Objective:
N9-GP is a glycoPEGylated recombinant factor-IX (rFIX) product that provides approximately two times incremental recovery, five times half-life, and 10 times area under the plasma concentration-time curve compared with standard rFIX. Phase 3 single-dose (40 IU/kg) in adults showed incremental recovery 2.34 %/IU/kg and 17% mean FIX activity at 7 days. This analysis investigates N9-GP 40 IU/kg as a single-dose on-demand (OD) treatment for hemophilia B, focusing on predictors of a second dose.
Methods:
In the paradigm™2 pivotal trial of previously treated adult/adolescent patients (≤2% FIX), the FDA requested that a group receive OD treatment prior to US enrollment into prophylaxis. This case-by-case analysis evaluated OD treatment in relationship to bleed type/pattern and prestudy treatment regimen. Hemostatic efficacy was reported by patients on a 4-point scale.
Summary:
Fifteen patients were enrolled for OD treatment (13 severe, two moderate); 13 were previously treated OD and two with prophylaxis. Overall, 14/15 patients experienced 143 bleeds during 26 weeks, of which 120 (84%) in 13 patients were treated with one dose. Seven patients (five severe, two moderate) treated all bleeds (62) with one dose (36 ‘excellent’ and 26 ‘good’ response). The other seven patients, described below, experienced 58 bleeds (72%) treated with one dose (seven ‘excellent’, 49 ‘good’, one ‘moderate’, one not reported); their other 23 bleeds (28%) required ≥2 doses (17 ‘good’, six ‘moderate’). Two of these seven had 4/11 (36%) recurrent target joints (TJ) bleeds/rebleeds treated with additional doses. An 18-year-old previously treating with plasma-derived FIX (pdFIX), 76 IU/kg/bleed, had three right elbow TJ bleeds in two months treated with one, five, and two doses. A 27-year-old previously on prophylaxis (pdFIX 100 IU/kg every 3 days and 100 IU/kg/bleed) had two bleeds in a right ankle TJ in 2 weeks treated with two doses (including one for early rebleeding) and six doses prior to withdrawing from the study. Another four patients with bleeds requiring multiple doses had been historically treated with multiple high FIX doses (IU/kg x doses per bleed: 60×2, 80×2, 80×2, and 81×3) with prescribed dosing of 120, 160, 160, and 243 IU/kg/bleed; they reported 63 bleeds, of which 45 (71%) were treated with a single 40-IU/kg dose, 17 with two, and one with four doses. Average N9-GP dosing was 44.0, 74.7, 97.9, and 52.8 IU/kg/bleed (63%, 53%, 39%, and 78% reduction in FIX use per episode). The last patient was treated prestudy with 10 IU/kg/bleed had seven bleeds (six treated with one dose, mean 46.8 IU/kg/bleed).
Conclusions:
N9-GP 40 IU/kg was effective as a single-dose OD bleed treatment (84%). Additional dose(s) for some bleeds were associated with recurrent TJ bleeds in patients not on prophylaxis or patients previously taking multiple high doses for bleeding.