First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results

Abstract

PUPs A-LONG evaluated safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, Phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at study start, 20 (19%) had family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI]: 21.8%-41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI: 8.8%-24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 non-treatment-related death due to intracranial hemorrhage (onset prior to first rFVIIIFc dose). The overall median (interquartile range) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within expected range, although high-titer inhibitor development was on the low end of the range reported in literature. rFVIIIFc was well-tolerated and effective as prophylaxis and for treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).

Long‐term immunogenicity, efficacy and tolerability of simoctocog alfa in patients with severe haemophilia A who had completed the NuProtect study in previously untreated patients

“…An estimated (negative binomial model) ABR of 2.37 (95% CI 1.79; 3.15) was reported for 65 PUPs treated with turoctocog alfa pegol prophylaxis for a mean of 2.2 years, and the haemostatic success rate for the treatment of BEs was 90.5% 25 . In a study of efmoroctocog alfa, median (IQR) overall ABR was 1.49 (0−4.4) in 89 PUPs who received prophylaxis for a median (range) of 91 (1−192) EDs and the subject's response to infusions was considered excellent or good for 80% of prophylactic infusions 26 …”

“…25 In a study of efmoroctocog alfa, median (IQR) overall ABR was 1.49 (0−4.4) in 89 PUPs who received prophylaxis for a median (range) of 91 (1−192) EDs and the subject's response to infusions was considered excellent or good for 80% of prophylactic infusions. 26 Approximately 5 million IU of simoctocog alfa were administered via 8646 infusions to 48 patients during the study. No AEs were assessed as possibly/probably related to simoctocog alfa by the investigators.…”

Considerations for shared decision management in previously untreated patients with hemophilia A or B

“…For instance, recent data from a clinical study of rFVIIIFc, involving 103 previously untreated pediatric patients with severe hemophilia A, 80 of whom were aged <1 year, reported an overall median annualized bleeding rate (ABR) of 1.49 [interquartile range (IQR) = 0.00–4.40]. 93 For hemophilia B, in a clinical study using nonacog beta pegol to treat 37 patients aged <6 years (median age = 1.0 years) who were previously untreated or had <3 exposure days to FIX-containing products, the modeled mean ABR for the 28 patients receiving weekly prophylaxis was 0.31. 94 There is, however, relatively little data on PUPs compared with older patients, and it is important to encourage data collection from PUPs/younger age groups to ensure these patients can benefit from the evolving treatment landscape, including nonreplacement therapy.…”

The More Recent History of Hemophilia Treatment

“…[27][28][29][30][31][32] However, EHL recombinant FVIII products achieved half-lives only 1.5 to 1.7 times longer than those of SHL FVIII concentrates. [33][34][35][36][37][38][39][40][41][42] This lesser improvement in pharmacokinetic parameters is due to the binding of FVIII to von Willebrand factor (VWF), which stabilizes this moiety in 20 and Ozelo and Yamaguti-Hayakawa, 2022. 48 plasma.…”

“…[27][28][29][30][31][32] However, EHL recombinant FVIII products achieved half-lives only 1.5 to 1.7 times longer than those of SHL FVIII concentrates. [33][34][35][36][37][38][39][40][41][42] This lesser improvement in pharmacokinetic parameters is due to the binding of FVIII to von Willebrand factor (VWF), which stabilizes this moiety in The More Recent History of Hemophilia Treatment Franchini, Mannucci plasma. Consequently, the maximum half-life that can be achieved by EHL FVIII products is the same as that of VWF.…”