Background: rVIII-SingleChain, a novel recombinant Factor VIII (rFVIII), has been designed as a B-domain truncated construct with a covalent bound between the heavy and light chain, aiming for a higher binding affinity to von Willebrand Factor (vWF). A currently ongoing study is investigating the pharmacokinetics, efficacy and safety of rVIII-SingleChain in children < 12 years of age with severe hemophilia A. Here, we report final PK and interim safety data for this fully enrolled but ongoing study. Final efficacy will be available for presentation.

Methods: The study has been approved by the relevant Ethics committee and national authorities and is conducted according to GCP and the Declaration of Helsinki. A total of 84 subjects have been enrolled into the study, 35 of them in the 0 to <6 years age group and 49 in the 6 to <12 years age group. PK samples of rVIII-SingleChain were collected prior to infusion (pre-dose), 1, 4 to 6, 10, 24, and 48 hours post-infusion. Plasma FVIII activity was measured in the blood samples using the chromogenic substrate assay.

Results: The PK results reported in the younger children (0-<6 years, n=20) were 10.4 h for t1/2, 5.07 mL/h/kg for CL, 12.4 h for MRT and 1077 IU*h/dL for AUCinf. In the older children (6-<12 years, n=19), they were 10.2 h for t1/2, 4.63 mL/h/kg for CL, 12.3 h for MRT and 1167 IU*h/dL for AUCinf. At the time of data cut, the study accumulated a total of 3651 exposure days (EDs) with 30 patients reaching > 50 EDs and 6 patients reaching >100EDs. No patient developed an inhibitor after exposure to rVIII-SingleChain. The rate of non-inhibitory anti-drug antibody formation was in line with recently published trials investigating novel rFVIII products. The most commonly observed AEs were nasopharyngitis and rhinitis. A total of 10 SAEs were reported in 7 patients the study so far, of which none was judged to be related by the investigators.

Conclusion: The increased binding of rVIII-SingleChain to vWF translates into favorable pharmacokinetics without the need for glycopegylation or fusion to antibody fragments. Expectedly, mean t1/2 was shorter and mean CL greater in children when compared to adults and adolescents. rVIII-SingleChain demonstrated a very positive safety profile in this clinical study in children aged 0 to 12 years with severe hemophilia A.

Disclosures

Bensen-Kennedy:CSL Behring: Employment. St. Ledger:CSL Behring: Employment. Limsakun:CSL Behring: Employment. Veldman:CSL Behring: Employment. Pabinger:Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

Topics:
antidrug antibody, antigens, cd98 light chains, child, hemophilia a, immunoglobulin fragments, infusion procedures, nasopharyngitis, pharmacokinetics, recombinant antihemophilic factor viii, rhinitis

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2015 by The American Society of Hematology
2015
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