The results also indicate that pdFVIII/VWF and rFVIII + VWF behave differently towards anti-FVIII antibodies. A possible explanation for this difference has both quantitative and qualitative elements. An incomplete rFVIII/VWF complex formation, probably due to partial Tyr1680 sulphation, allows some residual ‘free’ rFVIII Bioactive Compound Library high throughput to interact with inhibitors. Structural differences in physiological molecules obtained from pdFVIII/VWF and rFVIII + VWF may allow

anti-FVIII inhibitor antibodies greater access to FVIII in the rFVIII + VWF complex. R. KLAMROTH E-mail: [email protected] The development of inhibitory antibodies to infused FVIII is the most problematic complication associated with the treatment of haemophilia A. New strategies to minimize inhibitor development are therefore actively welcomed. IWR 1 A few years ago, a group in Germany described a new prophylaxis regimen [46]. The ‘München-Bremen’ scheme derived from a clinical decision to initiate prophylaxis

before the onset of a severe bleed in patients with severe haemophilia. As early prophylaxis was to involve mainly very young children (<1 year of age), it was decided to initiate treatment with a low dose of FVIII (20–30 U kg−1) given once weekly and escalate the dose over time as required. Interestingly, the inhibitor rate observed with once-weekly prophylaxis was markedly lower than that recorded with a standard prophylaxis regimen in

a medchemexpress historical cohort of patients (Fig. 11). For patients with severe haemophilia A, FVIII is essentially a foreign protein. To generate an immunological response, however, a protein must be recognized as being both foreign and dangerous. The rationale for early prophylaxis therefore is to familiarize the immune system with FVIII prior to the onset of immunological danger signals (e.g. surgery, vaccinations, infections, severe bleeds) which can promote inhibitor development. From a theoretical viewpoint the argument for early prophylaxis is highly convincing and was the impetus for design and conduct of the multinational Early Prophylaxis Immunologic Challenge (EPIC) study (ClinicalTrials.gov Identifier: NCT01376700) [47]. The aim of the EPIC study was to determine whether once-weekly administration of 25 U kg−1 FVIII initiated at or before 1 year of age and in the absence of immunological danger signals would reduce the incidence of inhibitor formation in PUPs with severe haemophilia A. As it happened, the study was terminated early when it became apparent that the objective of a 50% reduction in inhibitor rates compared with rates reported in the published literature was unlikely to be achieved. Not surprisingly, the failure of the EPIC study to meet its objective brought into question the results achieved by Kurnik et al. with the München-Bremen scheme. Specifically, is the 3.