Bexarotene Furor

Last week’s publication in Science of a paper by Cramer et al on the effects of bexarotene in transgenic mouse models of Alzheimer’s stirred up quite the media storm, and a flurry of requests from AD families for off-label prescriptions of this retinoid-X agonist drug used in oncology. Frankly, my first reaction was one of cynicism born of…. too many mice cured, not any humans. But digging deeper, and consulting with a number of Alzheimer’s experts, my skepticism is tempered, at least temporarily. The core concept of the tactic is that RXR agonists  increase APOE expression, leading to beta-amyloid clearance. The paper provided robust evidence that in these mice, both soluble and insoluble plaque levels were rapidly reduced. Very importantly, these mice also showed a rapid improvement in cognitive function, as would be predicted by the model that soluble AB interferes with synaptic function. Given that this is a drug with ample data regarding its shortterm use in humans, a compelling case exists for aggressively pursuing this as an AD candidate. However, several questions remain to be answered:

1) The predictive power of mouse models where amyloid production is hugely amplified has yet to be shown–indeed there have been numerous failures in trying to do so.
2) This does presume the primacy–or at least salience-of the amyloid model, where improving clearance of brain amyloid is seen as a key target. Again, this needs to be proven in humans.
3) Do acute changes establish longterm modification of the disease process?
4) Would bexarotene be safe when given longterm, and at what dose? (and would safe chronic dosing be sufficiently impactful on AB?)

The exciting part of the news is that some of these questions could be rapidly answered (not so much the safety of chronic dosing). The first step would be to see if bexarotene, in human AD patients, alters beta-amyloid biomarkers in what we believe to be the desirable direction. Based on the mice, one would expect to see such a shift quickly. One could first assess a sample population for biomarker changes, and then (if warranted) begin testing for cognitive changes compared to baseline–six months would be a sufficient pilot study for both the initial magnitude and durability of cognitive improvement. IP issues would complicate pharma investment in the US–but this might be a worthy use for some of the additional Alzheimer’s funding recently announced by HHS.


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6 Responses to Bexarotene Furor

  1. Postscript 1:(2/13/12) With the Case Western group having filed for a use patent on bexarotene in Alzheimer’s, spinning off the program into ReXceptor, that could force other companies to consider other retinoids (e.g. tazarotene) for testing, and it cannot be assumed that the findings would apply. Even the CW group has to confirm that bexarotene has BBB access in humans, not just mice.

    Postscript 2 (2/14/12): I have polled a number of my Alzheimer’s contacts, some of whom are prominent in the field. While they are cautious about the mouse-human translation obstacles, they are unusually impressed by the combination of biomarker and functional changes shown in this paper. The best part is that it isn’t a long path to sorting out whether it will work in humans. Usually, we hear about these findings for a drug that has yet to even be tried in humans, where there is no data regarding safety, and it will be years before we know if it really works. While bexaretone’s chronic dosing safety and tolerability have yet to be established, it’s not the leap of faith usually required. I’ve been in touch with the Case Western Reserve group that is spinning this out into a private company–they will be starting a human POC trial within the next month. Apparently they have done much if the prep work while waiting for the paper to be published. So, while I am still cynical about trangenic mouse data, this project deserves watchful attention, even if not yet overt optimism.

    Postscript 3 (2/17/12): It turns out that what ReXceptor was calling “clinical proof of principle” will be a biomarker study in healthy adults. That will be a useful demonstration of BBB penetrance. It will not only not be clinical POC, it will not even be clinical HOC. One cannot claim either of those without testing patients in the clinical population of interest.

  2. shirley j says:

    Bexarotene –
    Cking data… many humans with skin cancer also have had AD? Should be a few around.
    These people with both conditions using bexaroten – could be the proof that this drug works in humans…..

  3. Virginia says:

    Does anyone here know how to get in contact with the group at Case Western re: applying for someone to be part of the Alzheimer’s “test” group? I have a family member with advanced AD. Interested in what stage patient they are targeting. Thanks!

  4. Michael Gold, MD says:

    The putative mechanism (increased expression of APOE) is not the only potential mechanism for RxR agonists. RxR receptors are known to be involved in the expression of PGP and PGP has been shown to be an carrier for beta-amyloid from the CNS into the systemic circulation. In addition, PGP expression has been shown to be reduced in AD patients, consistent with the hypothesis that late-onset sporadic AD is more likely due to under-clearance of beta-amyloid than over production.

    Nonetheless, the finding is interesting and should lead to a human proof-of-concept study relatively quickly.

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