Pharmacokinetic Behavior of IB1001, An Investigational Recombinant Factor IX, in Patients with Hemophilia B: Repeat Pharmacokinetic Study and Subgroup Analysis
Authors: Martinowitz Uri , Shapiro Amy D. , Quon Doris V. , Escobar Miguel Antonio , Kempton Christine L , Collins Peter , Chowdary Pratima , Makris Michael , Mannucci Pier Mannuccio , Morfini Massimo , Valentino Leonard A. , Gomperts Edward D. , Lee Martin 
Published: October 2019

Abstract
Abstract 2267

Introduction
IB1001 is an investigational recombinant factor IX for the treatment and prevention of bleeding in individuals with hemophilia B. A randomized cross-over pharmacokinetic (PK) study demonstrated that IB1001 (75 IU/kg) compared with nonacog alfa (BeneFIX®). was non-inferior (lower bound of the 1-sided 95% confidence interval for the area under the concentration curve [AUC0–∞] was 90%) and was well tolerated. Here we report the findings from a repeat PK assessment, in which a subset of patients underwent a second PK evaluation with IB1001 only. In addition, we present the results of an exploratory analysis of IB1001 PK parameters to assess the relationship between the degree of sialylation and the pharmacokinetics of recombinant factor IX. [Griffith MJ et al. J Thromb Haemost 5 (Suppl 1), PM–043, 2007].

Methods
In the randomized PK study, patients were assigned to receive 75 ± 5 IU/kg of IB1001 or nonacog alfa following a washout period of ≥5 days. Factor IX levels were determined pre-infusion and at 30 minutes, 1, 3, 6, 9, 12, 24, 36, 48, 60, and 72 hours post-infusion. The evaluation was repeated 5–28 days later, when a 75 ± 5 IU/kg dose of the alternate therapy was administered. Factor IX levels were assessed at the same time points. The repeat PK assessment was planned to include patients who had received 3–6 months of IB1001 prophylaxis following their initial PK assessment. Calculated PK parameters were identical to those determined during the randomized PK study: half-life (β-phase t1/2, determined using a robust regression approach [Lee ML et al. XVIth ISTH Congress, Florence, Italy, 1997]), maximum plasma concentration (Cmax) and AUC(0-∞) (determined by the trapezoidal rule). To explore the association between sialylation level and the PK behavior of IB1001, patients in the randomized PK study (n=32) were allocated to one of three subgroups based on the sialylation levels of the IB1001 lots used (see Table).

Results
Thirty-two evaluable patients were enrolled in the randomized PK study (Feb 2009–Aug 2010). Of these, 13 underwent repeat PK assessments with IB1001 after receiving 4–18 months of prophylaxis with IB1001. The results demonstrate the stability of PK parameters following up to 18 months of exposure to IB1001. No significant reduction in factor IX recovery or elimination half-life occurred in any patients over time. The sialylation subgroup analysis revealed that the use of IB1001 lots with the lowest sialylation levels (Group 1) resulted in slightly lower AUC levels when compared with nonacog alfa (see Table). When lots with intermediate or the highest sialylation levels were used, the AUC of IB1001 appeared similar (Group 2), or slightly higher (Group 3), than the corresponding nonacog alfa values. Although Cmax of IB1001 was lower in Group 1, it appears comparable with the nonacog alfa controls in all groups, suggesting that this was not an effect of sialylation but of individual biological variation.

Conclusions
The stability of IB1001 PK profile during prophylactic use was demonstrated in 13 patients and supported observations of the lack of inhibitor development over this period. The continued PK stability of IB1001 over time is of interest for the prophylactic treatment of hemophilia B.Evaluation of IB1001 sialylation levels was consistent with observations from previously reported nonclinical studies [Griffith MJ et al. J Thromb Haemost 5 (Suppl 1). Although the level of sialylation resulted in slightly different PK behavior, these differences may simply reflect the biological variation between individuals.

Disclosures:
Gomperts: Inspiration Biopharmaceuticals Inc: Consultancy. Lee:Inspiration Biopharmaceuticals Inc: Consultancy.