Effect of Tarenflurbil on Cognitive Decline and Activities of Daily Living in Patients With Mild Alzheimer Disease<subtitle>A Randomized Controlled Trial</subtitle>

Abstract

EADING THEORIES ON THE PATHOphysiology of Alzheimer disease (AD) implicate overproduction of amyloid-␤ (A␤), particularly 42 amino acid peptide A␤ 42 . [1][2][3] Compounds modulating ␥-secretase enzyme cleaving ␤-amyloid precursor protein (APP) to release various forms of A␤ are candidates for treatment of AD. One such compound is tarenflurbil (formerly R-flurbiprofen), a selective A␤ 42lowering agent that has been shown in vitro and in vivo to modulate ␥secretase activity and reduce A␤ 42 production in favor of shorter less toxic forms of A␤ (eg, A␤ 38 and A␤ 37 ). 4,5 In mouse models of AD, tarenflurbil prevents learning and memory deficits and reduces A␤ 42 brain concentrations. 4,6 A phase 2 trial of tarenflurbil suggested that patients with mild AD and moderate AD responded differently to treatment, that patients with mild AD had a dose-related slower rate of decline than those treated with placebo, and that the drug was well tolerated with few adverse effects. 7 On the basis of these results, a large phase 3, randomized, placebo-controlled trial of tarenflurbil was conducted in patients with mild AD. METHODS Study DesignA randomized, double-blind, 2-group parallel study was conducted to com-pare tarenflurbil with placebo for 18 months involving 133 participating trial sites. Written informed consent was obtained from participants, their legally authorized representatives, or both. The See also pp 2565 and 2593.

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…This trial found no effect on cognition, although with higher dose and patients with mild AD there were small benefits [23]. This encouraged a phase 3 clinical trial in 1600 patients with AD but found no beneficial effects in cognitive function and quality of life [7], which resulted in termination of 2 additional phase 3 trials and further development of this compound. Currently, there are still a few phase 3 clinical trials ongoing for AD targeting Aβ, including the abovementioned gantenerumab and solanezumab, and a β-secretase inhibitor, MK-8931.…”

“…Accordingly, Aβ-based therapeutics have been extensively investigated in preclinical models and clinical trials. Most prominently, phase 3 trials have been performed on drugs that lower Aβ by inhibiting its production [7,8] and lowering its levels by immunotherapy [9,10], all of which failed to reach their respective clinical endpoints. There is an urgent need, therefore, for fresh approaches to treat AD.…”

Does nutrition have a role in the prevention of Alzheimer's disease?

“…By way of contrast, for example, a key study assessing the drug tarenflurbil analysed 1649 patients with mild Alzheimer's disease. 15 Obviously, prevention studies may need to be larger with a longer follow up than treatment trials enrolling patients with established Alzheimer's disease. Indeed, the authors of the Cochrane review assessing omega-3 PUFAs called for 'further studies of longer duration'.…”

“…10 Further studies needed A magic bullet for Alzheimer's disease seems as elusive as ever. As the disappointing recent results of clinical studies with tarenflurbil, 15 latrepirdine 16 and bapineuzumab 1 underscore, developing pharmacotherapies for Alzheimer's disease is notoriously difficult. But while there is currently no definitive evidence, it seems premature to rule out that some nutrients might, in particular patients and at specific stages in the disease, improve cognitive performance and perhaps reduce the risk of developing dementia.…”

Amyloid-β imaging with PET in Alzheimer’s disease: is it feasible with current radiotracers and technologies?

“…Drugs and vaccines that reached the latter stages of FDA testing, such as tramiprosate, tarenflurbil, bapineuzumab, semagacestat, and AN-1792, often proved exceptionally effective at reducing Aβ burden in the brain, but ultimately failed to demonstrate a significant slowdown in cognitive decline when compared to controls [44][45][46][47][48][49][50][51][52]. Furthermore, the literature reveals that 10-20% of patients with clinically diagnosed AD do not have amyloid pathology at autopsy, and that 15-20% of Aβ-positive PET scans are seen in subjects with no cognitive deficits.…”