilia A and B is based on the replacement of the deficient factor dosed by weight. However, dosing for hemophilia treatment has been arrived at by empiric assessment, essentially "trial and error" based on the pharmacokinetics (PK) of the factors and the characteristics of the replacement product. In the last decade clinical pharmacokinetics has gained popularity in hemophilia so that factor dosage can be adjusted according to the requirement of the individual patient. Factor-specific population pharmacokinetic models have been developed for individualized treatment of patients with hemophilia A and B. The math modeling technique presented in this project relies on minimal blood sampling to derive the constants necessary to predict the peak and trough levels within the commonly excepted error bounds.MethodsData that included FVIII, FIX levels and weight were obtained retrospectively from severe hemophilia A and B adult patients and approved by the ethics committee of the University of Texas Health Science Center. A single compartment decay model equation was used in both a custom iOS application and an Excel spreadsheet to calculate the decay constant between any 2 points on a decay curve. Using this local constant as the half-life in the standard decay equation allowed the calculation of the peak at time = 0. This peak combined with dosing information and the subject's weight allowed the calculation of the Recovery. These 2 constants in the equation: Level=(dose*Recovery/weight)*0.5^(time/half-life) allowed the calculation of the level at any point on the curve. Using this method on several example datasets showed that the model is reasonably able to predict peak and trough levels for both factor VIII and IX. Because of the time dependent nature of the local decay constant, better results are obtained using data points after the first half of the expected half-life. This method can also be used to predict steady state levels, peaks and troughs for any prophylaxis schedule.ConclusionAppropriate dosing of factor VIII or IX is at best an approximate calculation. The method described in this publication generates a math model that is generally as accurate as a multiple sample PK study with far fewer blood samples taken. Clinical applications of this model can be utilized to predict factor levels after a single infusion of factor VIII/IX in adults that are treated on-demand or prophylaxis. It can also be utilized in individuals that are infusing extended half-life products or in the surgical setting. DisclosuresEscobar:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Pfizer: Consultancy, Research Funding. Cantini:Pfizer: Research Funding. Cannon:Pfizer: Research Funding.

Lasting power of new clotting proteins.

Hemophilia is a genetic disease caused by a deficiency of one of the coagulation proteins. The term usually refers to either hemophilia A, factor VIII (FVIII), with an incidence of ∼1 in 5000 male births, or hemophilia B, factor IX (FIX), with an incidence of ∼1 in 30 000 male births. When severe, the disease leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions of therapeutic factor concentrates. Most patients administer the infusions at home every few days and must limit their physical activities to avoid bleeding when the factor activity levels are below normal. In March 2014, a new therapeutic FIX preparation was approved for clinical use in Canada and the United States and, in June 2014, a new FVIII preparation was approved for clinical use in the United States. Over the next couple of years, other new factor products for FIX, FVIIa, and FVIII, which are currently in late stages of clinical trials, will likely also be approved. These new factors have been engineered to extend their half-life in circulation, thus providing major therapeutic advances for patients with hemophilia primarily by allowing treatment with fewer infusions per month. In the clinical trials so far, >500 patients have successfully used these extended half-life products regularly for >1 year to prevent spontaneous bleeding, to treat successfully any bleeding episodes, and to provide effective coagulation for major surgery. Essentially all infusions were well tolerated and effective. These promising new therapies should allow patients to use fewer infusions to maintain appropriate clotting factor activity levels in all clinical settings.

Is there cost reduction potential for extended half-life cephalosporins?

Two new second-generation cephalosporin derivatives with extended half-lives, ceforanide and cefonicid, have recently entered the U.S. marketplace. Because longer dosing intervals require fewer daily doses, potential exists for overall cost reduction if pharmacy and nursing time can be effectively saved. Reduction in personnel costs, however, must be sufficient for these more expensive products to be truly cost effective. We studied the impact of substituting these newer agents for older, less expensive products with formulary status at our 200-bed community hospital. Results show that no nursing expenses could be recovered, and there is little chance of consistently reducing pharmacy compounding expenses. Within the constraints of these studies, particularly physician prescribing habits, the GRASP (Grace Reynolds Application and Study of PETO) system of determining nurse staffing, and our drug acquisition costs, we find that the newer extended half-life products have very limited usefulness and may only increase the cost of antibiotic utilization.