Simoctocog Alfa (NUWIQ®)
In Previously Untreated Patients With Severe Hemophilia A: Final Results of the NuProtect Study
Liesner RJ, Abraham A, Altisent C, et al. Thrombosis and Haemostasis. February, 2021.
INTRODUCTION
• Factor VIII (FVIII) inhibitor development is the most serious treatment-related complication in hemophilia A due to the detrimental impact on bleeding rates, mortality, quality of life and treatment costs
• Inhibitor risk is highest during the first 20 exposure days (EDs) to FVIII, but a residual risk persists until 75 EDs
• The type of F8 mutation that causes hemophilia A can affect inhibitor risk:
– Null F8 mutations are not capable of producing any FVIII protein and are associated with a more severe disease phenotype and a higher risk of inhibitor development
– Non-null F8 mutations are capable of producing FVIII
• NUWIQ is a 4th generation recombinant FVIII (rFVIII) produced in a human cell line without chemical modification or protein fusion, with the aim of reducing inhibitor development by more closely replicating the native human FVIII protein and avoiding incorporation of potentially immunogenic elements of animal-cell origin
• No inhibitors have developed with NUWIQ in clinical trials of previously treated patients (PTPs)
METHODS
• NuProtect was a prospective, multinational, open-label, noncontrolled, phase III study conducted in PUPs of any age and ethnicity with severe hemophilia A (FVIII clotting assay <1%) treated with NUWIQ for 100 EDs or a maximum of 5 years
– Patients were true PUPs, without prior exposure to FVIII concentrates or blood components
– Primary endpoint was the incidence of anti-FVIII inhibitors after NUWIQ administration
– Inhibitor titers were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL—1 (≥0.6 – <5 = low-titer; ≥5 = high-titer)
• 110 patients were recruited from 38 study centers in 17 countries
108 patients were treated with NUWIQ
– Median age at first treatment was 12.0 months
The
NuProtect study assessed the immunogenicity of NUWIQ in previously untreated patients (PUPs) of all ages with severe hemophilia A.
– 105 patients were analyzed for inhibitor development; 10 discontinued prior to 100 EDs (without inhibitor development); 95 reached ≥100 EDs or inhibitor development
• Patients received NUWIQ for prophylaxis or on-demand treatment, as well as for the treatment of breakthrough bleeding episodes (BEs) during prophylaxis and to cover surgical procedures
– Type of treatment and dose were determined by investigators based on patients’ clinical situation
– Patients could switch between on-demand and prophylactic treatment during the study
Indications and Usage
NUWIQ® is a recombinant antihemophilic factor [blood coagulation factor VIII (Factor VIII)] indicated in adults and children with Hemophilia A for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and for routine prophylaxis to reduce the frequency of bleeding episodes. NUWIQ is not indicated for the treatment of von Willebrand Disease.
Final Results Show Low Rate of Inhibitors in PUPs With NUWIQ
Of 105 PUPs evaluable for inhibitor development, absolute incidence of high-titer inhibitors was 16.2% and the cumulative incidence was 17.6%
• Overall incidence of inhibitors was 26.7% (absolute) and 27.9% (cumulative)
• Incidence of low-titer inhibitors was 10.5% (absolute) and 12.3% (cumulative)
– Almost half of low-titer inhibitors (5/11) were transient and patients subsequently reached ≥100 EDs
No Inhibitors Were Reported in PUPs With Non-null F8 Mutations
F8 mutation type was known for 102 patients: 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations
• Among patients with null F8 mutations, 27 (30.0%) developed inhibitors; 17 (18.9%) were high-titer
• Patients with large F8 deletions (n = 5) had the highest inhibitor incidence (80%)
• No PUPs with non-null F8 mutations developed inhibitors
NuProtect | Inhibitor Development With NUWIQ by F8 Mutation Status
Inhibitors
F8 mutations (N = 90) (95% CI: 20.8–40.6%
Incidence of High-Titer Inhibitors
• Treatment-related factors (treatment regimen, surgery, peak treatment moments, and dose) did not have a significant effect on the incidence of inhibitors over the whole study period
• While the NuProtect study spanned 100 EDs or 5 years, all inhibitors developed within 34 EDs
– Inhibitors developed within ≤20 EDs in 89% of cases (25/28)
– Inhibitors developed after ED 20 in only 3 cases: ED 24 (high-titer); ED 25 (low-titer), ED 34 (low-titer)
• Median time to inhibitor development was 11.0 EDs: 9.0 EDs for high-titer inhibitors; 12.0 for low-titer inhibitors
• Median peak inhibitor titer: 154.8 BU/mL—1 for high-titer inhibitors; and 3.0 BU/L—1 for low-titer inhibitors
Final NuProtect results demonstrated a 16.2% absolute incidence of high-titer inhibitors with NUWIQ in PUPs—and a cumulative incidence of high-titer inhibitors of 17.6%.
Contraindications NUWIQ is contraindicated in patients who have manifested life-threatening hypersensitivity reactions, including anaphylaxis, to the product or its components.
Please see accompanying full Prescribing Information.
Non-null F8 mutations (N = 12)
Inhibitors were more common in those with a family history of inhibitors and in younger patients (≤12 months)
• Patients with a family history of inhibitors (n = 13) had a higher incidence of inhibitors (46.2%) vs without (n = 92) (23.9%)
• Patients aged 1–6 months (37.5%; n = 8) and aged >6–12 months (36.2%; n = 47) at first treatment had a higher incidence of inhibitors compared with patients aged >12–24 months (20.0%; n = 25) or >24 months (12.5%; n = 24)
Important Safety Information
Hypersensitivity reactions, including anaphylaxis, are possible with NUWIQ. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, or pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.
The formation of neutralizing antibodies (inhibitors) to Factor VIII can occur following the administration of NUWIQ. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. If the plasma Factor VIII level fails to increase as expected, or if bleeding is not controlled after NUWIQ administration, suspect the presence of an inhibitor (neutralizing antibody).
Please see accompanying full Prescribing Information.
SUMMARY & DISCUSSION
NuProtect is the largest prospective study to assess immunogenicity with a single rFVIII product in true PUPs with severe hemophilia A. Final results showed a low incidence of inhibitors in PUPs treated with NUWIQ for 100 EDs.
• Absolute incidence of ALL INHIBITORS was 26.7% and HIGH-TITER INHIBITORS was 16.2%
• Cumulative incidence of ALL INHIBITORS was 27.9% and HIGH-TITER INHIBITORS was 17.6%
The incidence of high-titer inhibitors in PUPs treated with NUWIQ in the NuProtect study was lower than that seen in the SIPPET trial in PUPs treated with hamster cell line–derived rFVIII (28.4%)—and similar to that of PUPs treated with plasma-derived FVIII/von Willebrand factor (VWF) (18.6%)1*†
A post-hoc analysis of SIPPET 2 data suggests that NUWIQ follows the pattern exhibited by pdFVIII concentrates rather than that of the hamster cell line–derived rFVIII concentrates
Incidence of inhibitor development by F8 mutation status (Null vs Non-Null)
• Among SIPPET patients with null F8 mutations, cumulative incidence of inhibitors was 31% with pdFVIII and 47% with rFVIII. Among SIPPET patients with non-null F8 mutations, no inhibitors developed with pdFVIII treatment, whereas 43% developed inhibitors with rFVIII
• No inhibitors were reported in PUPs with non-null F8 mutations treated with NUWIQ or pdFVIII
* Information from the NuProtect study is presented in parallel to the SIPPET study for context, but please note that these trials were performed under different conditions and with different populations. The observed incidence of inhibitor formation may be influenced by a number of factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. Differences in high-titer inhibitor rates between pdFVIII and rFVIII in the SIPPET study were not found to be statistically significant. SIPPET authors suggested this may have been due to the small sample size of the study.
†The SIPPET trial (N = 251) studied inhibitor rates in PUPs treated with rFVIII products made from hamster cells and FVIII derived from human plasma. ‡Data on null or non-null F8 mutation not available for 3 patients.
Important Safety Information
Adverse Reactions
The most frequently occurring adverse reactions (>5%) in clinical trials were upper respiratory tract infection, headache, fever, cough, lower respiratory tract infection, rhinitis, chills, abdominal pain, arthralgia, anemia, and pharyngitis.
References: 1. Peyvandi F, et al. N Engl J Med. 2016;374:2054-2064. 2. Rosendaal FR, et al. Blood 2017;130:1757-59.
Please see accompanying full Prescribing Information.
©2021. Octapharma USA Inc. All rights reserved.
Date of preparation: 4/2021. NUW-0362-PRC