A Phase 2 clinical trial investigating the use of deferiprone to reduce brain iron levels in patients with early Alzheimer's disease has yielded disappointing results. The study, conducted across nine sites in Australia, found that deferiprone not only failed to slow cognitive decline but, in fact, accelerated cognitive deterioration in participants. These findings challenge the hypothesis that lowering brain iron could be a viable therapeutic strategy for Alzheimer's disease.
The double-masked, placebo-controlled trial, published in JAMA Neurology, involved 81 patients with amyloid-confirmed mild cognitive impairment or early Alzheimer's disease. Participants were randomized in a 2:1 ratio to receive either deferiprone at a dose of 15 mg/kg twice daily or a placebo for 12 months. The primary outcome was a composite cognitive measure assessed using a neuropsychological test battery (NTB) evaluating memory, executive function, and attention.
The results indicated that participants in the deferiprone group experienced accelerated cognitive decline compared to those in the placebo group (β for interaction = -0.50; 95% CI, -0.80 to -0.20). Specifically, the change in NTB composite z score for deferiprone was -0.80 (95% CI, -0.98 to -0.62), while for placebo, it was -0.30 (95% CI, -0.54 to -0.06). Further analysis revealed that the worsened cognitive performance was primarily driven by declines in executive function.
Quantitative susceptibility mapping (QSM) MRI confirmed that deferiprone effectively decreased iron levels in the hippocampus compared to placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). However, exploratory analysis of brain volume changes revealed increased volume loss in frontal areas among participants treated with deferiprone.
"These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD," the authors stated.
Elevated brain iron has been observed in Alzheimer's disease and has been associated with accelerated cognitive decline, making it a potential therapeutic target. However, this study suggests that simply lowering iron levels may not be beneficial and could even be harmful.
The trial also reported a higher frequency of neutropenia, a known adverse effect of deferiprone, in the treatment group (7.5%) compared to previous studies (1.6%-4.4%).
The study screened 167 patients, with 81 being ultimately included in the trial. Of those, 53 were randomized to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]). 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group).
The results of this trial highlight the complexities of Alzheimer's disease and the importance of rigorous clinical testing to validate potential therapeutic strategies. Further research is needed to fully understand the role of iron in Alzheimer's disease and to identify effective and safe interventions.
