Recently the long-term efficacy and safety results of the pathfinder2 and pathfinder5 clinical trials on N8-GP, an extended half-life FVIII (FVIII) molecule (Esperoct®, Novo Nordisk A/S, Bagsvaerd, Denmark), were published in the Journal of Thrombosis and Haemostasis. Together with an introductory editorial by Pratima Chowdary and an overview of the pathfinder clinical trials programme by Matsushita and Mangles, these long-term results build on the existing data previously published. Based on the recent publications, this illustrated summary takes a look at the long-term data and the outcomes of the pathfinder trials to date.
Introducing N8-GP: an extended half-life FVIII molecule
Extended half-life products aim to minimise treatment burden in Haemophilia A
People with severe haemophilia A exhibit spontaneous or recurrent bleeding in joints, muscles and soft tissue,1 which over time may result in arthropathy, muscular atrophy or other disabilities.1 People with haemophilia A are treated with (FVIII) replacement therapy as current standard of care. Standard half-life (SHL) FVIII products require regular intravenous injections, creating a notable and life-long treatment burden. To address this, various extended half-life (EHL) FVIII products have been developed in recent years to reduce the treatment burden in people with haemophilia A1 through reducing injection frequency.2 Additionally, EHL FVIII products aim to improve compliance to therapy over standard half-life plasma-derived or recombinant FVIII molecules2 and ultimately aim to provide a better quality of life for people living with haemophilia A.2
N8-GP is a pegylated FVIII with an extended half-life
The pathfinder clinical trials programme, discussed by Matsushita and Mangles,3 assessed long-term efficacy and safety of N8-GP, an extended half-life FVIII molecule. In the pathfinder1 study, early pharmacokinetic analyses showed that N8-GP had a prolonged mean terminal half-life of 19 hours compared with 12 for unmodified FVIII.3 Furthermore, the time taken to reach 1% of FVIII activity was shown to be longer for N8-GP than for SHL factor products (6.5 days and 3.7 days, respectively, at a dose of 50 IU/kg). The half-life of N8-GP is extended through the addition of a 40 kDa polyethylene glycol (PEG) moiety3; this PEG moiety firstly increases the molecule size which results in reduced renal excretion, and secondly shields the molecule from binding to clearance receptors.3 N8-GP is also stable at room temperature (≤30°C) in the unopened vial, for up to a year, and stable for up to 3 months at temperatures up to 40°C.3
The use of PEG initially raised hypothetical concerns around potential accumulation in tissues, beyond steady-state levels. However, a recent study by Novo Nordisk on plasma concentration of PEG in patients receiving long-term prophylaxis with N8-GP as part of the pathfinder trials, satisfactorily allayed these concerns.3,4
Simplified treatment regimens with N8-GP underline the advantages of switching
The Chowdary editorial reviews the advantages of a simplified, regular and consistent prophylaxis regimen.4 N8-GP is currently approved in the European Union, United States, Switzerland, Japan and Canada for routine prophylaxis and on-demand treatment of patients with haemophilia A, and perioperative management of patients with haemophilia A.4 N8-GP has the potential for simplified prophylaxis with a simple and fixed regimen.4 Furthermore, higher trough levels, reduced infusion frequency and improved outcomes following a switch to N8-GP resonates with certain patient groups, particularly those with breakthrough bleeding and those with low adherence rates.4
A closer look at the pathfinder clinical trials programme
The pathfinder clinical trials programme (Figure 1) was presented by Matsushita and Mangle. Pathfinder1 started in 2010 and was the first-in-human, dose-escalation trial in previously treated adult patients with severe haemophilia A. Two years later, the pivotal phase 3 pathfinder2 trial commenced evaluating long-term safety, pharmacokinetics and efficacy of N8-GP for on-demand treatment or prophylaxis in previously treated adolescent and adult patients. The pivotal paediatric trial, pathfinder5 commenced in early 2013. Accompanying pathfinder2 was the pathfinder3 surgery trial, which captured certain patients undergoing major surgery during the main pathfinder2 trial, and pathfinder7, a pharmacokinetic safety trial, started in 2016 with patients from the extension phase of the pathfinder2 trial. A phase 3 trial in previously untreated paediatric patients, pathfinder6, is still ongoing and pathfinder 8, a phase 3 trial in previously treated patients has recently ended; data from both of these trials is pending.
Key findings in the pivotal phase 3 trials
The long-term safety and efficacy results of the two pivotal phase 3 trials in adolescents and adults, pathfinder2, and in children, pathfinder5, were published by Giangrande et al. and Šaulytė Trakymienė et al. respectively,1,2,4 complementing the earlier publications of the main phases.
The pathfinder2 trial was in previously treated adolescent and adult patients with severe haemophilia A. This was a multi-national, open-label trial with a main phase and two parts of an extension phase. During the second part of the extension, patients were able to switch from prophylaxis every fourth day (Q4D) at 50 IU/kg or once weekly prophylaxis (Q7D) at 75 IU/kg, according to their bleeding status. Here, 186 patients with severe haemophilia A were followed up for 6.6 years, with a median exposure to N8-GP of 5.4 years,1 during which time, the estimated annualised bleeding rate (ABR) was 2.14 (median 0.84) and 1.31 (median 1.67) for the Q4D and Q7D prophylaxis arms, respectively.1 Nearly one-third of patients on the Q4D prophylaxis regimen achieved zero bleeds during the trial1 and for both regimens, the haemostatic response was 83.2%. Additionally, the proportion of patients who had no bleeds per year increased over the duration of the trial (Figure 2)
The patient reported outcomes, assessed via HAEM-A-QOL, Hemo-Sat and EQ-5D-VAS, were improved or maintained indicating that patients had maintained or slightly improved quality of life. During the trial, no safety concerns were detected.1
The paediatric equivalent, the pathfinder5 trial, was in previously treated paediatric patients with severe haemophilia A and was a multi-national, open-label, single arm, non-randomised, non-controlled trial with a main and extension phase. Patients were treated with twice-weekly N8-GP at 60 IU/kg for 50 exposure days, or approximately 26 weeks during the main phase, which was then continued following the same regimen during the extension phase until the end of the trial. Here, 68 patients with severe haemophilia A were followed up for 5.5 years, with a median exposure to N8-GP of 4.9 years (Figure 3).2 The estimated ABR was 1.08 (median 0.81), and almost 20% of patients experienced zero bleeds during the trial, and approximately 47% had no spontaneous bleeds (Figure 3).2 Over the course of the trial, the proportion of patients experiencing zero bleeds increased; in the fourth year, 56% of patients had no bleeds and 86% had no spontaneous bleeds. There were no safety concerns and inhibitors were not detected.2 This paediatric trial also looked at joint health, and the results showed that joint health improved, with all baseline target joints of all patients resolving in just over 2 years.2 N8-GP was shown to be efficacious and well tolerated2 in these previously treated paediatric patients.
Of particular interest, the long-term results of these trials showed that for both adults and adolescents, and in children, the estimated ABR decreased over the course of the trials, and the number of patients experiencing zero bleeding episodes increased with each year of N8-GP treatment.2,4
Overview of results of pathfinder trials
The long-term efficacy and safety results from pathfinder2 and pathfinder5 adds to the existing data published on the pathfinder clinical development programme.3
Long-term efficacy data from both pathfinder2 and pathfinder5 confirm the prophylactic effect of N8-GP3; over the course of the trials the ABRs decreased.3 Additionally, the trials confirmed the haemostatic effect of N8-GP, with the majority of all bleeds being successfully treated with N8-GP in paediatric, adolescent and adult patients. Furthermore, the vast majority of bleeds were successfully treated with less than two doses. No new safety concerns were reported in either pathfinder2 or pathfinder5. Throughout the pathfinder programme, only one patient (pathfinder2) developed FVIII inhibitors, no inhibitors were detected in any other patients in the clinical development programme.3 Furthermore, the rate of anti-drug or anti-PEG antibody development was low in patients in the pathfinder trials.3
Quality of life was assessed by HAEM-A-QOL questionnaire in adults and HAEMO-QOL questionnaire in children, for which lower scores represent a better quality of life. With long-term N8-GP treatment, minor improvements in quality of life scores were seen for patients in the pathfinder2 trial, and for children in the pathfinder5 trial, an overall improvement in the HAEMO-QOL score was seen.3
N8-GP in clinical practice in the future
As discussed by Matsushita and Mangles,3 compared with personalised and PK-tailored dosing regimens, N8-GP allows for a fixed regimen with fixed intervals and fixed weight-based dosing.3 The limitations of standard half-life molecules requiring intravenous injections approximately 3–4 times per week can be overcome by the less frequent dosing offered by N8-GP.3 Additionally, the higher trough levels achievable with N8-GP may provide benefits to patients experiencing breakthrough bleeds, those who are using on-demand treatment, or those who have adherence issues, or venous access problems.3
Authored by Novo Nordisk
- Giangrande P, Abdul Karim F, Nemes L, et al. Long-term safety and efficacy of N8-GP in previously treated adults and adolescents with hemophilia A: Final results from pathfinder2. J Thromb Haemost. 2020;18 Suppl 1:5-14.
- Šaulytė Trakymienė S, Economou M, Kenet G, Landorph A, Shen C, Kearney S. Long-term safety and efficacy of N8-GP in previously treated pediatric patients with hemophilia A: Final results from pathfinder5. J Thromb Haemost. 2020;18 Suppl 1:15-25.
- Matsushita T, Mangles S. An overview of the pathfinder clinical trials program: Long-term efficacy and safety of N8-GP in patients with hemophilia A. J Thromb Haemost. 2020;18 Suppl 1:26-33.
- Chowdary P. N8-GP: A new extended half-life recombinant factor VIII product for hemophilia A. J Thromb Haemost. 2020;18 Suppl 1:3-4.