Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B.

BACKGROUND: Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. METHODS: We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. RESULTS: As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia. CONCLUSIONS: Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B. (Funded by Biogen Idec; ClinicalTrials.gov number, NCT01027364.).

Long-acting recombinant factor IX Fc fusion protein (rFIXFc) for perioperative management of subjects with haemophilia B in the phase 3 B-LONG study.

In the phase 3 B-LONG (Recombinant Factor IX Fc Fusion Protein [rFIXFc] in Subjects With Haemophilia B) study, rFIXFc demonstrated a prolonged half-life compared with recombinant factor IX (rFIX), and safety and efficacy for prophylaxis and treatment of bleeding in subjects with moderately-severe to severe haemophilia B. In this B-LONG sub-analysis, rFIXFc was evaluated for efficacy in subjects requiring major surgery. Dosing was investigator-determined. Assessments included dosing, consumption, bleeding, transfusions and haemostatic response. A population pharmacokinetics model of rFIXFc was used to predict FIX activity. Twelve subjects underwent 14 major surgeries (including 11 orthopaedic surgeries); most subjects (11/12) received rFIXFc prophylaxis before surgery (range, ~2 weeks-12 months). Investigators/surgeons rated haemostatic responses as excellent (n = 13) or good (n = 1). In most surgeries (85·7%), haemostasis from the pre-surgical dose until the end of surgery was maintained with a single rFIXFc infusion. Blood loss was consistent with similar surgeries in subjects without haemophilia. The strong correlation (R(2) = 0·9586, P < 0·001) between observed and population pharmacokinetic model-predicted FIX activity suggests surgery did not impact rFIXFc pharmacokinetics. No unique safety concerns or inhibitors were observed. In conclusion, rFIXFc was safe and efficacious, with prolonged dosing intervals and low consumption, when used perioperatively in haemophilia B. Surgery did not appear to alter rFIXFc pharmacokinetics.

Impact of Medicines Helplines on patient satisfaction, patient outcomes and medicines safety for hospital patients: the development of a rating scale and an evaluation of patients' opinions.

OBJECTIVE: To develop a rating scale and assess the impact of advice from Medicines Helplines on patient outcomes, medicine-related risks and patient satisfaction. METHODS: All patients who contacted two hospital pharmacy Medicines Helplines during the study were invited to complete a questionnaire about their experience of the helpline service and the outcome following the advice. A rating scale was developed and an expert panel of Medicines Information (MI) pharmacists rated the impact of the helpline advice on patient care or outcomes and risk/safety. RESULTS: Of 111 questionnaires sent to patients, 67 were completed (60% response rate). The majority of patients said they would use the service again (96%; 64/67), 81% (54/67) felt more reassured after calling the helpline and 61% (41/67) rated the service excellent (highest rating). The majority followed the advice (93%, 62/67), of which 19% (12/62) reported improved health or cure as a result. The consensus of an independent expert panel found that helpline advice had a positive impact on patient outcomes in 74% (46/62) of cases, and on medication safety in 71% (44/62). The rating scale was used successfully and validated. CONCLUSIONS: The validated rating scale is a useful tool for rating the impact of MI advice on patient outcomes and medication-related risks. The Medicines Helplines had a positive impact on patient outcomes according to patients and the expert panel. The panel found patients reduced the risk of harm from their medicines when advice was followed. Patients valued the service as an easily accessible source of useful information about medicines.

CDP571, a humanized anti-tumor necrosis factor-alpha monoclonal antibody in pediatric Crohn's disease.

OBJECTIVES: The objectives of this study were to evaluate the safety, pharmacokinetics, and immunogenicity of CDP571 in pediatric patients with Crohn's disease. METHODS: A single dose of CDP571, 10 mg/kg, was administered by infusion to pediatric patients (aged 6-17 years) with Crohn's disease in a 12-week open-label study. Adverse events were monitored during infusion and throughout the study. Plasma concentrations of CDP571 and standard clinical and laboratory values were assessed. Changes in disease activity were monitored using the Pediatric Crohn's Disease Activity Index (PCDAI). RESULTS: Twenty patients were enrolled and stratified by age: 6 to 13 (n = 9) and 14 to 17 years (n = 11). Fourteen patients experienced adverse events, which were mainly mild or moderate in intensity. The plasma concentration profile was consistent with a half-life of approximately 2 weeks. At Week 4, 4 patients in the 6- to 13-year-old group and 2 patients in the 14- to 17-year-old group had detectable anti-CDP571 antibodies. By Week 2, 7 patients in the 6- to 13-year-old group and 6 patients in the 14- to 17-year-old group had responded to treatment (reduction in PCDAI score >10 points). CONCLUSION: In conclusion, CDP571 was well tolerated among pediatric patients with Crohn's disease.

The impact of Medicines Information enquiry answering on patient care and outcomes.

OBJECTIVES: To determine the impact of advice provided by UK Medicines Information (MI) services on patient care and outcomes. METHODS: Healthcare professionals who contacted MI centres with enquiries related to specific patients in 35 UK National Health Service hospitals completed questionnaires before and after receiving MI advice. A multidisciplinary expert panel rated the impact in a sample of enquiries. One investigator used the panel's ratings and principles to rate all enquiries. KEY FINDINGS: Of 179 completed questionnaire pairs, 178 (99%) enquirers used the advice provided. Most (145, 81%) judged advice had a positive impact: 110 (61.5%) on patient care, 35 (19.6%) on patient outcome. Medicines Information pharmacists actively advised on issues not previously identified by enquirers in 35 cases (19.6%). The expert panel judged that in 19/20 (95%) cases, advice had a positive impact on patient care or outcome, mainly due to risk reduction. Agreement was high between expert panel and enquirers' ratings of impact: 12 (60%) full agreement; 16 (80%) agreement within one point. The investigator's impact rating of the full sample was positive for 162 (92%) enquiries: 82 (47%) on patient care and 80 (45%) on actual or expected patient outcome. CONCLUSIONS: Enquirers and an independent expert panel both determined that MI services provided useful patient-specific advice that impacted positively on patients. Reduction of risk was central to this impact. MI pharmacists frequently identified and advised on issues that clinicians using the service had not recognised themselves, this generally had a positive impact on patients.

Evaluation of immunogenicity and efficacy of anthrax vaccine adsorbed for postexposure prophylaxis.

Antimicrobials administered postexposure can reduce the incidence or progression of anthrax disease, but they do not protect against the disease resulting from the germination of spores that may remain in the body after cessation of the antimicrobial regimen. Such additional protection may be achieved by postexposure vaccination; however, no anthrax vaccine is licensed for postexposure prophylaxis (PEP). In a rabbit PEP study, animals were subjected to lethal challenge with aerosolized Bacillus anthracis spores and then were treated with levofloxacin with or without concomitant intramuscular (i.m.) vaccination with anthrax vaccine adsorbed (AVA) (BioThrax; Emergent BioDefense Operations Lansing LLC, Lansing, MI), administered twice, 1 week apart. A significant increase in survival rates was observed among vaccinated animals compared to those treated with antibiotic alone. In preexposure prophylaxis studies in rabbits and nonhuman primates (NHPs), animals received two i.m. vaccinations 1 month apart and were challenged with aerosolized anthrax spores at day 70. Prechallenge toxin-neutralizing antibody (TNA) titers correlated with animal survival postchallenge and provided the means for deriving an antibody titer associated with a specific probability of survival in animals. In a clinical immunogenicity study, 82% of the subjects met or exceeded the prechallenge TNA value that was associated with a 70% probability of survival in rabbits and 88% probability of survival in NHPs, which was estimated based on the results of animal preexposure prophylaxis studies. The animal data provide initial information on protective antibody levels for anthrax, as well as support previous findings regarding the ability of AVA to provide added protection to B. anthracis-infected animals compared to antimicrobial treatment alone.

A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease.

BACKGROUND & AIMS: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab' fragment of anti-tumor necrosis factor, CDP870) in Crohn's disease. METHODS: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of > or = 100 points or remission [Crohn's Disease Activity Index < or = 150 points]) in the intent-to-treat population. RESULTS: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. CONCLUSIONS: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab.