These recommendations address the two main objectives of product labelling: (i) to define the quantity of the active substance in the vial and (ii) to guide physicians on the dose to be used for treatment that would correlate with recovery data measured in clinical laboratories. This implies that it should be possible for physicians to correlate label potency with postinfusion levels as assayed by clinical laboratories. For individual next-generation products such correlations may be particularly difficult to establish. The SSC recommendations emphasize that this issue should be resolved at the level of
the manufacturers and regulators prior to market approval . By this approach, the notorious RG7420 price burden of discrepant assay results remains to be carried by manufacturers and not by clinicians. As described in the preceding sections of this article, many of the previously observed assay discrepancies find their origin in (i) the use of chromogenic versus one-stage assays, and (ii) the sensitivity of some – but not all – of PD-0332991 ic50 the newer products for the various APTT-reagents used for the one-stage clotting assay. These include several of the newest generation FVIII and FIX products that have
been engineered to have prolonged half-life. Trials of several candidate drugs have been running in parallel , and the results thereof have been presented at the recent ISTH congress and the current World Federation of Haemophilia (WFH) meeting. As for potency assessment, initial data are encouraging in that most products can be assayed against the current IS for FVIII and FIX by chromogenic assays. As anticipated, however, results of selleck one-stage assays proved dependent on the APTT-reagents used [35-37]. It should be recognized that the current engineering strategies to prolong half-life actually imply limited changes to the coagulation factors involved. The current strategies
include chemical modification (PEGylation) or fusion with plasma proteins with much longer half-life than FVIII or FIX. The latter particularly involves fusion with albumin and the Fc-part of IgG. The rationale behind this approach is that these fusions will target FVIII or IX to the neonatal Fc-receptor (FcRn) on endothelial cells. This is a recycling receptor which, after uptake, releases the fusion proteins back into the circulation, and as such protects from endocytosis and endosomal degradation. Within the current long-acting investigational drugs, two categories may be distinguished. First, FVIII or FIX may be specifically modified in parts that are released upon proteolytic activation. This implies that the resulting FVIIIa or FIXa species are indistinguishable from their natural, wild-type counterparts. Thus, once activated, these products should be directly comparable to the ISs for FVIII and IX, thus allowing a precise quantification of the active ingredient in terms of International Units.