Long-Term Prophylaxis with Simoctocog Alfa for the Management of Haemophilia Α: Immunogenicity, Efficacy and Safety Results from the Nuprotect PUP Extension Study

Prophylaxis with factor VIII (FVIII) is the gold standard approach for management of haemophilia A, and long-term bleed prevention remains the key goal for patients and clinicians. For previously untreated patients (PUPs), minimising the risk of FVIII inhibitor development is an important concern during FVIII treatment. Simoctocog alfa (Nuwiq^®) is a 4^th generation recombinant FVIII (rFVIII), produced in a human cell line without chemical modification or protein fusion to faithfully replicate endogenous FVIII. The NuProtect extension study (NCT01992549) assessed the long-term immunogenicity, haemostatic efficacy and tolerability of simoctocog alfa in paediatric patients who had completed the NuProtect study. The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki.

In the NuProtect study, PUPs with severe haemophilia A who were treated with simoctocog alfa for 100 exposure days (EDs) showed a 17.6% cumulative incidence of high-titre inhibitors [Liesner RJ, Neufeld EJ. Blood 2019; 134 (Suppl. 1): 903], while the hamster cell line-derived rFVIII arm of the SIPPET study showed a cumulative incidence of 28.4% (Peyvandi F, et al. New Engl J Med 2016; 374:2054-34). In the NuProtect study, children who received continuous prophylaxis had a median spontaneous annualised bleeding rate (ABR) of 0 [mean (SD): 0.54 (1.07)]. In the extension study, the dosing regimen and frequency of infusions were determined by the Investigator based on the patient’s clinical situation.

Forty-eight patients continued into the NuProtect extension study at 15 centres in 9 countries. The median (range) age at enrolment into the extension study was 2.8 (1.3–11.9) years. All 48 patients were included in the safety analysis. One patient was lost to follow-up after 1 ED. The remaining 47 patients received prophylaxis for a mean (SD) of 20.6 (6.5) months and 179 (72) EDs and were included in the efficacy analysis. By the end of the study, 85% of patients were on a twice-weekly infusion schedule. No patient developed FVIII inhibitors during the NuProtect extension study. During prophylaxis, the median (IQR) spontaneous ABR was 0 (0–0.50) [mean (SD): 0.29 (0.66), estimated (negative binomial counting regression model) mean (95% CI): 0.28 (0.15, 0.53)]. The median (IQR) total ABR was 1.0 (0–1.95) [mean (SD): 1.63 (2.25), estimated mean (95% CI): 1.62 (1.09, 2.42)]. Of the 47 patients, 34% experienced no bleeding episodes (BEs) and 72% experienced no spontaneous BEs. Treatment efficacy was rated either “excellent” or “good” in 86 of 110 (78.2%) rated BEs treated with simoctocog alfa. Three patients had 4 surgeries that were treated with simoctocog alfa; an overall efficacy assessment was performed jointly by the haematologist and surgeon for 2 of the surgeries, and both ratings were "excellent". There were no treatment-related adverse events as assessed by the Investigator.

In conclusion, no children with severe haemophilia A developed FVIII inhibitors during the NuProtect extension study. Most patients received twice-weekly prophylaxis. Simoctocog alfa was effective for both the prevention and treatment of BEs and was well-tolerated, with no new safety signals in a mean follow-up of 20.6 months.