R.J. Liesner1, M. Jansen2, S. Knaub3

1Great Ormond Hospital for Children NHS Trust Haemophilia Centre, London, UK; 2Octapharma Pharmazeutika Produktionsges.mbH, Vienna, Austria; 3Octapharma AG, Lachen, Switzerland

Introduction

  • Neutralising antibodies against exogenous clotting factor VIII (FVIII) remain the most significant treatment complication in patients with haemophilia A, particularly in previously untreated patients (PUPs)1-4
    • Inhibitors develop in approximately 35% of PUPs with severe haemophilia A5,6
    • Inhibitors in PUPs usually develop within the first 20 exposure days (EDs)7
    • Approximately 70% of inhibitors in PUPs are high-titre ( ≥ 5 BU/mL)5,6
  • Several risk factors for inhibitor development variables have been identified, including family history, ethnicity, specific F8 gene mutations, product type and treatment intensity7,8
  • In the SIPPET study6 – a prospective, randomised, controlled study in PUPs – the cumulative rates of inhibitor development were
    • 26.8% (18.6% high-titre) in patients treated with plasma-derived FVIII products containing von Willebrand factor (pdFVIII/VWF)
    • 44.5% (28.4% high-titre) in patients treated with recombinant FVIII (rFVIII) products derived from hamster cell lines
  • A post-hoc analysis of SIPPET data9 revealed that in patients with non-null F8 mutations (some level of functional protein remaining), no inhibitors developed in patients receiving pdFVIII/VWF treatment, whereas the cumulative incidence of inhibitors was 43% in patients treated with rFVIII derived from hamster cell lines
  • Nuwiq® (simoctocog alfa) is a 4th generation rFVIII product produced in a human cell line, without chemical modification or protein fusion10
  • The efficacy and safety of Nuwiq® were demonstrated in studies of previously treated patients with severe haemophilia A, including 59 children under 12 years of age10
  • The NuProtect study was initiated in 2013 to assess the immunogenicity, efficacy and safety of Nuwiq® in PUPs

Patients and methods

  • NuProtect was a prospective, multicentre, multinational, open-label, non-controlled, phase III study
  • True PUPs (no previous FVIII treatment) with severe haemophilia A of any age and ethnicity were enrolled and treated for 100 EDs or a maximum of 5 years with Nuwiq®
  • Patients received Nuwiq® for prophylaxis or on-demand treatment, for treatment of breakthrough bleeding episodes (BEs) during prophylaxis and for surgical prophylaxis
    • The type of treatment and dose were determined by the investigator
  • Inhibitor screening by the modified Bethesda assay was performed at screening, every 3–4 EDs until ED20, then every 10–12 EDs or at least every 3 months, at completion visit, and if inhibitor development was suspected
    • Inhibitor titres of ≥ 0.6 to < 5 BU/mL were defined as low-titre and ≥ 5 BU/mL as high-titre (based on peak titre)
    • Cumulative inhibitor incidence (primary endpoint) and 95% confidence intervals (CIs) were calculated using Kaplan-Meier methods

Results

  • The study was conducted at 38 sites in 17 countries
    • 110 patients were enrolled and 108 treated with Nuwiq®
    • 105 patients had at least one inhibitor test after ED1
  • Median (range) age at ED1 was 12.0 (0–146) months; 82 (75.9%) patients were aged < 24 months
  • The majority of patients had null (non-functional) F8 mutations (90 of 102 patients with available data [88.2%]) (Figure 1)
  • 13 of 42 (31.0%) patients with a family history of haemophilia A had a family history of inhibitors
  • Patients were treated for a median of 100 EDs (range 1–120), with 91 patients treated for at least 100 EDs (or until inhibitor development)

Figure 1: F8 gene mutation analysis: NuProtect vs a general severe haemophilia A population

Inhibitor development

  • The cumulative inhibitor incidence (Figure 2) was
    • 17.6% (95% CI: 10.0%, 25.3%) for high-titre inhibitors
    • 12.3% (95% CI: 5.5%, 19.2%) for low-titre inhibitors
    • 27.9% (95% CI: 19.1%, 36.7%) for all inhibitors
  • Cumulative high-titre inhibitor incidence is shown alongside SIPPET6 data in Figure 3.
  • The median (range) time to inhibitor development was
    • 9.0 (4–24) EDs for high-titre inhibitors
    • 12.0 (6–34) EDs for low-titre inhibitors
    • 11.0 (4–34) EDs for all inhibitors

Figure 2: Cumulative inhibitor risk in PUPs treated with Nuwiq®

Figure 3: Cumulative incidence of high-titre inhibitors in SIPPET and NuProtect

  • Of 90 patients with null F8 mutations, 27 (30.0%, 95% CI: 20.8%, 40.6%) developed inhibitors
  • No patients with a non-null mutation developed inhibitors (0%; N=12; 95% CI: 0.0%, 26.5%) (Figure 4);
    • Data are shown together with corresponding SIPPET9 data in Table 1
    • In SIPPET9, 43% of patients with a non-null F8 mutation treated with hamster cell line-derived rFVIII developed inhibitors
    • None of the patients with a non-null F8 mutation developed an inhibitor when treated with pdFVIII/VWF in SIPPET9 or with Nuwiq® in NuProtect

Table 1: Risk of inhibitor development by F8 mutation status in the SIPPET and NuProtect studies

Figure 4: Cumulative inhibitor risk in PUPs treated with Nuwiq® according to F8 gene mutation

Safety

  • 88 serious adverse events (SAEs) were documented in 48 (44.4%) patients
  • At least possibly related SAEs, according to the investigator’s assessment, were reported in 29 patients
    • FVIII inhibition (28 patients)
    • Rash (1 patient, severity mild, required hospitalisation, resolved)

Conclusions

  • In patients treated with Nuwiq®, the cumulative incidence of high-titre inhibitors was 17.6% and cumulative incidence of all inhibitors was 27.9%
    • The cumulative incidence of high-titre and all inhibitors with Nuwiq® is lower than that for rFVIII from hamster cell lines in the SIPPET study6 (28.4% and 44.5%, respectively)
  • PUPs with non-null F8 mutations did not develop inhibitors with Nuwiq® from a human cell line, as was the case for pdFVIII/VWF in the SIPPET study6, but did develop inhibitors with rFVIII from hamster cell lines in the SIPPET study9
    • Nuwiq® exhibits an immunogenicity profile similar to native pdFVIII/VWF in the SIPPET study6
  • Nuwiq® was well tolerated

References

  1. Darby SC et al. J Thromb Haemost 2004; 2:1047-54.
  2. Fischer K et al. Haemophilia 2005; 11:43-8.
  3. Di Minno M et al. Haemophilia 2010; 16:e190-201.
  4. Walsh CE et al. Thromb Haemost 2016; 116(Suppl. 1): S10-17.
  5. Gouw SC et al. N Engl J Med 2013; 368:231-9.
  6. Peyvandi F et al. N Engl J Med 2016; 374:2054-64.
  7. Goudemand J et al. Thromb Haemost 2016; 116(Suppl. 1):S2-9.
  8. Oldenburg J et al. Haematologica 2015; 100:149-56.
  9. Rosendaal FR et al. Blood 2017; 130:1757-9.
  10. Lissitchkov T et al. Ther Adv Hematol 2019; doi:10.1177/2040620719858471.
  11. Gouw SC et al. Blood 2012; 119:2922-34.