Lisa Patrone

Key Points: BAX 855, a pegylated full-length rFVIII with extended half-life, was highly effective in the prevention and treatment of bleeding events. No subjects receiving BAX 855 developed FVIII inhibitory antibodies nor experienced unexpected adverse events.

Detailed analysis of data from studies of recombinant antihemophilic factor produced using a plasma/albumin-free method (rAHF-PFM) in previously treated patients showed a substantial level of interpatient variation in pharmacokinetics (PKs), factor VIII dosing, and annualized bleed rate (ABR), suggesting that individual patient characteristics contributed to outcome. For example, plasma half-life (t_1/2), recovery, and clearance appeared to differ between patients aged PPPP1/2, and recovery), was as effective as standard prophylaxis and that both prophylactic regimens were superior to episodic treatment with respect to ABR and quality of life measures. Thus, compared with standard prophylaxis, the PK-guided regimen achieved comparable efficacy with fewer weekly infusions. A two-compartment population PK model describes the PK data across the entire age range and forms the basis for future PK-guided therapy with rAHF-PFM. The model confirmed a shorter t_1/2 and faster clearance of rAHF-PFM in children <6 years of age versus patients ≥10 years and predicted similar PK parameters with either a full or reduced blood sampling schedule, offering the potential for the use of PK-guided, individualized treatment in the routine clinical care setting.

Hemophilia A is an X-linked bleeding disorder that results from insufficient levels of factor VIII (FVIII) coagulant activity. To evaluate the efficacy and safety of ADVATE rAHF-PFM (Baxter Healthcare Corporation), a recombinant FVIII concentrate manufactured without human or bovine blood-derived additives, and to assess the effect of compliance with prophylactic use in preventing bleeding episodes (BEs). Clinical data were integrated from six prospective studies. Two hundred thirty-four hemophilia A subjects (FVIII levels < or = 2%) (median age 14.7 (range: 0.02 - 72.7) years) were included. BEs were managed with one or two infusions and nearly all (1953/1956) responded to treatment. Compliance with a prophylactic treatment regimen significantly reduced the incidence of BEs (p = 0.0061) and prevented non-traumatic joint BEs (median annualized BE rate was 0). One previously treated subject developed an inhibitor; no other safety concerns were observed. These results reinforce the efficacy and safety of rAHF-PFM and suggest that compliance is an essential contributor to the effectiveness of prophylaxis in the treatment of hemophilia A.

The present clinical study was designed to evaluate the efficacy, pharmacokinetics and safety of a new 10% liquid intravenous immune globulin in patients with primary immunodeficiency diseases. Sixty-one adults and children with primary immuno-deficiency diseases received doses of 300–600 mg/kg body weight every 21–28 days for 12 months. No validated acute serious bacterial infections were reported. The 95% confidence interval for the annualized rate of acute serious bacterial infections (primary endpoint) was 0–0.060. A total of four predefined validated other bacterial infections commonly occurring in primary immunodeficiency disease subjects were observed; none were serious, severe or resulted in hospitalization. The median elimination half-life of IgG was 35 days. Median total IgG trough levels varied from 9.6 to 11.2 g/L. Temporally associated adverse experiences were determined for 72 h after each infusion and the most common adverse experience was headache, which was associated with 6.9% of infusions. The study met the primary endpoint for efficacy and demonstrated excellent tolerability of the new 10% liquid intravenous imunoglobulin preparation.

The human, murine, and rat B29 (Igβ, CD79b) genes are highly conserved in sequence and organization and exhibit strict B cell-specific expression. In the human and rat genomes, the B29 gene is located between the skeletal muscle-specific Na-channel αsubunit (SCN4A) gene and the pituitary-specific growth hormone (GH-N) gene. The human pituitary-specific GH-N gene is controlled by a tissue-specific locus control region (LCR) located just upstream of the B29 promoter that mediates tissue-specific enhancement, histone acetylation, and an open chromatin conformation across the B29 gene in growth hormone (GH)-expressing pituitary cells. Here we show that B29 mRNA is not detected in a GH-expressing pituitary cell line and that GH-N mRNA is not detected in B cells. This differential expression suggests that the B29 gene is insulated or otherwise protected from the regulatory influences of the closely proximal GH LCR. We searched available sequences upstream of the human, mouse, and rat B29 genes and found a highly conserved sequence that fulfills the criteria recently established for non-coding DNA elements potentially involved in gene control. This B29 conserved sequence (BCS) bound ubiquitously expressed nuclear protein complexes. DNase I protection analysis of the BCS revealed a central `footprinted' core which was confirmed to bind the multifunctional transcription factor, YY1. However, neither the BCS nor the YY1-binding core motif exhibited silencer or enhancer activity in transient transfections or position-independent insulator activity in enhancer-blocking assays. Thus, the BCS may function as a tissue-specific LCR or position-dependent insulator specifically countering the influences of the 5′ GH LCR and controlling B29 gene expression.