Cummings JL, Zhong K, Kinney JW, Heaney C, Moll-Tudla J, Joshi A, Pontecorvo M, Devous M, Tang A, Bena J. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease. Alzheimers Res Ther. 2016 Jan 29;8:4. PubMed.

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  1. Four years after the controversial bexarotene publication from the Landreth group, Cummings and colleagues publish this clinical trial. This proof of concept (POC) trial tested bexarotene (300 mg/kg) in 16 mild to moderate AD patients versus placebo controls. The authors found no efficacy in their primary objective—evaluating amyloid burden as measured by florbetapir PET at baseline and following four weeks of treatment in treated versus placebo controls, neither stratified by APOE4 status. There was efficacy in reducing amyloid burden for the APOE4 non-carriers (n=4) versus placebo (n=3). However, the small sample size limits the overall impact. Additionally, in the APOE4 non-carrier group only, increased efficacy (reduced amyloid signal) correlated with increased serum cholesterol and triglyceride, highlighting safety concerns and the potential benefits of a tissue selective nuclear receptor agonist. The findings confirm ApoE as a therapeutic target for AD. Unfortunately, instead of clarifying the effects of this drug on AD pathology, the results seem to complicate the understanding of the mechanisms of the disease and contribute to the consensus that bexarotene is not a drug for AD.

    A lack of efficacy cannot be explained by the short treatment duration because, overall, reduction of cortical amyloid burden correlated with increased cholesterol and triglycerides (due to activation of RXR receptors in the liver), and decreased cognition. Furthermore, even in APOE4 non-carriers, the safety of long-term bexarotene is questionable, given that the side effects are known to increase AD risk, potentially nullifying any benefits. Lastly, as oligomeric Aβ is likely the proximal neurotoxin in AD, mobilization of Aβ from plaques may increase the levels of soluble Aβ in brain, possibly increasing synapto-toxicity and explaining the reduction in cognition.

    This study also adds to the controversy regarding the role of ApoE in Aβ clearance, because bexarotene apparently has a different effect in AD patients than in familial AD-transgenic (FAD-Tg) mice. In the latter, it decreases soluble Aβ but not insoluble Aβ levels, but only in FAD-Tg APOE4 carriers. In contrast, this very limited human data suggests treatment is effective only in APOE4 non-carriers.

    Although the authors justify the number of participants as a POC study, there were not enough APOE4 carrier placebo subjects for a proper statistical comparison. The “mean” for APOE4 carriers in the placebo group was based on one person. The authors report that the study was not powered to detect differences in cognition, but they also report a significant p-value indicating that cognition is compromised by bexarotene treatment (or that it improved in placebo). It is not clear why this readout is included if the trial was insufficiently powered to detect an effect. Relevant data such as APOE genotype stratified by sex and baseline characteristics, as well as a clear definition of safety parameters, would have been helpful.

    Lack of amyloid burden excluded 16 potential participants. Importantly, because positive APOE4 status correlates with increased amyloid burden, basing inclusion on a positive amyloid scan likely biased the sample to APOE4 carriers.

    View all comments by Leon Tai

  2. A few points are worth making:

    • The analysis of the amyloid imaging by genotype was prespecified as part of the primary outcome, and this study can be seen as meeting its prespecified primary outcome measure. 
    • The increased serum Aβ1-42 correlated with decreased brain amyloid only in the ApoE4 non-carriers, suggesting that bexarotene affected two pools of amyloid—fibrillar/insoluble (measured by amyloid imaging) and soluble (as measured in the serum).
    • The number of patients included in the study is small, but the necessary sample size is related to the magnitude of the effect. It takes only a few patients to show a large magnitude effect, and we need large effects for our patients.

    Proof-of-mechanism (POM) studies are by nature exploratory and are intended only to decide if further exploration of an agent or mechanism is warranted. Many current agents in advanced trials have not shown that they affect the target biology in early POM studies. To my knowledge only one other agent currently at the human level of investigation—aducanumab—has shown reduction of fibrillar amyloid in a double-blind randomized trial. Soluble amyloid is reduced in CSF by BACE inhibitors, providing increased confidence that these agents are affecting the desired target.

    The observations in our study suggest that bexarotene affects both soluble and insoluble amyloid. The preliminary effects of bexarotene suggest that bexarotene or other retinoid-X receptor agonists should be investigated in Alzheimer's disease.  We eagerly anticipate further studies to determine if the initial observations with bexarotene are confirmed.

    View all comments by Jeffrey Cummings

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