Abstract

Abstract 2225

Introduction

IB1001 is a recombinant factor IX product being investigated for the treatment and prevention of bleeding in individuals with hemophilia B. Pharmacokinetics (PK) in adults (>12 years) demonstrated that IB1001 had results similar to the currently available recombinant FIX with respect to parameters such as terminal phase half-life and incremental recovery.

We report the interim findings from a PK assessment in children <12 years, with severe hemophilia B (FIX <2%), >50 prior exposure days to FIX, and no history of or currently detectable inhibitor to FIX.

Methods

Non-randomized, open-label PK study with patients receiving 75±5 IU/kg of IB1001 following a washout period of ≥4 days from a previous FIX infusion. Factor IX levels were determined pre-infusion and at 15–30 minutes, 4–6, 24–26, and 68–72 hours post-infusion. Additional samples could be drawn at 1–3 and 10–14 hours.

Calculated PK parameters were: half-life (β-phase t1/2, determined using a robust regression approach [Lee ML et al. XVIth ISTH Congress, Florence, Italy, 1997]) but generally assuming a single compartmental model because of the small number of points, maximum plasma concentration (Cmax), in vivo recovery (IVR) and AUC(0-∞) (determined by the trapezoidal rule). In addition, the AUC(0-t) and mean residence time (MRT) were calculated.

Results
Subject t 1/2 α (hr) t 1/2 β (hr) MRT (hr) Cmax (IU/dl) In vivo Recovery (IU/dl) AUC0-∞ (IU/dl/hr) AUC0-t (IU/dl/hr) Age (years) 
Subjects 6 - 12 Years of Age 
32001 n/a 17.7 22 63 0.84 1461 1359 
12001 n/a 17.5 21.2 57 0.76 1138 1062 7.5 
32003 20.7 24 58 0.77 1067 977 11.1 
35002 n/a 33.6 55 22 0.29 605 410 10 
mean±SD (median) 22.4±7.6 (19.2) 30.6±16.3 (23) 50±19 (57.5) 0.66±0.25 (0.765) 1068±353 (1102.5) 952±397 (1019.5) 9.4±1.5 (9.5) 
Subjects < 6 Years of Age 
4001 n/a 7.6 12.1 60 0.8 942 941 
35001 n/a 16.3 19.5 64 0.85 1217 1147 
32002 n/a 21.9 29.4 40 0.53 986 870 4.5 
mean±SD (median) 15.3±7.2 (16.3) 20.3±8.7 (19.5) 55±13 (60) 0.73±0.17 (0.8) 1048±148 (986) 986±144 (941) 3.5±1.3 (4) 
Subject t 1/2 α (hr) t 1/2 β (hr) MRT (hr) Cmax (IU/dl) In vivo Recovery (IU/dl) AUC0-∞ (IU/dl/hr) AUC0-t (IU/dl/hr) Age (years) 
Subjects 6 - 12 Years of Age 
32001 n/a 17.7 22 63 0.84 1461 1359 
12001 n/a 17.5 21.2 57 0.76 1138 1062 7.5 
32003 20.7 24 58 0.77 1067 977 11.1 
35002 n/a 33.6 55 22 0.29 605 410 10 
mean±SD (median) 22.4±7.6 (19.2) 30.6±16.3 (23) 50±19 (57.5) 0.66±0.25 (0.765) 1068±353 (1102.5) 952±397 (1019.5) 9.4±1.5 (9.5) 
Subjects < 6 Years of Age 
4001 n/a 7.6 12.1 60 0.8 942 941 
35001 n/a 16.3 19.5 64 0.85 1217 1147 
32002 n/a 21.9 29.4 40 0.53 986 870 4.5 
mean±SD (median) 15.3±7.2 (16.3) 20.3±8.7 (19.5) 55±13 (60) 0.73±0.17 (0.8) 1048±148 (986) 986±144 (941) 3.5±1.3 (4) 

When compared to the findings previously reported with IB1001 in adult (≥12 years of age) subjects (Martinowitz U et al. Haemophilia, 18, 2012), the results in pediatric patients demonstrate a more rapid metabolism of factor IX as is indicated by the shorter terminal half-life (mean±SD of 19.3±7.8 h versus 29.6±18.2 h in adults) and the smaller AUC0-∞ (mean±SD of 1059±264 versus 1668±598 in adults). In addition, the in vivo recovery was lower (mean±SD of 0.69±0.21) versus that seen in adults (mean±SD of 0.98±0.22). These results are similar to those reported by Berntorp et al (Haemophilia, 7, 2001) with nonacog alfa.

Conclusions

The pharmacokinetics of IB1001 has previously been shown to be non-inferior to nonacog alfa, another recombinant factor IX, in hemophilia B individuals >12 years of age. The current study is intended to provide information on children <12 and, particularly, <6 years of age. IB1001 is metabolized faster and has a lower recovery than the comparable findings in patients >12 years of age. Although the study is ongoing, these may represent important implications for the potential use of IB1001 in pediatric patients.

Disclosures:

Gomperts:Inspiration Biopharmaceuticals Inc: Consultancy. Apte:Inspiration Biopharmacauticals Inc: Research Funding. Chaudhuri:Inspiration Biopharmaceuticals Inc: Research Funding. John:Inspiration Biopharmaceuticals Inc: Research Funding. Ramanan:Inspiration Biopharmaceuticals Inc: Research Funding. Liesner:Inspiration Biopharmaceuticals Inc: Research Funding. Shapiro:Inspiration Biopharmaceuticals Inc: Honoraria, Research Funding. Mills:Inspiration Biopharmaceuticals Inc: Employment. Lee:Inspiration Biopharmaceuticals Inc: Employment.

Author notes

*

Asterisk with author names denotes non-ASH members.