Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial

Staff

et al. 2015

JAD

231

159

Abstract.Background: As tau aggregation pathology correlates with clinical dementia in Alzheimer's disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. Methods: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6-and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333). Results: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: −5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations. Conclusion:The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD.

Section: Discussionmentioning

confidence: 99%

Tau Aggregation Inhibitor Therapy: An Exploratory Phase 2 Study in Mild or Moderate Alzheimer's Disease

Staff

et al. 2015

JAD

231

159

“…Later, a γ-secretase modulator, tarenflurbil, was tested in a 12-month phase 2 study in people with mild-to-moderate AD. 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.…”

Section: Clinical Trial Setbacks For Drugs That Target Aβmentioning

confidence: 98%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

“…In addition, whatever the mechanism for NSAID effectiveness in preventative therapy in the short-term is, the data for their usefulness in already-diagnosed individuals is inconsistent. Aβ-lowering NSAIDs indomethacin and the R-enantiomer of fluriprofen appear to reduce the progression of cognitive decline during short-term use (6-24 months) [4,120]. However, for long-term therapy, the clinical trials for therapeutic use of NSAIDs in individuals already diagnosed with AD have not shown similar degrees of protection against advancing disease [24,121,122], suggesting NSAIDs are unable to serve beyond a preventative capacity.…”

Section: S383mentioning

confidence: 99%

The Mitochondrial Secret(ase) of Alzheimer's Disease

Young

Bennett

2010

JAD

Abstract. Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-β (Aβ) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Aβ overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field's understanding of AD pathogenesis and the development of potential therapeutics (i.e., Aβ-reducing agents). Though Aβ has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Aβ overproduction and deposition. However, the development of Aβ-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for γ-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction.