Transition considerations for extended half‐life factor products

After years of anticipation and recent publication of pivotal clinical trials 1, 2, extended half-life (EHL) factor VIII (FVIII) and FIX products have arrived on the market, signalling potentially important advances in the treatment of haemophilia. Biogen-Idec's Fc-fusion technology products are currently the only licensed EHL products; however, products from other manufacturers and using alternate technology are expected in the near future. The modified pharmacokinetic properties of EHLs provide the opportunity for equivalent (or perhaps optimized) trough activity levels for patients on prophylaxis regimens with the potential added benefit in many cases of less frequent infusions. Although lumped into the same ‘extended half-life’ designation, the current FVIII and FIX products have very different pharmacokinetics; therefore, the potential impact for patients with haemophilia A and haemophilia B must be considered separately. Deciding whether an EHL product will benefit an individual patient is not straightforward. Here, we discuss issues such as balancing effective and cost-effective treatment, use of pharmacokinetics to inform dosing strategy and logistics for product transition. The ideal prophylaxis regimen simultaneously minimizes both bleeding events and excessive factor usage. Such an achievement is not realized by employing the same dosing schema for every patient. A thoughtful approach to dosing will assess: (i) maintenance or improvement the clinical benefit of prophylaxis (by attention to trough levels and bleed events), (ii) avoidance of excess dosing (i.e. high or supra-therapeutic prophylaxis factor levels) and (iii) reduction in the frequency of infusions without compromising #1 or #2. The currently marketed FIX Fc-fusion product proposes two dosing strategies on its label and the FVIII product proposes a starting dose and a range of doses and dose intervals; however, these strategies are not equivalent with respect to total factor dosage used, factor coverage, number of infusions or cost (Table 1). Strategy #1 25 IU kg−1 every other daya Strategy #2 30 IU kg−1 every other day Strategy #1 25 IU kg−1 every 3rd day Strategy #2 50 IU kg−1 every 4th day Having one regimen (strategy #2 for both EHL factor products) that boasts fewer infusions but at the cost of comparatively less factor coverage (in particular longer times at lower levels) and higher annual product cost, sets the prescriber up for challenging patient conversions (and likely payer exchanges) when trying to optimize efficacious prophylaxis, cost-effective care and patient/parent desire for less frequent dosing. As a specific example, the Alprolix™ dosing strategy using 100 IU kg−1 every 10 days results in a significantly higher annual cost (40% more, compared to 50 IU weekly) without evidence of improved efficacy or higher trough levels. Another way of evaluating the mathematical and treatment assumptions of the models is to calculate the expected ‘cost per dose saved’ (i.e. the annual increment in cost divided by the annual number of doses saved, or $209 475 per 15 doses saved, which is $13 965 per infusion not given, in this adult patient example). Adopting a dosing strategy that results in both less optimal trough levels and higher annual costs cannot be justified even if fewer infusions are required, in our opinion. We see this problem as one of the label, not the product. We are left in a position where the dosage recommendations on a product's package insert are insufficient to provide useful guidance to providers and also to payers with regard to effective and cost-conscience regimens. In our view, best practices for initiating a prophylactic regimen are rooted in pharmacokinetics, efficacy and cost-effectiveness. Basic principles include: Beyond the per unit price of the EHL factor products, other resource utilizations costs such as a pharmacy's ability to dispense vial sizes within a desired window (say ±5–10% of the prescribed dose) must be considered. Inadequate nominal vial size availability is frequently an issue for paediatric patients 3. Given the increased cost per unit of EHL products, each percent overage dispensed could add thousands of dollars to the annual per patient cost of factor replacement. At present the Fc-fusion FIX product has especially limited vial size availability in paediatric ranges making dosing, let alone dose adjusting, challenging. The relative price per unit of standard factor products and EHL products and the current paucity of data on how to effectively employ EHL products in the setting of an acute bleed or injury, suggests an opportunity to individualize treatment regimens using both standard and EHL products to optimize both factor activity coverage and minimize cost. Manufacturer protestations that it is not ‘necessary’ to have two products on hand are based on limited clinical trial results, not real-world experience, and do not take cost into account. For example, using the composite PK data presented by Powell et al. 2, if a patient on Alprolix™ prophylaxis sustains a significant injury or bleed event on day 3 following a prophylactic dose of Alprolix™ his anticipated factor level is between 9% and 15%. Depending on the peak and trough levels desired to treat this event, administration of factor is likely warranted. Short interval re-dosing of Alprolix™ is costly without demonstrated improved benefit over a standard factor product. Our basic framework for considering the integration of EHL and standard factor products is presented in Figure S1. The same principle holds true for Eloctate; the incremental cost per unit compared to the nominally extended half-life makes the use of additional doses of Eloctate instead of a standard FVIII product less appealing. There is no regulatory prohibition on having more than one factor type available. Taking examples from many other diseases into account, this may well be preferable and demands further study on cost and efficacy. There is no evidence that EHL products are better for treating an acute bleed, and they are significantly more expensive. We are attempting to prescribe EHL products for prophylaxis dosing while maintaining a bleed dose prescription of standard factor product. Tailoring a prophylaxis regimen to an individual patient's need based on a pharmacokinetic profile and baseline physical activity level is the necessary trend of haemophilia care 4-7. Knowing a patient's half-life on his current FVIII product will help inform a regimen on an EHL product. For example (Fig. 1a) an adult patient with a standard FVIII half-life of 12 h is anticipated to achieve adequate coverage with an EHL product prophylaxis regimen of 25 IU kg−1 every 4 days given the expected half-life extension to 18 h (1.5× baseline). In contrast (Fig. 1b), a patient with a half-life of 7 h on a standard FVIII replacement does not receive a sufficient half-life extension with an EHL product to increase the dosing interval from say every 48 h to every 72 h. Short half-lives are common among paediatric patients, prompting concern about the benefit of EHL products in this sub-population. Patients with short half-lives and frequent breakthrough bleeding despite adherence to a prophylaxis regimen may benefit from the increased factor activity provided by the EHL product even though the dosing interval would remain at 48 h. The half-life extension observed with the marketed EHL FIX product (Alprolix™) is much more robust than that seen for the marketed EHL FVIII product (Eloctate™). The kinetics of FIX are complex, and there is no straight forward translation for a patient's half-life on a standard FIX product (plasma-derived or recombinant) to an anticipated half-life on the EHL product. The kinetics of FVIII and the translation from standard to EHL products is more straightforward, with data published or presented on this class of factor products, showing an average half-life extension of 1.5 times that of standard factor. We have developed a standardized approach for transitioning patients to EHL products (Fig. 2). As we discussed above, knowing a patient's half-life on a standard FVIII product is an important element in understanding the potential benefit of transitioning to an EHL product. We have offered individualized PK assessments to patients at our centre since 2012 and continue to recommend these studies for patients prior to considering transition to an EHL product. We have been greatly influenced by the work of Collins and Bjorkman, which demonstrates that sparse sampling is adequate to determine half-life and predict trough levels 7. We greatly anticipate tools that will provide haemophilia providers with an easy mechanism to determine an individual's PK profile based on population-PK modelling and with sparse sampling of post-infusion levels 8. As stewards of this precious resource of expensive, innovative factor products, providers are obliged to think critically about the balance of convenience and cost and have frank discussions with patients about these elements before transitioning to an EHL product. We thank Biogen-Idec for explaining in detail the rationale used for pricing strategy of Alprolix™ and Eloctate™. SEC is the recipient of a 2014 Hemostasis and Thrombosis Research Society/Novo Nordisk Clinical Fellowship Award in Hemophilia and Rare Bleeding Disorders, supported by Novo Nordisk and a 2014–2016 National Hemophilia Foundation (NHF)-Baxter Clinical Fellowship, supported by Baxter. SEC has served on advisory boards for Pfizer and Octapharma. EJN has served as a consultant and/or on advisory boards for Novo Nordisk, Baxter, Biogen-Idec and Pfizer. He is a member of Data Safety Monitoring Boards for Bayer, Pfizer and rEVO Biologics. In addition, our institution receives research funding for studies in which Drs. Neufeld and Croteau are involved from Octapharma, Novo Nordisk, Novartis and Baxter. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.