Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814).

Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer's disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aß) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aß production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aß species and soluble amyloid precursor proteins (sAPPß) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aß1-40 and Aß1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.

Bridging the Gap between Research and Clinical Practice in Asymptomatic Alzheimer's Disease.

Due to the growing global health impact of Alzheimer's disease (AD), there is a greater need for interventions that prevent or delay the onset of clinical symptoms of this debilitating disease. Clinical trials for disease-modifying compounds in AD have shifted towards earlier stages in the spectrum of illness, including the stage prior to cognitive symptoms. A population of specific interest for clinical research includes individuals with evidence of Alzheimer's disease pathology who are asymptomatic (ADPa). The challenges and barriers regarding medical treatment of ADPa must be identified and addressed prior to the completion of a positive clinical trial in order to accelerate the translation of research findings to clinical practice. This report applies an existing public health impact model from Spencer and colleagues (2013) to evaluate the readiness of the clinical practice environment to treat ADPa individuals if a disease-modifying agent achieves approval. We contrast the current clinical practice environment with a potential future state through investigating the effectiveness, reach, feasibility, sustainability, and transferability of the practice of treating ADPa individuals.

Genomewide association for schizophrenia in the CATIE study: results of stage 1.

Little is known for certain about the genetics of schizophrenia. The advent of genomewide association has been widely anticipated as a promising means to identify reproducible DNA sequence variation associated with this important and debilitating disorder. A total of 738 cases with DSM-IV schizophrenia (all participants in the CATIE study) and 733 group-matched controls were genotyped for 492,900 single-nucleotide polymorphisms (SNPs) using the Affymetrix 500K two-chip genotyping platform plus a custom 164K fill-in chip. Following multiple quality control steps for both subjects and SNPs, logistic regression analyses were used to assess the evidence for association of all SNPs with schizophrenia. We identified a number of promising SNPs for follow-up studies, although no SNP or multimarker combination of SNPs achieved genomewide statistical significance. Although a few signals coincided with genomic regions previously implicated in schizophrenia, chance could not be excluded. These data do not provide evidence for the involvement of any genomic region with schizophrenia detectable with moderate sample size. However, a planned genomewide association study for response phenotypes and inclusion of individual phenotype and genotype data from this study in meta-analyses hold promise for eventual identification of susceptibility and protective variants.

Validating clinical reasoning: a question of perspective, but whose perspective?

This paper explores the notion of validity from different perspectives and addresses its integration with clinical reasoning. Whilst valuing the evidence-based practice (EBP) perspective in our quest for validation of practice, the authors posit that other perspectives may provide added value through their potential for offering validity in differing circumstances. The reality of the EBP aspiration is discussed and nuances within the evolved term 'research-enhanced practice' are shared. Validity theory applied through different perspectives may, it is argued help to get to grips with the balancing act of validating manual therapy practice.