BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression

Gene therapy has the potential to maintain therapeutic blood clotting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene into liver cells. This phase 1/2, open-label dose-escalation study investigated BAX 335 (AskBio009, AAV8.sc-TTR-FIXR338Lopt), an adeno-associated virus serotype 8 (AAV8)-based FIX Padua gene therapy, in patients with hemophilia B. This report focuses on 12-month interim analyses of safety, pharmacokinetic variables, effects on FIX activity, and immune responses for dosed participants. Eight adult male participants (aged 20-69 years; range FIX activity, 0.5% to 2.0%) received 1 of 3 BAX 335 IV doses: 2.0 × 1011; 1.0 × 1012; or 3.0 × 1012 vector genomes/kg. Three (37.5%) participants had 4 serious adverse events, all considered unrelated to BAX 335. No serious adverse event led to death. No clinical thrombosis, inhibitors, or other FIX Padua-directed immunity was reported. FIX expression was measurable in 7 of 8 participants; peak FIX activity displayed dose dependence (32.0% to 58.5% in cohort 3). One participant achieved sustained therapeutic FIX activity of ∼20%, without bleeding or replacement therapy, for 4 years; in others, FIX activity was not sustained beyond 5 to 11 weeks. In contrast to some previous studies, corticosteroid treatment did not stabilize FIX activity loss. We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses, including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization. This trial was registered at www.clinicaltrials.gov as #NCT01687608

Advancing personalized care in hemophilia A: ten years' experience with an advanced category antihemophilic factor prepared using a plasma/albumin-free method.

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 (t1/2), recovery, and clearance appeared to differ between patients aged <6 years and 10-65 years. Prophylaxis resulted in lower ABRs than episodic treatment in both age groups; better adherence to the prophylactic regimen resulted in a lower ABR in patients aged 10-65 years. The weekly frequency of dosing and adherence to dosing were both significantly and inversely related to the rate of bleeding (young children, P<0.0001 for both all bleeds and joint bleeds; older patients, P<0.0001 for all bleeds and P<0.05 for joint bleeds), as was adherence to dosing frequency (P<0.0001 for all comparisons). A post-marketing randomized study of prophylaxis demonstrated that a PK-guided dosing regimen, based on an individual patient's rAHF-PFM PK (infusion interval, estimated t1/2, 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 t1/2 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

The relative burden of haemophilia A and the impact of target joint development on health-related quality of life: results from the ADVATE Post-Authorization Safety Surveillance (PASS) study.

Studies with haemophilia A (HA) patients have shown burden in health-related quality of life (HRQOL) when compared with general population norms. In the current study, HA patients' SF-36v2 health survey scores were compared with general population norms and to patients with other chronic conditions. The impact of target joints (TJs) on HRQOL was also examined. The sample was a subset of HA patients enrolled in the Post-Authorization Safety Surveillance (PASS) programme: a prospective open-label study in which ADVATE [Antihaemophilic Factor (Recombinant), Plasma/Albumin-Free Method] was prescribed. A total of 205 patients who were ≥ 18 years old and had SF-36v2 baseline scores were selected for this study. To measure the burden of HA on HRQOL, manova analyses compared these SF-36v2 scores to age- and gender-matched general population US and EU norms and to patients from other chronic condition groups. manova and correlational analyses examined the relations among TJ, age and SF-36v2 scores. Comparisons with general population norms confirm that HA negatively impacts physical, but not mental, HRQOL. Comparison with other chronic conditions shows the physical burden of HA is greater than for chronic back pain but similar to diabetes and rheumatoid arthritis, while the mental burden of HA is less than for all three patient groups. The presence of TJs was negatively associated with physical HRQOL, although this association was much larger for older patients (45+ years) than for younger ones. Physical, but not mental, HRQOL is diminished in HA patients. Target joints are associated with lower physical HRQOL, although this effect is moderated by age

Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A

Background: Hemophilia A is an X-linked bleeding disorder that results from insufficient levels of factor VIII (FVIII) coagulant activity. Objective: 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). Methods: Clinical data were integrated from six prospective studies. Two hundred thirty-four hemophilia A subjects (FVIII levels ≤ 2%) (median age 14.7 (range: 0.02 – 72.7) years) were included. Results: 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. Conclusions: 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

Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study

Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate-one virally inactivated with solvent detergent, the other with an additional heat-treatment step--were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction

Population pharmacokinetics of recombinant factor VIII: The relationships of pharmacokinetics to age and body weight

Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PK-based dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling