Tramiprosate in mild-to-moderate Alzheimer’s disease – a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study)

Abstract

IntroductionThe aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMEDTM) in mild-to-moderate Alzheimer’s disease (AD).Material and methodsDouble-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged ≥ 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. Intervention: 78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. Measurements: Alzheimer Disease Assessment Scale – cognitive subscale (ADAS-cog) and Clinical Dementia Rating – Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients. ResultsA total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups. ConclusionsThe primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.

P4‐159: Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease

“…Another hypothesis is that the sulfonic acid group in taurine may bind to Ab peptides and prevent glycosaminoglycans from binding to Ab, thereby inhibiting Ab aggregation 32,40 . The structural similarity of homotaurine (tramiprosate), a former drug candidate, and taurine ( Figure 4) suggests that taurine may also interfere in glycosaminoglycans recruiting Ab 41 . We observed the increased expression of GFAP by taurine, in both wild-type and transgenic mice.…”

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.…”

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

“…Tramiprosate was shown to significantly reduce amyloid burden in Tg2576 mice (APP Swedish mutation transgenic strain) (Gervais et al 2007), and was well tolerated in human clinical trials. However, in phase III trials, cognitive assessments and MRI measures were unaffected in response to the treatment, the reasons for which remain unclear (Aisen et al 2011). The other therapy, ELND005 (scyllo-inositol) was well tolerated in humans at lower doses, but as yet the therapy's effect on Aβ aggregation and on AD patients remains to be determined (Salloway et al 2011;Schenk et al 2012).…”