Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.

BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. RESULTS: There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. CONCLUSIONS: Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).

Timing and locations of reef fish spawning off the southeastern United States.

Managed reef fish in the Atlantic Ocean of the southeastern United States (SEUS) support a multi-billion dollar industry. There is a broad interest in locating and protecting spawning fish from harvest, to enhance productivity and reduce the potential for overfishing. We assessed spatiotemporal cues for spawning for six species from four reef fish families, using data on individual spawning condition collected by over three decades of regional fishery-independent reef fish surveys, combined with a series of predictors derived from bathymetric features. We quantified the size of spawning areas used by reef fish across many years and identified several multispecies spawning locations. We quantitatively identified cues for peak spawning and generated predictive maps for Gray Triggerfish (Balistes capriscus), White Grunt (Haemulon plumierii), Red Snapper (Lutjanus campechanus), Vermilion Snapper (Rhomboplites aurorubens), Black Sea Bass (Centropristis striata), and Scamp (Mycteroperca phenax). For example, Red Snapper peak spawning was predicted in 24.7-29.0°C water prior to the new moon at locations with high curvature in the 24-30 m depth range off northeast Florida during June and July. External validation using scientific and fishery-dependent data collections strongly supported the predictive utility of our models. We identified locations where reconfiguration or expansion of existing marine protected areas would protect spawning reef fish. We recommend increased sampling off southern Florida (south of 27° N), during winter months, and in high-relief, high current habitats to improve our understanding of timing and location of reef fish spawning off the southeastern United States.