Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.

BACKGROUND AND OBJECTIVES: Accumulation of tau pathology in Alzheimer disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not evaluated in prior studies. Lauriet is a phase 2 study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD. METHODS: The phase 2 Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks. Coprimary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated. RESULTS: Between December 3, 2018, and February 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population (received ≥1 dose(s) of study medication and underwent baseline and ≥1 postbaseline assessment(s)). Baseline characteristics were well balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% CI -4.56 to -1.21, p = 0.0008) in decline on the ADAS-Cog11 (coprimary endpoint) relative to the placebo arm. However, no treatment effects were observed on the ADCS-ADL scale (coprimary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of -0.83 points, 95% CI -3.39 to 1.72, p = 0.52) or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well tolerated. DISCUSSION: Based on the results of the prespecified coprimary endpoints, this study was negative. While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild-to-moderate AD. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD. TRIAL REGISTRATION INFORMATION: The Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87.

Pesticides in mountain yellow-legged frogs (Rana muscosa) from the Sierra Nevada Mountains of California, USA.

In 1997, pesticide concentrations were measured in mountain yellow-legged frogs (Rana muscosa) from two areas in the Sierra Nevada Mountains of California, USA. One area (Sixty Lakes Basin, Kings Canyon National Park) had large, apparently healthy populations of frogs. A second area (Tablelands, Sequoia National Park) once had large populations, but the species had been extirpated from this area by the early 1980s. The Tablelands is exposed directly to prevailing winds from agricultural regions to the west. When an experimental reintroduction of R. muscosa in 1994 to 1995 was deemed unsuccessful in 1997, the last 20 (reintroduced) frogs that could be found were collected from the Tablelands, and pesticide concentrations in both frog tissue and the water were measured at both the Tablelands and at reference sites at Sixty Lakes. In frog tissues, dichlorodiphenyldichloroethylene (DDE) concentration was one to two orders of magnitude higher than the other organochlorines (46+/-20 ng/g wet wt at Tablelands and 17+/-8 Sixty Lakes). Both gamma-chlordane and trans-nonachlor were found in significantly greater concentrations in Tablelands frog tissues compared with Sixty Lakes. Organophosphate insecticides, chlorpyrifos, and diazinon were observed primarily in surface water with higher concentrations at the Tablelands sites. No contaminants were significantly higher in our Sixty Lakes samples.

Biomarker responses in Macoma nasuta (Bivalvia) exposed to sediments from northern San Francisco Bay.

Our study investigates biomarker responses and survival of Macoma nasuta exposed to sediments collected from six locations in northern San Francisco Bay. Biomarkers analyzed were stress proteins (hsp70) in gill, mantle and digestive gland, lysosomal membrane damage and histopathologic lesions. Sediments and clam tissues were analyzed for a comprehensive suite of heavy metals and trace organic pollutants. Sediment grain size and organic carbon content were determined. Clams accumulated metals, polyaromatic hydrocarbons (PAHs) and organochlorine pesticides (aldrin and p,p(')-DDT and its metabolites p,p(')-DDD and p,p(')-DDE). Pearson and Spearman correlation analysis revealed that mortality, hsp70 in gill and histopathologic lesion scores in gonads, and lysosomal membrane damage were significantly correlated with tissue concentrations of DDT and/or its metabolites. Tissue concentrations of metals, in particular nickel, chromium, and copper, were associated with macrophage aggregates in digestive gland and germ cell necrosis. Cadmium was linked to mortality and lysosomal membrane damage.

A simplified method for sampling and analysis of high volume surface water for organic contaminants using XAD-2.

A simple compressed-gas driven system for field processing and extracting water for subsequent analyses of hydrophobic organic compounds is presented. The pumping device is a pneumatically driven pump and filtration system that can easily clarify at 4 L/min. The extraction device uses compressed gas to drive filtered water through two parallel XAD-2 resin columns, at about 200 mL/min. No batteries or inverters are required for water collection or processing. Solvent extractions were performed directly in the XAD-2 glass columns. Final extracts are cleaned-up on Florisil cartridges without fractionation and contaminants analyzed by GC-MS. Method detection limits (MDLs) and recoveries for dissolved organic contaminants, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and pesticides are reported along with results of surface water analysis for the San Francisco Bay, CA.

A simple method for the determination of trace levels of alkylphenolic compounds in fish tissue using pressurized fluid extraction, solid phase cleanup, and high-performance liquid chromatography fluorescence detection.

A simple automated extraction method for the determination of alkylphenolic compounds in fish tissue is reported. Pressurized fluid extraction is used to extract ground fish tissue, and the resulting extract is purified on aminopropyl silica (APS) extraction cartridges. With no further sample preparation, nonylphenol (NP) and its ethoxylates, up to nonylphenol pentaethoxylate, are quantitated using normal phase (APS Hypersil) high-performance liquid chromatography with fluorescence detection. The major advantage of this technique is elimination of the conventional gel permeation cleanup step, a lengthy procedure designed to remove fish lipids. Spiked recoveries with lake trout averaged 85% for the six NP and NP ethoxylates that were investigated. Tissue concentrations of NP and NP ethoxylates determined in fish from various locations of the Great Lakes region ranged from 18 to 2075 ng/g, wet weight.