1. Curious Wavefunction on February 13, 2012 9:21 AM writes...

The biggest question I have about this - and one that makes me skeptical about potential results in humans - is why, if they saw such dramatic effects on the brain in mice, have they not seen similar effects in cancer patients who have been taking this drug? Maybe it's the dosing or other parameters, but you would think that a drug that has such rapid and significant effects on memory and cognition would have produced some spectacular fireworks in humans.

2. PPedroso on February 13, 2012 9:48 AM writes...

@1

The effects were on b-amyloid and I do not think that on Cancer Clinical Trials that constitutes an endpoint.

3. Morten G on February 13, 2012 9:53 AM writes...

Phenotypic screens...

4. Cytirps on February 13, 2012 9:55 AM writes...

Does anyone know if bexarotene, a carboxylic acid, can get into human brain?

5. PharmaHeretic on February 13, 2012 9:58 AM writes...

The next question is- can you make an analogue of this compound that has the desired (amyloid clearing effect) with a reduced anti-neoplastic effect?

6. Curious Wavefunction on February 13, 2012 10:01 AM writes...

@2: I was thinking about the effects on memory and cognition which if pronounced might have been obvious, at least in the long term.

7. Cpstar on February 13, 2012 10:07 AM writes...

That exocyclic olefin surely gets epoxidized in short order, wouldn't you think?

8. drug_hunter on February 13, 2012 10:33 AM writes...

@7 - Definitely appears to be a CYP magnet, but could be lots of hotspots. The human half-life is decent. Highly protein bound, as you'd expect.

9. MTK on February 13, 2012 10:43 AM writes...

Wouldn't this then also have potential implications for cardiovascular disease?

10. NoDrugsNoJobs on February 13, 2012 10:48 AM writes...

I think ApoE is regulated by a number of nuclear receptors. Although I don't have the paper, I assume RXR works through heterodimerization and activation of one or more ApoE affecting nuclear receptors such as LXR or PPARgamma. I believe both LXR and PPARgamma have effects in mice models and PPARgamma is even being investigated for its effects in humans since those drugs are already widely used (pioglitazone, rosiglitazone). One cause of a lot of alzheimers is an APOe allele epsilon 4 (APOe4) I would assume that if the person had this allele, upregulation would do no good and might even cause harm. Havind said all this, I reckon that a major threat to all our hopes is that once a patient has alzheimer's, they are much like a person who has had a stroke - the damage to the brain is done and largely cannot be reversed. The trick would be to treatpeople before they have the disease and the damage has been done but how to do that? A clear genetic predictor for the disease is the apoe4 allele but the treatment of people with this could be different then folks with other alleles. These are my thought off the top of the head and are probably worth what it cost you to read this, just tossing them out for discussion.

11. Anonymous on February 13, 2012 11:02 AM writes...

@6

I do not have the paper but I read somewhere that the behavioral experiments that they used were "nesting" and olfactive capacity. I do not know how well these effects translate into humans. And once againg if the clearance of beta-amyloid is the cause for these behavioral benefits, in a cancer clinical trial I suspect that alzheimer should be a exclusion criterium and therefore we won't be having subjects with amyloid plaques in cancer trials which means that we won't be seeing any behavioral effects of bexarotene. If this is indeed its mechanism of action.
My suspicion is that there is some kind of balance between soluble and solid beta-amyloid and that by clearing the soluble one the solid one will revert to soluble in order to maintain the equilibrium. However, the rapid effect is a bit surprising!

12. dickydoo on February 13, 2012 11:15 AM writes...

If this medicine has been around for approx 10 years, wouldn't alzheimer patients with skin cancer have received this drug at some point in time.

13. Cytirps on February 13, 2012 11:20 AM writes...

@7
Epoxidation of the gem disubstituted olefin was not detected in vivo, probably due to steric hindrance. The oxidative metabolic sites are on the cyclohexyl ring.

14. PPEdroso on February 13, 2012 11:33 AM writes...

Here are 2 exclusion criteria for a completed bexarotene Phase II study for Leukemia:

1) Serious medical or psychiatric conditions that may compromise the safety of the patient while participating in this study.
2)Unable/unwilling to perform required follow-up.

If the patient had alzheimer these two would exclude it.

Regarding @12 comment, alzheimer is known for good and bad days, with all the medication that is normally taken it would be difficult to understand that the improvements were due to another drug for a different indication.

15. cirby on February 13, 2012 11:42 AM writes...

As other have noted, this drug has been in use for a while, and one of the most obvious steps would be to go back and check the people who have received treatment - and see how many of them have Alzheimer's symptoms.

If the number is dramatically lower than expected, it's one more bit of evidence to poke around with.

16. You're Pfizered on February 13, 2012 2:59 PM writes...

As other have noted, this drug has been in use for a while, and one of the most obvious steps would be to go back and check the people who have received treatment - and see how many of them have Alzheimer's symptoms.

I'd imagine that you probably don't have a whole lot of longer term data from folks taking this drug.

17. John Schilling on February 13, 2012 4:15 PM writes...

#16: If this stuff clears up amyloid plaques in three days flat, with immediate cognitive improvement, we may not need longer term data to see something interesting.

We would need to sort out the results from everything else that affects Alzheimer's symptoms in the general population. This might be the sort of thing that Andy Groves' proposed database of expanded clinical trial results would be good for...

18. BioBritSD on February 13, 2012 8:34 PM writes...

This is perhaps a more general question - but for a medication already approved for another indication - how do you actually get the data to support a new use? as in, who/why would an organization fund that when it can be prescribed off-label? can they ever hope to make their study costs back? How should the system be changed to enable that?

(this assumes that the compound is off patent)

19. Advo on February 13, 2012 9:18 PM writes...

It is quite possible that quite a few cancer sufferers saw improvements in their neurological condition due to a treatment with the drug and that this simply didn't become known to the medical public.
Consider stomach ulcers. Over the several decades where there was thought to be no cure tens or hundreds of thousands must have been cured or seen significant relief due to antibiotic treatment, many of them in fact doctors!
Yet this went unnoticed until the early nineties. I have no problem imagining that hundreds have already been cured of Alzheimer's and that that simply hasn't penetrated into the consciousness of the medical community yet.

20. passionlessDrone on February 14, 2012 9:39 AM writes...

@17: his might be the sort of thing that Andy Groves' proposed database of expanded clinical trial results would be good for...

Very clever thinking.

- pD

21. You're Pfizered on February 14, 2012 12:39 PM writes...

Two things that I've been pondering.

Wonder what Eisai thinks about this? They purchased this drug from Ligand a few years ago. According to a few sources I've read, the patent on this molecule goes until 2016 (have not looked in depth on this). This does not appear to have an Eisai connection to the Case research.

Second, is anyone else bothered by CWRU launching a public statement about pre-clincial data? What was their goal? Are they the ones pursuing this compound or is there a biotech that's behind the supposed next round of clinical studies?

I'm not a fan of such public 'announcements' of preclinical data. If it was a pharma company doing this, they'd get roasted on quite a few sides for something like this. I can't image Case didn't think this would spread like wildfire...

22. LJStewartTweet on February 15, 2012 2:04 AM writes...

Derek. Great Blog, and comments on a very important topic. Is Bexarotene a "Lazarus Effect Molecule?" Well, it's a darn sure bet that alot of Rx's are being written now where Physicians and Patients will figure this out. One problem. None of the data collection will be organized in any manner. There needs to be a system in place for massive registration and testing of off label use of compounds (Wishful thinking).

How many safe drug candidate molecules (past Phase I) exist with CNS activity (penetration of the Blood Brain Barrier), but with no clear therapeutic efficacy for their original intended clinical use? Could such molecules be found to work for a different indication such as Alzheimer’s Disease? Would Pharma cos. consider making their failed assets available to the community to be freely used for study?

The answers to these questions are unknown! However, we (pharma, patients, caregivers) need to find out the answers to such questions as soon as possible. If we are to reduce the economic burden (and suffering therein) of brain disease in a meaningful way within the next 10 years, we will need to make use of existing chemical assets in a very significant manner. Key societal changes need to occur very soon so that we may begin to repeatedly test compounds in small clinical trials designed to look for big and rapid effects, from existing "failed" Pharma assets.

23. dickydoo on February 22, 2012 3:29 PM writes...

Dr. Branick, please keep us posted as to how well bexarotene works for Harriet. I've had my wife with AD taking 9 anatabloc daily which seems to be helping. I can't wait to hear how well bexarotene works. It could be the answer to many prayers.

24. Steve on February 24, 2012 2:59 PM writes...

Since Parkinson's Disease appears to have a similar causative mechanism and PD often leads to AD is it likely to benefit PD patients? PD progresses more slowly than AD and in the early stages only 60-80% of dopamine synthesis capacity is lost the window of opportunity for effective intervention would be lsrger. If it works......

25. Jeri Hartung on February 25, 2012 3:25 PM writes...

I read on the internet, that a clinical test on humans was to be started in March, 2012 through April 2012. If results show promise as dramatically as in mice, Drs. will be able to prescribe Bexarotene to their AD patients, & that people are already clamoring for a prescriiption.

26. Ron on March 2, 2012 10:50 AM writes...

it appears some "human" clinical trials have already been performed back in 2008 with positive results (see attached URL)

27. Ron on March 2, 2012 10:52 AM writes...

Sorry, here is the URL:

http://journals.lww.com/clinicalneuropharm/Abstract/2008/01000/Bexarotene_as_Add_On_to_Antipsychotic_Treatment_in.4.aspx

28. pratik shah on March 12, 2012 11:57 PM writes...

Simply give bexarotene to affected people for a month and reveal the result. One must understand that quality of life for affected people are so miserable so what is wrong to try it and clear the doubts for all....

29. hmmm on March 24, 2012 11:27 PM writes...

Since the drug is already cleared for human use and while it has some side effects, those are far less troubling than AD, and since the effects are seen rapidly which reduces the sidde effect exposure...I wouldn't even hesitate to try this is I were suffering AD.

The risk is minimal and the reward significant.

30. Joseph on April 15, 2012 5:45 PM writes...

These are all good thoughts. I don't know exactly what else is involved in the treatment of skin cancer of those taking bexarotene. However, if any stage of the disease or treatment involves deleterious effects on cognition like so many other forms of cancer, then patients reporting normal cognitive functioning may be an indication of the drug counteracting some of these effects. Thus, another reason why people may not have noticed overt cognitive effects. Furthermore, people may have wrongly interpreted cognitive decline before successful treatment as due to the disease or treatment, and assuming cognitive improvement was due to successful treatment of the disease and cessation of the treatment, when in fact another disease process was halted or slowed.

31. wagno on May 17, 2012 7:31 PM writes...

o meu pai tem alzheimer e presizo de ajuda para curar ele ja esta com o problema ja tem 5 anos mais ou menos anda normal so nao tem mas memoria para fazer nada mas acredito na cura presizo saber se concigo o remedio atravez de telefones ou augun tipo de contato na internete obrigado pelo espaço oferesido para noz