Chowdary, P. (2020), N8?GP: A new extended half?life recombinant factor VIII product for hemophilia A. J Thromb Haemost, 18: 3-4.
N8?GP (turoctocog alfa pegol; Esperoct®, Novo Nordisk A/S, Bagsvaerd, Denmark) is a state?of?the?art, recombinant factor VIII (FVIII) molecule1 recently approved for routine prophylaxis and on?demand treatment of patients with hemophilia A in the European Union, United States, Canada, Switzerland, and Japan. N8?GP exhibits an extended circulatory half?life as a result of site?directed glycoPEGylation (using a 40?kDa polyethylene glycol [PEG] molecule) within the truncated, 21?amino?acid B?domain of its parent molecule, turoctocog alfa,2, 3 yielding native activated FVIII (FVIIIa) upon activation.1, 4 This supplement comprises an overview of the N8?GP clinical development program and presents end?of?trial results for the pivotal phase 3 study in adolescents and adults, pathfinder2 (ClinicalTrials.gov identifier: NCT01480180), as well as end?of?trial results for the pivotal phase 3 study in children, pathfinder5 (NCT01731600). The pathfinder trials are part of a comprehensive clinical development program, involving extensive evaluation of N8?GP’s pharmacokinetic characteristics, general efficacy and safety, as well as efficacy and safety during surgery. Challenges faced during the pathfinder clinical development program and lessons learned are also discussed within the supplement. The wide scope of the pathfinder clinical program means that data are currently available for more than 1000 patient?years of exposure, with a total of 270 patients treated with N8?GP, some for >5 years.5, 6 Results from the pathfinder clinical program support the long?term efficacy and safety of N8?GP in previously treated children, adolescents, and adults with hemophilia A. Of particular interest are the results regarding target joint resolution in children treated with N8?GP, showing that all target joints among patients that participated in both the main and extension phases of pathfinder5 were resolved after slightly more than 2 years (using very stringent criteria compared with the ISTH 2014 target joint definition. See the pathfinder5 end?of?trial results publication in this supplement for more details). Also, it is worth highlighting that the number of patients who experienced no bleeding episodes increased with each year of N8?GP treatment during both the pediatric and adolescent/adult trials (see the pathfinder2 end?of?trial results and pathfinder5 end?of?trial results publications for more details). N8?GP has the potential for simplified prophylaxis in the form of a simple, fixed regimen (fixed intervals; fixed weight?based dosing), thereby representing a potential paradigm shift in terms of the current approach to hemophilia A treatment regimens. Patients switching to N8?GP can begin their initial dosing using the labeled dose and frequency (50 IU/kg every 4 days in adults and adolescents), which has been shown to provide effective prophylaxis, maintaining mild hemophilia FVIII levels for >90% of the week.7 The simplicity of such a regimen can be advantageous for patients as it offers assured protection and improved postswitch outcomes. Patients can subsequently be monitored and treatment tailored to further improve outcomes, if needed. Switching patients to an extended half?life product benefits the majority because of higher trough levels and reduced infusion frequency achieved. This can be particularly beneficial for certain patient populations, such as those experiencing breakthrough bleeds on their current treatment, those receiving on?demand treatment or those with adherence issues and difficult venous access. Hypothetical concerns have been raised with respect to long?term exposure to PEG in plasma and tissues with repeated administration of PEGylated coagulation factors, including N8?GP. It is worth noting that the size of the PEG moiety differs between the currently available PEGylated rFVIII products (Adynovate/Adynovi: 20?kDa PEG; Jivi: 60?kDa PEG), although the weekly PEG load is comparable.8, 9 Interestingly, a closer examination of PEG exposure in patients treated with N8?GP for periods up to 5 years showed that plasma PEG levels rapidly achieved a steady state, with no unexpected increase above steady?state levels, even with long?term treatment.10 PEG is ubiquitous and is used extensively in various consumer products, including commercial medicines. The attainment of a steady state is reassuring, as it demonstrates the ability of the body to excrete this moiety, confirming the long?term safety observed with other PEG molecules used in patients with chronic conditions. Perioperative management of patients with hemophilia can be particularly challenging. There is extensive experience with N8?GP use during both minor and major procedures. Excellent/good hemostasis was achieved in the vast majority (>95%) of major procedures, as reported in a recent publication assessing N8?GP safety and efficacy during surgery in children, adolescent, and adults.11 Importantly, no FVIII inhibitors were reported during the study and no safety concerns were identified. Overall, the extensive clinical data available for N8?GP, which are summarized in this supplement, show that it is a safe and efficacious treatment for hemophilia A. Additional results from the ongoing pathfinder6 (efficacy and safety in previously untreated patients with hemophilia A; NCT02137850) and pathfinder8 (efficacy and safety in previously N8?GP?treated patients; NCT03528551) trials are eagerly awaited.