Nonacog beta pegol (N9-GP) in hemophilia B: First report on safety and efficacy in previously untreated and minimally treated patients

Anthony K Chan, Jayanthi Alamelu, Chris Barnes, Ampaiwan Chuansumrit, May-Lill Garly, Rikke Medom Meldgaard, Guy Young, Anthony K Chan, Jayanthi Alamelu, Chris Barnes, Ampaiwan Chuansumrit, May-Lill Garly, Rikke Medom Meldgaard, Guy Young

Abstract

Background/objective: We report the first analysis of an extended half-life recombinant factor IX, nonacog beta pegol (N9-GP), in previously untreated patients (PUPs) and minimally treated patients with hemophilia B.

Methods: Paradigm 6 (Safety and Efficacy of Nonacog Beta Pegol [N9-GP] in Previously Untreated Patients With Haemophilia B) is a multicenter, open-label, single-arm, phase 3 trial. Main inclusion criteria were males aged < 6 years, with hemophilia B with factor IX (FIX) activity ≤ 2%, who were previously untreated or with ≤ 3 exposure days (EDs) to FIX-containing products. Patients received N9-GP 40 IU/kg once weekly (prophylaxis) or individualized dosing (preprophylaxis). Bleeds were treated with N9-GP 40 IU/kg (80 IU/kg if severe). The primary end point was incidence of anti-FIX inhibitory antibodies (inhibitors). Secondary end points included safety outcomes and annualized bleeding rate (ABR).

Results: At data cutoff (August 31, 2018), 38 patients had been screened, and 37 had received N9-GP (median age, 1.0 years [range, 0-4]). Total in-trial EDs amounted to 2833, representing ~ 65 patient-years. Two (6.1%) of 33 "at-risk" patients (patients with ≥ 10 EDs plus patients who developed inhibitors) developed high-titer inhibitors and were withdrawn. No other safety concerns, including thromboembolic events, were identified. In the prophylaxis group (n = 28), 67.9% were bleed free; all bleeds (n = 15) were treated with one N9-GP injection; and overall, spontaneous, and traumatic ABRs were low (median ABRs of 0.0, 0.0, and 0.0, respectively; modeled mean ABRs of 0.31, 0.08, and 0.23, respectively). Estimated mean FIX trough activity was 15.0%.

Conclusion: We report an inhibitor incidence of 6.1%, which is within the expected range for PUPs with hemophilia B. No other safety concerns were identified; moreover, N9-GP provided effective hemostatic coverage.

Keywords: factor IX; hemophilia B; nonacog beta pegol; previously untreated patients; prophylaxis; recombinant proteins.

© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

Figures

Figure 1
Figure 1
Patient flow chart showing patient attrition.A, the numbers of patients at various trial stages; B, schema to demonstrate the recruitment timeline. ED, exposure day; EOT, end of trial. aPatients who switched from preprophylaxis to prophylaxis are analyzed in all groups. Numbers in parentheses denote patients ongoing in the trial at time of analysis
Figure 2
Figure 2
Number of bleedsa according to (A) type and (B) percentage of patients without bleeds and spontaneous bleeds. N9‐GP, nonacog beta pegol. aBleeds treated with N9‐GP. Note: Bleed type was unknown for one bleed in the preprophylaxis group
Figure 3
Figure 3
Hemostatic response of all 48 bleeds during the analysis period.a N9‐GP, nonacog beta pegol. aBleeds treated with N9‐GP. Note: Bleeds in the “Overall” column add up to 100.1% due to decimal point rounding
Figure 4
Figure 4
Mean profiles of FIX activity in prophylaxis. FIX, coagulation factor IX. Points are means; error bars represent standard error of means. The analysis is based on a mixed model on the log‐transformed plasma concentrations with patient as a random effect. The mean FIX activity level is presented back‐transformed to the natural scale. Only patients with a minimum of 4 weeks of prophylaxis were included. Measurements (n = 188) must have been taken ≥ 5 days and ≤ 10 days after the last dose. Measurements associated with doses within ≥ 14 days after a bleed were not included in the analysis. FIX activity up to 196 exposure days is reported

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